Meredith M. Curtis
- Courses2
- Reviews3
- School: Brookhaven College
- Campus:
- Department: Biology
- Email address: Join to see
- Phone: Join to see
-
Location:
3939 Valley View Ln
Dallas, TX - 75244 - Dates at Brookhaven College: November 2012 - July 2014
- Office Hours: Join to see
Biography
Brookhaven College - Biology
Instructor, Biology Department at Texas Christian University
Research
Meredith
Curtis, PhD
Fort Worth, Texas
I am currently an Instructor in the Biology Department at Texas Christian University. My area of expertise is in host: pathogen interactions during infection. I trained as a postdoctoral researcher in the Department of Microbiology at UT Southwestern Medical Center in the laboratory of Dr. Vanessa Sperandio. Prior to my training at UT Southwestern, I trained in the Department of Immunology at the University of Washington in the laboratory of Dr. Chris Wilson, where I received my Ph.D.
Experience
UT Southwestern Medical Center
Research Technician
Examined the impact of attenuated immune signaling on biological outcomes in the laboratory of Dr. Nicolai van Oers; results have clinical importance for cancer and autoimmune diseases.
Additional highlights:
--Invited speaker at the 2003 American Association of Immunologists (AAI) annual meeting
--4 peer-reviewed publications, with 1 first-author publicationUT Southwestern Medical Center
Postdoctoral Researcher
Performed research in the laboratory of Dr. Vanessa Sperandio. Collaborated with biochemists, pharmacologists, and microbiologists in an effort to discover small molecule inhibitors of bacterial virulence. Investigated the role of the intestinal microbiota during enterohemorrhagic E. coli O157:H7 infection.
Additional highlights include:
--Finalist for the 2014-2015 Award for Excellence in Postdoctoral Research at UT Southwestern Medical Center
--Recipient of an NIH Institutional Research Training Grant (2011-2014)
--Lecturer in the Principles of Microbiology course
--Laboratory Assistant in the Medical Microbiology course
--Invited speaker at the 2014 (Amercian Society for Microbiology) ASM annual meeting
--Poster presenter at the Microbial Toxins & Pathogenicity Gordon Research Conference (2014), Cell Symposia for Microbiome and Host Health (2013), 8th International Symposium on Shiga Toxin (Verocytotoxin) Producing Escherichia coli Infections (2012), and ASM annual meeting (2011)
--6 peer-reviewed publications, with 2 first-author publications and 1 reviewBrookhaven College
Adjunct Instructor
Lectured in biological science courses (Biology, Microbiology). Prepared course material and wrote exams.
MedBio Publications
Freelance Medical Writer
Analyzed data from quality improvement initiatives to generate evidence-based medical communications.
Texas Christian University
Instructor, Biology Department
Meredith worked at Texas Christian University as a Instructor, Biology Department
Education
University of Washington
Doctor of Philosophy (PhD)
Immunology
Identified immune signals required for maintaining host defense during intracellular bacterial and viral infection in the laboratory of Dr. Chris Wilson; results have clinical importance in vaccine development. Additional highlights: --Sandra L. Clark Immunology Education Fund, Travel Award, Int'l Congress of Immunology --Bill & Melinda Gates' Foundation Scholarship, Immunologic Memory Keystone Symposia --National Institutes of Health (NIH) Cell & Molecular Biology Training Grant (2005-2007) --National Cancer Institute Training Grant (2004) --Teaching assistant in the Immunology 441 course at UW --5 peer-reviewed publications, with 3 first-author publications --Invited speaker at the 2009 American Association of Immunologists (AAI) annual meetingBaylor University
Bachelor's Degree
Biology (major), Business administration (minor)
Additional Highlights: --Phi Beta Kappa --Magna Cum Laude --Outstanding Biology Student, Baylor University
Publications
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
A complex relationship: the interaction among symbiotic microbes, invading pathogens, and their mammalian host.
Mucosal Immunol.
Symbiosis between microbes and their mammalian host is vital to maintaining homeostasis. Symbiotic microbes within the gastrointestinal tract provide an array of benefits to the host, including promotion of host immunity. A coordinated effort of the host and symbiotic microbes deters the colonization and survival of many invading pathogens. However, pathogens have devised strategies to overcome these mechanisms. Furthermore, some pathogens can hijack host hormones and bacterial autoinducers to induce virulence traits. Intra- and inter-species (bacteria/bacteria) and interkingdom (bacteria/host) communication orchestrates the complex relationship among symbiotic microbes, invading pathogens, and their mammalian host. Insight into this communication will provide a foundation for the development of targeted antimicrobial therapies.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
A complex relationship: the interaction among symbiotic microbes, invading pathogens, and their mammalian host.
Mucosal Immunol.
Symbiosis between microbes and their mammalian host is vital to maintaining homeostasis. Symbiotic microbes within the gastrointestinal tract provide an array of benefits to the host, including promotion of host immunity. A coordinated effort of the host and symbiotic microbes deters the colonization and survival of many invading pathogens. However, pathogens have devised strategies to overcome these mechanisms. Furthermore, some pathogens can hijack host hormones and bacterial autoinducers to induce virulence traits. Intra- and inter-species (bacteria/bacteria) and interkingdom (bacteria/host) communication orchestrates the complex relationship among symbiotic microbes, invading pathogens, and their mammalian host. Insight into this communication will provide a foundation for the development of targeted antimicrobial therapies.
IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons.
J Immunol.
In contrast to CD4 T cells, CD8 T cells inherently differentiate into IFN-gamma-producing effectors. Accordingly, while generation of IFN-gamma-producing Th1 CD4 T cells was profoundly impaired in mice deficient for both type-I IFN and IL-12 signaling in response to infection with Listeria monocytogenes, generation of Ag-specific, IFN-gamma-producing CD8 T cells was unimpaired. However, a fraction of these CD8 T cells also produced IL-17 in an IL-23-dependent manner. Furthermore, the addition of IL-23 in vitro was sufficient for some naive CD8 T cells to differentiate into IFN-gamma/IL-17 dual-producing cells and was associated with increased expression of ROR-gammat and ROR-alpha. Addition of IL-6 and TGF-beta to IL-23 further augmented ROR-gammat and ROR-alpha expression and suppressed Eomes expression, thereby enhancing IL-17 production by CD8 T cells. A loss of cytotoxic function accompanied the production of IL-17, as the addition of IL-6 and TGF-beta resulted in a marked reduction of granzyme B and perforin expression. Thus, CD8 T cells retain sufficient plasticity to respond to environmental cues and can acquire additional effector functions in response to their environmental context.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
A complex relationship: the interaction among symbiotic microbes, invading pathogens, and their mammalian host.
Mucosal Immunol.
Symbiosis between microbes and their mammalian host is vital to maintaining homeostasis. Symbiotic microbes within the gastrointestinal tract provide an array of benefits to the host, including promotion of host immunity. A coordinated effort of the host and symbiotic microbes deters the colonization and survival of many invading pathogens. However, pathogens have devised strategies to overcome these mechanisms. Furthermore, some pathogens can hijack host hormones and bacterial autoinducers to induce virulence traits. Intra- and inter-species (bacteria/bacteria) and interkingdom (bacteria/host) communication orchestrates the complex relationship among symbiotic microbes, invading pathogens, and their mammalian host. Insight into this communication will provide a foundation for the development of targeted antimicrobial therapies.
IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons.
J Immunol.
In contrast to CD4 T cells, CD8 T cells inherently differentiate into IFN-gamma-producing effectors. Accordingly, while generation of IFN-gamma-producing Th1 CD4 T cells was profoundly impaired in mice deficient for both type-I IFN and IL-12 signaling in response to infection with Listeria monocytogenes, generation of Ag-specific, IFN-gamma-producing CD8 T cells was unimpaired. However, a fraction of these CD8 T cells also produced IL-17 in an IL-23-dependent manner. Furthermore, the addition of IL-23 in vitro was sufficient for some naive CD8 T cells to differentiate into IFN-gamma/IL-17 dual-producing cells and was associated with increased expression of ROR-gammat and ROR-alpha. Addition of IL-6 and TGF-beta to IL-23 further augmented ROR-gammat and ROR-alpha expression and suppressed Eomes expression, thereby enhancing IL-17 production by CD8 T cells. A loss of cytotoxic function accompanied the production of IL-17, as the addition of IL-6 and TGF-beta resulted in a marked reduction of granzyme B and perforin expression. Thus, CD8 T cells retain sufficient plasticity to respond to environmental cues and can acquire additional effector functions in response to their environmental context.
The Gut Commensal Bacteroides thetaiotaomicron Exacerbates Enteric Infection through Modification of the Metabolic Landscape
Cell Host Microbe
The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea, but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
A complex relationship: the interaction among symbiotic microbes, invading pathogens, and their mammalian host.
Mucosal Immunol.
Symbiosis between microbes and their mammalian host is vital to maintaining homeostasis. Symbiotic microbes within the gastrointestinal tract provide an array of benefits to the host, including promotion of host immunity. A coordinated effort of the host and symbiotic microbes deters the colonization and survival of many invading pathogens. However, pathogens have devised strategies to overcome these mechanisms. Furthermore, some pathogens can hijack host hormones and bacterial autoinducers to induce virulence traits. Intra- and inter-species (bacteria/bacteria) and interkingdom (bacteria/host) communication orchestrates the complex relationship among symbiotic microbes, invading pathogens, and their mammalian host. Insight into this communication will provide a foundation for the development of targeted antimicrobial therapies.
IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons.
J Immunol.
In contrast to CD4 T cells, CD8 T cells inherently differentiate into IFN-gamma-producing effectors. Accordingly, while generation of IFN-gamma-producing Th1 CD4 T cells was profoundly impaired in mice deficient for both type-I IFN and IL-12 signaling in response to infection with Listeria monocytogenes, generation of Ag-specific, IFN-gamma-producing CD8 T cells was unimpaired. However, a fraction of these CD8 T cells also produced IL-17 in an IL-23-dependent manner. Furthermore, the addition of IL-23 in vitro was sufficient for some naive CD8 T cells to differentiate into IFN-gamma/IL-17 dual-producing cells and was associated with increased expression of ROR-gammat and ROR-alpha. Addition of IL-6 and TGF-beta to IL-23 further augmented ROR-gammat and ROR-alpha expression and suppressed Eomes expression, thereby enhancing IL-17 production by CD8 T cells. A loss of cytotoxic function accompanied the production of IL-17, as the addition of IL-6 and TGF-beta resulted in a marked reduction of granzyme B and perforin expression. Thus, CD8 T cells retain sufficient plasticity to respond to environmental cues and can acquire additional effector functions in response to their environmental context.
The Gut Commensal Bacteroides thetaiotaomicron Exacerbates Enteric Infection through Modification of the Metabolic Landscape
Cell Host Microbe
The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea, but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility.
Virulence meets metabolism: Cra and KdpE gene regulation in enterohemorrhagic Escherichia coli.
MBio
Gastrointestinal (GI) bacteria sense diverse environmental signals as cues for differential gene regulation and niche adaptation. Pathogens such as enterohemorrhagic Escherichia coli (EHEC), which causes bloody diarrhea, use these signals for the temporal and energy-efficient regulation of their virulence factors. One of the main virulence strategies employed by EHEC is the formation of attaching and effacing (AE) lesions on enterocytes. Most of the genes necessary for the formation of these lesions are grouped within a pathogenicity island, the locus of enterocyte effacement (LEE), whose expression requires the LEE-encoded regulator Ler. Here we show that growth of EHEC in glycolytic environments inhibits the expression of ler and consequently all other LEE genes. Conversely, growth within a gluconeogenic environment activates expression of these genes. This sugar-dependent regulation is achieved through two transcription factors: KdpE and Cra. Both Cra and KdpE directly bind to the ler promoter, and Cra's affinity to this promoter is catabolite dependent. Moreover, we show that the Cra and KdpE proteins interact in vitro and that KdpE's ability to bind DNA is enhanced by the presence of Cra. Cra is important for AE lesion formation, and KdpE contributes to this Cra-dependent regulation. The deletion of cra and kdpE resulted in the ablation of AE lesions. One of the many challenges that bacteria face within the GI tract is to successfully compete for carbon sources. Linking carbon metabolism to the precise coordination of virulence expression is a key step in the adaptation of pathogens to the GI environment. IMPORTANCE An appropriate and prompt response to environmental cues is crucial for bacterial survival. Cra and KdpE are two proteins found in both nonpathogenic and pathogenic bacteria that regulate genes in response to differences in metabolite concentration.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
A complex relationship: the interaction among symbiotic microbes, invading pathogens, and their mammalian host.
Mucosal Immunol.
Symbiosis between microbes and their mammalian host is vital to maintaining homeostasis. Symbiotic microbes within the gastrointestinal tract provide an array of benefits to the host, including promotion of host immunity. A coordinated effort of the host and symbiotic microbes deters the colonization and survival of many invading pathogens. However, pathogens have devised strategies to overcome these mechanisms. Furthermore, some pathogens can hijack host hormones and bacterial autoinducers to induce virulence traits. Intra- and inter-species (bacteria/bacteria) and interkingdom (bacteria/host) communication orchestrates the complex relationship among symbiotic microbes, invading pathogens, and their mammalian host. Insight into this communication will provide a foundation for the development of targeted antimicrobial therapies.
IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons.
J Immunol.
In contrast to CD4 T cells, CD8 T cells inherently differentiate into IFN-gamma-producing effectors. Accordingly, while generation of IFN-gamma-producing Th1 CD4 T cells was profoundly impaired in mice deficient for both type-I IFN and IL-12 signaling in response to infection with Listeria monocytogenes, generation of Ag-specific, IFN-gamma-producing CD8 T cells was unimpaired. However, a fraction of these CD8 T cells also produced IL-17 in an IL-23-dependent manner. Furthermore, the addition of IL-23 in vitro was sufficient for some naive CD8 T cells to differentiate into IFN-gamma/IL-17 dual-producing cells and was associated with increased expression of ROR-gammat and ROR-alpha. Addition of IL-6 and TGF-beta to IL-23 further augmented ROR-gammat and ROR-alpha expression and suppressed Eomes expression, thereby enhancing IL-17 production by CD8 T cells. A loss of cytotoxic function accompanied the production of IL-17, as the addition of IL-6 and TGF-beta resulted in a marked reduction of granzyme B and perforin expression. Thus, CD8 T cells retain sufficient plasticity to respond to environmental cues and can acquire additional effector functions in response to their environmental context.
The Gut Commensal Bacteroides thetaiotaomicron Exacerbates Enteric Infection through Modification of the Metabolic Landscape
Cell Host Microbe
The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea, but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility.
Virulence meets metabolism: Cra and KdpE gene regulation in enterohemorrhagic Escherichia coli.
MBio
Gastrointestinal (GI) bacteria sense diverse environmental signals as cues for differential gene regulation and niche adaptation. Pathogens such as enterohemorrhagic Escherichia coli (EHEC), which causes bloody diarrhea, use these signals for the temporal and energy-efficient regulation of their virulence factors. One of the main virulence strategies employed by EHEC is the formation of attaching and effacing (AE) lesions on enterocytes. Most of the genes necessary for the formation of these lesions are grouped within a pathogenicity island, the locus of enterocyte effacement (LEE), whose expression requires the LEE-encoded regulator Ler. Here we show that growth of EHEC in glycolytic environments inhibits the expression of ler and consequently all other LEE genes. Conversely, growth within a gluconeogenic environment activates expression of these genes. This sugar-dependent regulation is achieved through two transcription factors: KdpE and Cra. Both Cra and KdpE directly bind to the ler promoter, and Cra's affinity to this promoter is catabolite dependent. Moreover, we show that the Cra and KdpE proteins interact in vitro and that KdpE's ability to bind DNA is enhanced by the presence of Cra. Cra is important for AE lesion formation, and KdpE contributes to this Cra-dependent regulation. The deletion of cra and kdpE resulted in the ablation of AE lesions. One of the many challenges that bacteria face within the GI tract is to successfully compete for carbon sources. Linking carbon metabolism to the precise coordination of virulence expression is a key step in the adaptation of pathogens to the GI environment. IMPORTANCE An appropriate and prompt response to environmental cues is crucial for bacterial survival. Cra and KdpE are two proteins found in both nonpathogenic and pathogenic bacteria that regulate genes in response to differences in metabolite concentration.
Fidelity of pathogen-specific CD4+ T cells to the Th1 lineage is controlled by exogenous cytokines, interferon-gamma expression, and pathogen lifestyle.
Cell Host Microbe
The degree of lineage stability achieved by pathogen-specific CD4(+) T cells in vivo, and how this impacts host defense against infection, remains unclear. We demonstrate that in response to Th1-polarizing intracellular bacterial or viral pathogens, only 80%-90% of responding polyclonal T cells become indelibly committed to this lineage. Th1 commitment was nearly invariant in cells that proliferated extensively, but perturbations to the extrinsic cytokine milieu or the pathogen's ability to enter the cytosol impeded commitment and promoted plasticity for future IL-17 expression. Conversely, cell-intrinsic interferon-gamma expression and acquisition of permissive chromatin at the Ifng gene during priming predicted heritable Th1 commitment. Importantly, CD4(+) T cells that retained plasticity conferred protection against Mycobacterium tuberculosis, while these protective effects were abolished with Th17 polarization. These findings illustrate the immune signals that induce memory CD4(+) T cell responses required for maintaining host defense against infection yet are adaptable in novel environmental contexts.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
A complex relationship: the interaction among symbiotic microbes, invading pathogens, and their mammalian host.
Mucosal Immunol.
Symbiosis between microbes and their mammalian host is vital to maintaining homeostasis. Symbiotic microbes within the gastrointestinal tract provide an array of benefits to the host, including promotion of host immunity. A coordinated effort of the host and symbiotic microbes deters the colonization and survival of many invading pathogens. However, pathogens have devised strategies to overcome these mechanisms. Furthermore, some pathogens can hijack host hormones and bacterial autoinducers to induce virulence traits. Intra- and inter-species (bacteria/bacteria) and interkingdom (bacteria/host) communication orchestrates the complex relationship among symbiotic microbes, invading pathogens, and their mammalian host. Insight into this communication will provide a foundation for the development of targeted antimicrobial therapies.
IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons.
J Immunol.
In contrast to CD4 T cells, CD8 T cells inherently differentiate into IFN-gamma-producing effectors. Accordingly, while generation of IFN-gamma-producing Th1 CD4 T cells was profoundly impaired in mice deficient for both type-I IFN and IL-12 signaling in response to infection with Listeria monocytogenes, generation of Ag-specific, IFN-gamma-producing CD8 T cells was unimpaired. However, a fraction of these CD8 T cells also produced IL-17 in an IL-23-dependent manner. Furthermore, the addition of IL-23 in vitro was sufficient for some naive CD8 T cells to differentiate into IFN-gamma/IL-17 dual-producing cells and was associated with increased expression of ROR-gammat and ROR-alpha. Addition of IL-6 and TGF-beta to IL-23 further augmented ROR-gammat and ROR-alpha expression and suppressed Eomes expression, thereby enhancing IL-17 production by CD8 T cells. A loss of cytotoxic function accompanied the production of IL-17, as the addition of IL-6 and TGF-beta resulted in a marked reduction of granzyme B and perforin expression. Thus, CD8 T cells retain sufficient plasticity to respond to environmental cues and can acquire additional effector functions in response to their environmental context.
The Gut Commensal Bacteroides thetaiotaomicron Exacerbates Enteric Infection through Modification of the Metabolic Landscape
Cell Host Microbe
The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea, but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility.
Virulence meets metabolism: Cra and KdpE gene regulation in enterohemorrhagic Escherichia coli.
MBio
Gastrointestinal (GI) bacteria sense diverse environmental signals as cues for differential gene regulation and niche adaptation. Pathogens such as enterohemorrhagic Escherichia coli (EHEC), which causes bloody diarrhea, use these signals for the temporal and energy-efficient regulation of their virulence factors. One of the main virulence strategies employed by EHEC is the formation of attaching and effacing (AE) lesions on enterocytes. Most of the genes necessary for the formation of these lesions are grouped within a pathogenicity island, the locus of enterocyte effacement (LEE), whose expression requires the LEE-encoded regulator Ler. Here we show that growth of EHEC in glycolytic environments inhibits the expression of ler and consequently all other LEE genes. Conversely, growth within a gluconeogenic environment activates expression of these genes. This sugar-dependent regulation is achieved through two transcription factors: KdpE and Cra. Both Cra and KdpE directly bind to the ler promoter, and Cra's affinity to this promoter is catabolite dependent. Moreover, we show that the Cra and KdpE proteins interact in vitro and that KdpE's ability to bind DNA is enhanced by the presence of Cra. Cra is important for AE lesion formation, and KdpE contributes to this Cra-dependent regulation. The deletion of cra and kdpE resulted in the ablation of AE lesions. One of the many challenges that bacteria face within the GI tract is to successfully compete for carbon sources. Linking carbon metabolism to the precise coordination of virulence expression is a key step in the adaptation of pathogens to the GI environment. IMPORTANCE An appropriate and prompt response to environmental cues is crucial for bacterial survival. Cra and KdpE are two proteins found in both nonpathogenic and pathogenic bacteria that regulate genes in response to differences in metabolite concentration.
Fidelity of pathogen-specific CD4+ T cells to the Th1 lineage is controlled by exogenous cytokines, interferon-gamma expression, and pathogen lifestyle.
Cell Host Microbe
The degree of lineage stability achieved by pathogen-specific CD4(+) T cells in vivo, and how this impacts host defense against infection, remains unclear. We demonstrate that in response to Th1-polarizing intracellular bacterial or viral pathogens, only 80%-90% of responding polyclonal T cells become indelibly committed to this lineage. Th1 commitment was nearly invariant in cells that proliferated extensively, but perturbations to the extrinsic cytokine milieu or the pathogen's ability to enter the cytosol impeded commitment and promoted plasticity for future IL-17 expression. Conversely, cell-intrinsic interferon-gamma expression and acquisition of permissive chromatin at the Ifng gene during priming predicted heritable Th1 commitment. Importantly, CD4(+) T cells that retained plasticity conferred protection against Mycobacterium tuberculosis, while these protective effects were abolished with Th17 polarization. These findings illustrate the immune signals that induce memory CD4(+) T cell responses required for maintaining host defense against infection yet are adaptable in novel environmental contexts.
Restrictive streptomycin-resistant mutations decrease the formation of attaching and effacing lesions in Escherichia coli O157:H7 strains.
Antimicrob Agents Chemother.
Streptomycin binds to the bacterial ribosome and disrupts protein synthesis by promoting misreading of mRNA. Restrictive mutations on the ribosomal subunit protein S12 confer a streptomycin resistance (Strr) phenotype, and concomitantly increase the accuracy of the decoding process and decrease the rate of translation. Spontaneous Strr mutants of Escherichia coli O157:H7 have been generated for in vivo studies to promote colonization, and to provide a selective marker for this pathogen. The locus of enterocyte effacement (LEE) in E. coli O157:H7 encodes a type III secretion system (T3SS), which is required for attaching and effacing to intestinal epithelium. In this study, we observed decreases in both the expression and secretion levels of the T3SS translocated proteins EspA and EspB in E. coli O157:H7 Strr restrictive mutants, which have K42T or K42I mutations in S12. However, mildly restrictive (K87R) and non-restrictive (K42R) mutants showed slight or indistinguishable change in EspA and EspB secretion. Adherence and actin staining assays indicated that restrictive mutations compromised the formation of attaching and effacing lesions in E. coli O157:H7. Therefore, we suggest that E. coli O157:H7 strains selected for Strr should be thoroughly characterized before in vivo and in vitro experiments that assay for LEE-directed phenotypes, and that strains carrying non-restrictive mutations such as K42R make better surrogates of wild-type strains than those carrying restrictive mutations.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
A complex relationship: the interaction among symbiotic microbes, invading pathogens, and their mammalian host.
Mucosal Immunol.
Symbiosis between microbes and their mammalian host is vital to maintaining homeostasis. Symbiotic microbes within the gastrointestinal tract provide an array of benefits to the host, including promotion of host immunity. A coordinated effort of the host and symbiotic microbes deters the colonization and survival of many invading pathogens. However, pathogens have devised strategies to overcome these mechanisms. Furthermore, some pathogens can hijack host hormones and bacterial autoinducers to induce virulence traits. Intra- and inter-species (bacteria/bacteria) and interkingdom (bacteria/host) communication orchestrates the complex relationship among symbiotic microbes, invading pathogens, and their mammalian host. Insight into this communication will provide a foundation for the development of targeted antimicrobial therapies.
IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons.
J Immunol.
In contrast to CD4 T cells, CD8 T cells inherently differentiate into IFN-gamma-producing effectors. Accordingly, while generation of IFN-gamma-producing Th1 CD4 T cells was profoundly impaired in mice deficient for both type-I IFN and IL-12 signaling in response to infection with Listeria monocytogenes, generation of Ag-specific, IFN-gamma-producing CD8 T cells was unimpaired. However, a fraction of these CD8 T cells also produced IL-17 in an IL-23-dependent manner. Furthermore, the addition of IL-23 in vitro was sufficient for some naive CD8 T cells to differentiate into IFN-gamma/IL-17 dual-producing cells and was associated with increased expression of ROR-gammat and ROR-alpha. Addition of IL-6 and TGF-beta to IL-23 further augmented ROR-gammat and ROR-alpha expression and suppressed Eomes expression, thereby enhancing IL-17 production by CD8 T cells. A loss of cytotoxic function accompanied the production of IL-17, as the addition of IL-6 and TGF-beta resulted in a marked reduction of granzyme B and perforin expression. Thus, CD8 T cells retain sufficient plasticity to respond to environmental cues and can acquire additional effector functions in response to their environmental context.
The Gut Commensal Bacteroides thetaiotaomicron Exacerbates Enteric Infection through Modification of the Metabolic Landscape
Cell Host Microbe
The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea, but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility.
Virulence meets metabolism: Cra and KdpE gene regulation in enterohemorrhagic Escherichia coli.
MBio
Gastrointestinal (GI) bacteria sense diverse environmental signals as cues for differential gene regulation and niche adaptation. Pathogens such as enterohemorrhagic Escherichia coli (EHEC), which causes bloody diarrhea, use these signals for the temporal and energy-efficient regulation of their virulence factors. One of the main virulence strategies employed by EHEC is the formation of attaching and effacing (AE) lesions on enterocytes. Most of the genes necessary for the formation of these lesions are grouped within a pathogenicity island, the locus of enterocyte effacement (LEE), whose expression requires the LEE-encoded regulator Ler. Here we show that growth of EHEC in glycolytic environments inhibits the expression of ler and consequently all other LEE genes. Conversely, growth within a gluconeogenic environment activates expression of these genes. This sugar-dependent regulation is achieved through two transcription factors: KdpE and Cra. Both Cra and KdpE directly bind to the ler promoter, and Cra's affinity to this promoter is catabolite dependent. Moreover, we show that the Cra and KdpE proteins interact in vitro and that KdpE's ability to bind DNA is enhanced by the presence of Cra. Cra is important for AE lesion formation, and KdpE contributes to this Cra-dependent regulation. The deletion of cra and kdpE resulted in the ablation of AE lesions. One of the many challenges that bacteria face within the GI tract is to successfully compete for carbon sources. Linking carbon metabolism to the precise coordination of virulence expression is a key step in the adaptation of pathogens to the GI environment. IMPORTANCE An appropriate and prompt response to environmental cues is crucial for bacterial survival. Cra and KdpE are two proteins found in both nonpathogenic and pathogenic bacteria that regulate genes in response to differences in metabolite concentration.
Fidelity of pathogen-specific CD4+ T cells to the Th1 lineage is controlled by exogenous cytokines, interferon-gamma expression, and pathogen lifestyle.
Cell Host Microbe
The degree of lineage stability achieved by pathogen-specific CD4(+) T cells in vivo, and how this impacts host defense against infection, remains unclear. We demonstrate that in response to Th1-polarizing intracellular bacterial or viral pathogens, only 80%-90% of responding polyclonal T cells become indelibly committed to this lineage. Th1 commitment was nearly invariant in cells that proliferated extensively, but perturbations to the extrinsic cytokine milieu or the pathogen's ability to enter the cytosol impeded commitment and promoted plasticity for future IL-17 expression. Conversely, cell-intrinsic interferon-gamma expression and acquisition of permissive chromatin at the Ifng gene during priming predicted heritable Th1 commitment. Importantly, CD4(+) T cells that retained plasticity conferred protection against Mycobacterium tuberculosis, while these protective effects were abolished with Th17 polarization. These findings illustrate the immune signals that induce memory CD4(+) T cell responses required for maintaining host defense against infection yet are adaptable in novel environmental contexts.
Restrictive streptomycin-resistant mutations decrease the formation of attaching and effacing lesions in Escherichia coli O157:H7 strains.
Antimicrob Agents Chemother.
Streptomycin binds to the bacterial ribosome and disrupts protein synthesis by promoting misreading of mRNA. Restrictive mutations on the ribosomal subunit protein S12 confer a streptomycin resistance (Strr) phenotype, and concomitantly increase the accuracy of the decoding process and decrease the rate of translation. Spontaneous Strr mutants of Escherichia coli O157:H7 have been generated for in vivo studies to promote colonization, and to provide a selective marker for this pathogen. The locus of enterocyte effacement (LEE) in E. coli O157:H7 encodes a type III secretion system (T3SS), which is required for attaching and effacing to intestinal epithelium. In this study, we observed decreases in both the expression and secretion levels of the T3SS translocated proteins EspA and EspB in E. coli O157:H7 Strr restrictive mutants, which have K42T or K42I mutations in S12. However, mildly restrictive (K87R) and non-restrictive (K42R) mutants showed slight or indistinguishable change in EspA and EspB secretion. Adherence and actin staining assays indicated that restrictive mutations compromised the formation of attaching and effacing lesions in E. coli O157:H7. Therefore, we suggest that E. coli O157:H7 strains selected for Strr should be thoroughly characterized before in vivo and in vitro experiments that assay for LEE-directed phenotypes, and that strains carrying non-restrictive mutations such as K42R make better surrogates of wild-type strains than those carrying restrictive mutations.
QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens
MBio
Invasive pathogens interface with the host and its resident microbiota through interkingdom signaling. The bacterial receptor QseC, which is a membrane-bound histidine sensor kinase, responds to the host stress hormones epinephrine and norepinephrine and the bacterial signal AI-3, integrating interkingdom signaling at the biochemical level. Importantly, the QseC signaling cascade is exploited by many bacterial pathogens to promote virulence. Here, we translated this basic science information into development of a potent small molecule inhibitor of QseC, LED209. Extensive structure activity relationship (SAR) studies revealed that LED209 is a potent prodrug that is highly selective for QseC. Its warhead allosterically modifies lysines in QseC, impairing its function and preventing the activation of the virulence program of several Gram-negative pathogens both in vitro and during murine infection. LED209 does not interfere with pathogen growth, possibly leading to a milder evolutionary pressure toward drug resistance. LED209 has desirable pharmacokinetics and does not present toxicity in vitro and in rodents. This is a unique antivirulence approach, with a proven broad-spectrum activity against multiple Gram-negative pathogens that cause mammalian infections. IMPORTANCE: There is an imminent need for development of novel treatments for infectious diseases, given that one of the biggest challenges to medicine in the foreseeable future is the emergence of microbial antibiotic resistance. Here, we devised a broad-spectrum antivirulence approach targeting a conserved histidine kinase, QseC, in several Gram-negative pathogens that promotes their virulence expression. The LED209 QseC inhibitor has a unique mode of action by acting as a prodrug scaffold to deliver a warhead that allosterically modifies QseC, impeding virulence in several Gram-negative pathogens.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
A complex relationship: the interaction among symbiotic microbes, invading pathogens, and their mammalian host.
Mucosal Immunol.
Symbiosis between microbes and their mammalian host is vital to maintaining homeostasis. Symbiotic microbes within the gastrointestinal tract provide an array of benefits to the host, including promotion of host immunity. A coordinated effort of the host and symbiotic microbes deters the colonization and survival of many invading pathogens. However, pathogens have devised strategies to overcome these mechanisms. Furthermore, some pathogens can hijack host hormones and bacterial autoinducers to induce virulence traits. Intra- and inter-species (bacteria/bacteria) and interkingdom (bacteria/host) communication orchestrates the complex relationship among symbiotic microbes, invading pathogens, and their mammalian host. Insight into this communication will provide a foundation for the development of targeted antimicrobial therapies.
IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons.
J Immunol.
In contrast to CD4 T cells, CD8 T cells inherently differentiate into IFN-gamma-producing effectors. Accordingly, while generation of IFN-gamma-producing Th1 CD4 T cells was profoundly impaired in mice deficient for both type-I IFN and IL-12 signaling in response to infection with Listeria monocytogenes, generation of Ag-specific, IFN-gamma-producing CD8 T cells was unimpaired. However, a fraction of these CD8 T cells also produced IL-17 in an IL-23-dependent manner. Furthermore, the addition of IL-23 in vitro was sufficient for some naive CD8 T cells to differentiate into IFN-gamma/IL-17 dual-producing cells and was associated with increased expression of ROR-gammat and ROR-alpha. Addition of IL-6 and TGF-beta to IL-23 further augmented ROR-gammat and ROR-alpha expression and suppressed Eomes expression, thereby enhancing IL-17 production by CD8 T cells. A loss of cytotoxic function accompanied the production of IL-17, as the addition of IL-6 and TGF-beta resulted in a marked reduction of granzyme B and perforin expression. Thus, CD8 T cells retain sufficient plasticity to respond to environmental cues and can acquire additional effector functions in response to their environmental context.
The Gut Commensal Bacteroides thetaiotaomicron Exacerbates Enteric Infection through Modification of the Metabolic Landscape
Cell Host Microbe
The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea, but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility.
Virulence meets metabolism: Cra and KdpE gene regulation in enterohemorrhagic Escherichia coli.
MBio
Gastrointestinal (GI) bacteria sense diverse environmental signals as cues for differential gene regulation and niche adaptation. Pathogens such as enterohemorrhagic Escherichia coli (EHEC), which causes bloody diarrhea, use these signals for the temporal and energy-efficient regulation of their virulence factors. One of the main virulence strategies employed by EHEC is the formation of attaching and effacing (AE) lesions on enterocytes. Most of the genes necessary for the formation of these lesions are grouped within a pathogenicity island, the locus of enterocyte effacement (LEE), whose expression requires the LEE-encoded regulator Ler. Here we show that growth of EHEC in glycolytic environments inhibits the expression of ler and consequently all other LEE genes. Conversely, growth within a gluconeogenic environment activates expression of these genes. This sugar-dependent regulation is achieved through two transcription factors: KdpE and Cra. Both Cra and KdpE directly bind to the ler promoter, and Cra's affinity to this promoter is catabolite dependent. Moreover, we show that the Cra and KdpE proteins interact in vitro and that KdpE's ability to bind DNA is enhanced by the presence of Cra. Cra is important for AE lesion formation, and KdpE contributes to this Cra-dependent regulation. The deletion of cra and kdpE resulted in the ablation of AE lesions. One of the many challenges that bacteria face within the GI tract is to successfully compete for carbon sources. Linking carbon metabolism to the precise coordination of virulence expression is a key step in the adaptation of pathogens to the GI environment. IMPORTANCE An appropriate and prompt response to environmental cues is crucial for bacterial survival. Cra and KdpE are two proteins found in both nonpathogenic and pathogenic bacteria that regulate genes in response to differences in metabolite concentration.
Fidelity of pathogen-specific CD4+ T cells to the Th1 lineage is controlled by exogenous cytokines, interferon-gamma expression, and pathogen lifestyle.
Cell Host Microbe
The degree of lineage stability achieved by pathogen-specific CD4(+) T cells in vivo, and how this impacts host defense against infection, remains unclear. We demonstrate that in response to Th1-polarizing intracellular bacterial or viral pathogens, only 80%-90% of responding polyclonal T cells become indelibly committed to this lineage. Th1 commitment was nearly invariant in cells that proliferated extensively, but perturbations to the extrinsic cytokine milieu or the pathogen's ability to enter the cytosol impeded commitment and promoted plasticity for future IL-17 expression. Conversely, cell-intrinsic interferon-gamma expression and acquisition of permissive chromatin at the Ifng gene during priming predicted heritable Th1 commitment. Importantly, CD4(+) T cells that retained plasticity conferred protection against Mycobacterium tuberculosis, while these protective effects were abolished with Th17 polarization. These findings illustrate the immune signals that induce memory CD4(+) T cell responses required for maintaining host defense against infection yet are adaptable in novel environmental contexts.
Restrictive streptomycin-resistant mutations decrease the formation of attaching and effacing lesions in Escherichia coli O157:H7 strains.
Antimicrob Agents Chemother.
Streptomycin binds to the bacterial ribosome and disrupts protein synthesis by promoting misreading of mRNA. Restrictive mutations on the ribosomal subunit protein S12 confer a streptomycin resistance (Strr) phenotype, and concomitantly increase the accuracy of the decoding process and decrease the rate of translation. Spontaneous Strr mutants of Escherichia coli O157:H7 have been generated for in vivo studies to promote colonization, and to provide a selective marker for this pathogen. The locus of enterocyte effacement (LEE) in E. coli O157:H7 encodes a type III secretion system (T3SS), which is required for attaching and effacing to intestinal epithelium. In this study, we observed decreases in both the expression and secretion levels of the T3SS translocated proteins EspA and EspB in E. coli O157:H7 Strr restrictive mutants, which have K42T or K42I mutations in S12. However, mildly restrictive (K87R) and non-restrictive (K42R) mutants showed slight or indistinguishable change in EspA and EspB secretion. Adherence and actin staining assays indicated that restrictive mutations compromised the formation of attaching and effacing lesions in E. coli O157:H7. Therefore, we suggest that E. coli O157:H7 strains selected for Strr should be thoroughly characterized before in vivo and in vitro experiments that assay for LEE-directed phenotypes, and that strains carrying non-restrictive mutations such as K42R make better surrogates of wild-type strains than those carrying restrictive mutations.
QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens
MBio
Invasive pathogens interface with the host and its resident microbiota through interkingdom signaling. The bacterial receptor QseC, which is a membrane-bound histidine sensor kinase, responds to the host stress hormones epinephrine and norepinephrine and the bacterial signal AI-3, integrating interkingdom signaling at the biochemical level. Importantly, the QseC signaling cascade is exploited by many bacterial pathogens to promote virulence. Here, we translated this basic science information into development of a potent small molecule inhibitor of QseC, LED209. Extensive structure activity relationship (SAR) studies revealed that LED209 is a potent prodrug that is highly selective for QseC. Its warhead allosterically modifies lysines in QseC, impairing its function and preventing the activation of the virulence program of several Gram-negative pathogens both in vitro and during murine infection. LED209 does not interfere with pathogen growth, possibly leading to a milder evolutionary pressure toward drug resistance. LED209 has desirable pharmacokinetics and does not present toxicity in vitro and in rodents. This is a unique antivirulence approach, with a proven broad-spectrum activity against multiple Gram-negative pathogens that cause mammalian infections. IMPORTANCE: There is an imminent need for development of novel treatments for infectious diseases, given that one of the biggest challenges to medicine in the foreseeable future is the emergence of microbial antibiotic resistance. Here, we devised a broad-spectrum antivirulence approach targeting a conserved histidine kinase, QseC, in several Gram-negative pathogens that promotes their virulence expression. The LED209 QseC inhibitor has a unique mode of action by acting as a prodrug scaffold to deliver a warhead that allosterically modifies QseC, impeding virulence in several Gram-negative pathogens.
Fucose sensing regulates bacterial intestinal colonization.
Nature
The mammalian gastrointestinal tract provides a complex and competitive environment for the microbiota. Successful colonization by pathogens requires scavenging nutrients, sensing chemical signals, competing with the resident bacteria and precisely regulating the expression of virulence genes. The gastrointestinal pathogen enterohaemorrhagic Escherichia coli (EHEC) relies on inter-kingdom chemical sensing systems to regulate virulence gene expression. Here we show that these systems control the expression of a novel two-component signal transduction system, named FusKR, where FusK is the histidine sensor kinase and FusR the response regulator. FusK senses fucose and controls expression of virulence and metabolic genes. This fucose-sensing system is required for robust EHEC colonization of the mammalian intestine. Fucose is highly abundant in the intestine. Bacteroides thetaiotaomicron produces multiple fucosidases that cleave fucose from host glycans, resulting in high fucose availability in the gut lumen. During growth in mucin, B. thetaiotaomicron contributes to EHEC virulence by cleaving fucose from mucin, thereby activating the FusKR signalling cascade, modulating the virulence gene expression of EHEC. Our findings suggest that EHEC uses fucose, a host-derived signal made available by the microbiota, to modulate EHEC pathogenicity and metabolism.
Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens.
Immunology
The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.
A complex relationship: the interaction among symbiotic microbes, invading pathogens, and their mammalian host.
Mucosal Immunol.
Symbiosis between microbes and their mammalian host is vital to maintaining homeostasis. Symbiotic microbes within the gastrointestinal tract provide an array of benefits to the host, including promotion of host immunity. A coordinated effort of the host and symbiotic microbes deters the colonization and survival of many invading pathogens. However, pathogens have devised strategies to overcome these mechanisms. Furthermore, some pathogens can hijack host hormones and bacterial autoinducers to induce virulence traits. Intra- and inter-species (bacteria/bacteria) and interkingdom (bacteria/host) communication orchestrates the complex relationship among symbiotic microbes, invading pathogens, and their mammalian host. Insight into this communication will provide a foundation for the development of targeted antimicrobial therapies.
IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons.
J Immunol.
In contrast to CD4 T cells, CD8 T cells inherently differentiate into IFN-gamma-producing effectors. Accordingly, while generation of IFN-gamma-producing Th1 CD4 T cells was profoundly impaired in mice deficient for both type-I IFN and IL-12 signaling in response to infection with Listeria monocytogenes, generation of Ag-specific, IFN-gamma-producing CD8 T cells was unimpaired. However, a fraction of these CD8 T cells also produced IL-17 in an IL-23-dependent manner. Furthermore, the addition of IL-23 in vitro was sufficient for some naive CD8 T cells to differentiate into IFN-gamma/IL-17 dual-producing cells and was associated with increased expression of ROR-gammat and ROR-alpha. Addition of IL-6 and TGF-beta to IL-23 further augmented ROR-gammat and ROR-alpha expression and suppressed Eomes expression, thereby enhancing IL-17 production by CD8 T cells. A loss of cytotoxic function accompanied the production of IL-17, as the addition of IL-6 and TGF-beta resulted in a marked reduction of granzyme B and perforin expression. Thus, CD8 T cells retain sufficient plasticity to respond to environmental cues and can acquire additional effector functions in response to their environmental context.
The Gut Commensal Bacteroides thetaiotaomicron Exacerbates Enteric Infection through Modification of the Metabolic Landscape
Cell Host Microbe
The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea, but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility.
Virulence meets metabolism: Cra and KdpE gene regulation in enterohemorrhagic Escherichia coli.
MBio
Gastrointestinal (GI) bacteria sense diverse environmental signals as cues for differential gene regulation and niche adaptation. Pathogens such as enterohemorrhagic Escherichia coli (EHEC), which causes bloody diarrhea, use these signals for the temporal and energy-efficient regulation of their virulence factors. One of the main virulence strategies employed by EHEC is the formation of attaching and effacing (AE) lesions on enterocytes. Most of the genes necessary for the formation of these lesions are grouped within a pathogenicity island, the locus of enterocyte effacement (LEE), whose expression requires the LEE-encoded regulator Ler. Here we show that growth of EHEC in glycolytic environments inhibits the expression of ler and consequently all other LEE genes. Conversely, growth within a gluconeogenic environment activates expression of these genes. This sugar-dependent regulation is achieved through two transcription factors: KdpE and Cra. Both Cra and KdpE directly bind to the ler promoter, and Cra's affinity to this promoter is catabolite dependent. Moreover, we show that the Cra and KdpE proteins interact in vitro and that KdpE's ability to bind DNA is enhanced by the presence of Cra. Cra is important for AE lesion formation, and KdpE contributes to this Cra-dependent regulation. The deletion of cra and kdpE resulted in the ablation of AE lesions. One of the many challenges that bacteria face within the GI tract is to successfully compete for carbon sources. Linking carbon metabolism to the precise coordination of virulence expression is a key step in the adaptation of pathogens to the GI environment. IMPORTANCE An appropriate and prompt response to environmental cues is crucial for bacterial survival. Cra and KdpE are two proteins found in both nonpathogenic and pathogenic bacteria that regulate genes in response to differences in metabolite concentration.
Fidelity of pathogen-specific CD4+ T cells to the Th1 lineage is controlled by exogenous cytokines, interferon-gamma expression, and pathogen lifestyle.
Cell Host Microbe
The degree of lineage stability achieved by pathogen-specific CD4(+) T cells in vivo, and how this impacts host defense against infection, remains unclear. We demonstrate that in response to Th1-polarizing intracellular bacterial or viral pathogens, only 80%-90% of responding polyclonal T cells become indelibly committed to this lineage. Th1 commitment was nearly invariant in cells that proliferated extensively, but perturbations to the extrinsic cytokine milieu or the pathogen's ability to enter the cytosol impeded commitment and promoted plasticity for future IL-17 expression. Conversely, cell-intrinsic interferon-gamma expression and acquisition of permissive chromatin at the Ifng gene during priming predicted heritable Th1 commitment. Importantly, CD4(+) T cells that retained plasticity conferred protection against Mycobacterium tuberculosis, while these protective effects were abolished with Th17 polarization. These findings illustrate the immune signals that induce memory CD4(+) T cell responses required for maintaining host defense against infection yet are adaptable in novel environmental contexts.
Restrictive streptomycin-resistant mutations decrease the formation of attaching and effacing lesions in Escherichia coli O157:H7 strains.
Antimicrob Agents Chemother.
Streptomycin binds to the bacterial ribosome and disrupts protein synthesis by promoting misreading of mRNA. Restrictive mutations on the ribosomal subunit protein S12 confer a streptomycin resistance (Strr) phenotype, and concomitantly increase the accuracy of the decoding process and decrease the rate of translation. Spontaneous Strr mutants of Escherichia coli O157:H7 have been generated for in vivo studies to promote colonization, and to provide a selective marker for this pathogen. The locus of enterocyte effacement (LEE) in E. coli O157:H7 encodes a type III secretion system (T3SS), which is required for attaching and effacing to intestinal epithelium. In this study, we observed decreases in both the expression and secretion levels of the T3SS translocated proteins EspA and EspB in E. coli O157:H7 Strr restrictive mutants, which have K42T or K42I mutations in S12. However, mildly restrictive (K87R) and non-restrictive (K42R) mutants showed slight or indistinguishable change in EspA and EspB secretion. Adherence and actin staining assays indicated that restrictive mutations compromised the formation of attaching and effacing lesions in E. coli O157:H7. Therefore, we suggest that E. coli O157:H7 strains selected for Strr should be thoroughly characterized before in vivo and in vitro experiments that assay for LEE-directed phenotypes, and that strains carrying non-restrictive mutations such as K42R make better surrogates of wild-type strains than those carrying restrictive mutations.
QseC Inhibitors as an Antivirulence Approach for Gram-Negative Pathogens
MBio
Invasive pathogens interface with the host and its resident microbiota through interkingdom signaling. The bacterial receptor QseC, which is a membrane-bound histidine sensor kinase, responds to the host stress hormones epinephrine and norepinephrine and the bacterial signal AI-3, integrating interkingdom signaling at the biochemical level. Importantly, the QseC signaling cascade is exploited by many bacterial pathogens to promote virulence. Here, we translated this basic science information into development of a potent small molecule inhibitor of QseC, LED209. Extensive structure activity relationship (SAR) studies revealed that LED209 is a potent prodrug that is highly selective for QseC. Its warhead allosterically modifies lysines in QseC, impairing its function and preventing the activation of the virulence program of several Gram-negative pathogens both in vitro and during murine infection. LED209 does not interfere with pathogen growth, possibly leading to a milder evolutionary pressure toward drug resistance. LED209 has desirable pharmacokinetics and does not present toxicity in vitro and in rodents. This is a unique antivirulence approach, with a proven broad-spectrum activity against multiple Gram-negative pathogens that cause mammalian infections. IMPORTANCE: There is an imminent need for development of novel treatments for infectious diseases, given that one of the biggest challenges to medicine in the foreseeable future is the emergence of microbial antibiotic resistance. Here, we devised a broad-spectrum antivirulence approach targeting a conserved histidine kinase, QseC, in several Gram-negative pathogens that promotes their virulence expression. The LED209 QseC inhibitor has a unique mode of action by acting as a prodrug scaffold to deliver a warhead that allosterically modifies QseC, impeding virulence in several Gram-negative pathogens.
Fucose sensing regulates bacterial intestinal colonization.
Nature
The mammalian gastrointestinal tract provides a complex and competitive environment for the microbiota. Successful colonization by pathogens requires scavenging nutrients, sensing chemical signals, competing with the resident bacteria and precisely regulating the expression of virulence genes. The gastrointestinal pathogen enterohaemorrhagic Escherichia coli (EHEC) relies on inter-kingdom chemical sensing systems to regulate virulence gene expression. Here we show that these systems control the expression of a novel two-component signal transduction system, named FusKR, where FusK is the histidine sensor kinase and FusR the response regulator. FusK senses fucose and controls expression of virulence and metabolic genes. This fucose-sensing system is required for robust EHEC colonization of the mammalian intestine. Fucose is highly abundant in the intestine. Bacteroides thetaiotaomicron produces multiple fucosidases that cleave fucose from host glycans, resulting in high fucose availability in the gut lumen. During growth in mucin, B. thetaiotaomicron contributes to EHEC virulence by cleaving fucose from mucin, thereby activating the FusKR signalling cascade, modulating the virulence gene expression of EHEC. Our findings suggest that EHEC uses fucose, a host-derived signal made available by the microbiota, to modulate EHEC pathogenicity and metabolism.
Deviation from a strong Th1-dominated to a modest Th17- dominated CD4 T cell response in the absence of IL-12p40 and type I IFNs sustains protective CD8 T cells.
J Immunol.
The differentiation of naive CD4 T cells into specific effector subsets is controlled in large part by the milieu of cytokines present during their initial encounter with Ag. Cytokines that drive differentiation of the newly described Th17 lineage have been characterized in vitro, but the cytokines that prime commitment to this lineage in response to infection in vivo are less clear. Listeria monocytogenes (Lm) induces a strong Th1 response in wild-type mice. By contrast, we demonstrate that in the absence of IL-12p40 (or IFN-gamma) and type I IFN receptor signaling, the Th1 Ag-specific CD4 T cell response is virtually abolished and replaced by a relatively low magnitude Th17-dominated response. This Th17 response was dependent on TGF-beta and IL-6. Despite this change in CD4 T cell response, neither the kinetics of the CD4 and CD8 T cell responses, the quality of the CD8 T cell response, nor the ability of CD8 T cells to mediate protection were affected. Thus, generation of protective CD8 T cell immunity was resilient to perturbations that replace a strong Th1-dominated to a reduced magnitude Th17-dominated Ag-specific CD4 T cell response.
