SIGIRR, a Negative Regulator of TLR/IL-1R Signalling Promotes Microbiota Dependent Resistance to Colonization by Enteric Bacterial Pathogens
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{"title"=>"SIGIRR, a Negative Regulator of TLR/IL-1R Signalling Promotes Microbiota Dependent Resistance to Colonization by Enteric Bacterial Pathogens", "type"=>"journal", "authors"=>[{"first_name"=>"Ho Pan", "last_name"=>"Sham", "scopus_author_id"=>"35768584700"}, {"first_name"=>"Emily Yi Shan", "last_name"=>"Yu", "scopus_author_id"=>"55843671700"}, {"first_name"=>"Muhammet F.", "last_name"=>"Gulen", "scopus_author_id"=>"16229993100"}, {"first_name"=>"Ganive", "last_name"=>"Bhinder", "scopus_author_id"=>"55356932400"}, {"first_name"=>"Martin", "last_name"=>"Stahl", "scopus_author_id"=>"57130107500"}, {"first_name"=>"Justin M.", "last_name"=>"Chan", "scopus_author_id"=>"54079390600"}, {"first_name"=>"Lara", "last_name"=>"Brewster", "scopus_author_id"=>"55842955000"}, {"first_name"=>"Vijay", "last_name"=>"Morampudi", "scopus_author_id"=>"36990386100"}, {"first_name"=>"Deanna L.", "last_name"=>"Gibson", "scopus_author_id"=>"14123289800"}, {"first_name"=>"Michael R.", "last_name"=>"Hughes", "scopus_author_id"=>"7402468112"}, {"first_name"=>"Kelly M.", "last_name"=>"McNagny", "scopus_author_id"=>"6701876377"}, {"first_name"=>"Xiaoxia", "last_name"=>"Li", "scopus_author_id"=>"7501702579"}, {"first_name"=>"Bruce A.", "last_name"=>"Vallance", "scopus_author_id"=>"7003803048"}], "year"=>2013, "source"=>"PLoS Pathogens", "identifiers"=>{"sgr"=>"84883432951", "doi"=>"10.1371/journal.ppat.1003539", "isbn"=>"1553-7374 (Electronic)\\r1553-7366 (Linking)", "pmid"=>"23950714", "issn"=>"15537366", "scopus"=>"2-s2.0-84883432951", "pui"=>"369735842"}, "id"=>"6008038c-ab84-3449-9bcb-db2d2b80310a", "abstract"=>"Enteric bacterial pathogens such as enterohemorrhagic E. coli (EHEC) and Salmonella Typhimurium target the intestinal epithelial cells (IEC) lining the mammalian gastrointestinal tract. Despite expressing innate Toll-like receptors (TLRs), IEC are innately hypo-responsive to most bacterial products. This is thought to prevent maladaptive inflammatory responses against commensal bacteria, but it also limits antimicrobial responses by IEC to invading bacterial pathogens, potentially increasing host susceptibility to infection. One reason for the innate hypo-responsiveness of IEC is their expression of Single Ig IL-1 Related Receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and TLR signaling. To address whether SIGIRR expression and the innate hypo-responsiveness of IEC impacts on enteric host defense, Sigirr deficient (-/-) mice were infected with the EHEC related pathogen Citrobacter rodentium. Sigirr -/- mice responded with accelerated IEC proliferation and strong pro-inflammatory and antimicrobial responses but surprisingly, Sigirr -/- mice proved dramatically more susceptible to infection than wildtype mice. Through haematopoietic transplantation studies, it was determined that SIGIRR expression by non-haematopoietic cells (putative IEC) regulated these responses. Moreover, the exaggerated responses were found to be primarily dependent on IL-1R signaling. Whilst exploring the basis for their susceptibility, Sigirr -/- mice were found to be unusually susceptible to intestinal Salmonella Typhimurium colonization, developing enterocolitis without the typical requirement for antibiotic based removal of competing commensal microbes. Strikingly, the exaggerated antimicrobial responses seen in Sigirr -/- mice were found to cause a rapid and dramatic loss of commensal microbes from the infected intestine. This depletion appears to reduce the ability of the microbiota to compete for space and nutrients (colonization resistance) with the invading pathogens, leaving the intestine highly susceptible to pathogen colonization. Thus, SIGIRR expression by IEC reflects a strategy that sacrifices maximal innate responsiveness by IEC in order to promote commensal microbe based colonization resistance against bacterial pathogens.", "link"=>"http://www.mendeley.com/research/sigirr-negative-regulator-tlril1r-signalling-promotes-microbiota-dependent-resistance-colonization-e", "reader_count"=>55, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>17, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>2, "Student > Master"=>5, "Other"=>3, "Student > Bachelor"=>6, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>17, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>2, "Student > Master"=>5, "Other"=>3, "Student > Bachelor"=>6, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Nursing and Health Professions"=>2, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>32, "Medicine and Dentistry"=>9, "Veterinary Science and Veterinary Medicine"=>1, "Chemistry"=>1, "Immunology and Microbiology"=>3}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>32}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>2}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>2, "Norway"=>1, "China"=>1, "Mexico"=>1, "France"=>1}, "group_count"=>3}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1147654"], "description"=>"<p>No significant differences were found between (A) the commensal microbiota found in WT and <i>Sigirr −/−</i> mice as measured by (B) qPCR and (C) FISH staining. Rapid commensal depletion in <i>Sigirr −/−</i> mice was observed as early as D1 pi by <i>C. rodentium</i> (D) and <i>S.</i> Typhimurium (E) while intestinal crypts isolated from <i>Sigirr −/−</i> mice (F) possess greater killing activity against commensal <i>E. coli</i> and <i>Lactobacilli</i>. Results are pooled from 2–3 independent experiments (or infections) with n = 3–5 per group. Error bars = SEM, (Student t test (Figure A) one way ANOVA (Figures B–F, *P<0.05, **P<0.01).</p>", "links"=>[], "tags"=>["immunology", "immunity", "Immune defense", "Immune tolerance", "Immunity to infections", "immunoregulation", "Innate immunity", "Immune response", "Gastroenterology and hepatology", "Bacterial and foodborne illness", "Gastrointestinal infections", "Inflammatory bowel disease", "mice", "antimicrobial", "commensal"], "article_id"=>768000, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ho Pan Sham", "Emily Yi Shan Yu", "Muhammet F. Gulen", "Ganive Bhinder", "Martin Stahl", "Justin M. Chan", "Lara Brewster", "Vijay Morampudi", "Deanna L. Gibson", "Michael R. Hughes", "Kelly M. McNagny", "Xiaoxia Li", "Bruce A. Vallance"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003539.g009", "stats"=>{"downloads"=>2, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sigirr_8722_8722_mice_display_strong_antimicrobial_activity_against_commensal_microbes_/768000", "title"=>"<i>Sigirr −/−</i> mice display strong antimicrobial activity against commensal microbes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-08 03:28:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1147652"], "description"=>"<p>The cecal tissues from infected <i>Sigirr −/−</i> mice show increased abundance of IL-1α gene transcripts (A) as compared to WT mice. The <i>Sigirr −/−</i> mice also express increased levels of IL-1β protein in their cecal tissues under uninfected and <i>C. rodentium</i> infected conditions as measured by (B) ELISA and (C) Western blot. <i>Il-1r/Sigirr −/−</i> mice exhibit increased (D) mortality rates, (E) elevated pathogen burdens and (F) severe mucosal damage. The severe damage suffered by the <i>Il-1r/Sigirr −/−</i> mice was accompanied by impaired IEC proliferation as shown by (G) immunostaining for Ki-67 and by higher IEC permeability as quantified by (H) FD4 in serum. Pathogen counts represent mucosal associated bacteria. Results are pooled from 2–4 independent infections with n = 3–4 per group. Error bars = SEM, (Student t test (Figure A, B, E), one-way ANOVA (Figure G, H), *P<0.05, **P<0.01). Images were taken at 200× magnification.</p>", "links"=>[], "tags"=>["immunology", "immunity", "Immune defense", "Immune tolerance", "Immunity to infections", "immunoregulation", "Innate immunity", "Immune response", "Gastroenterology and hepatology", "Bacterial and foodborne illness", "Gastrointestinal infections", "Inflammatory bowel disease", "exaggerated", "iec", "responses"], "article_id"=>767998, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ho Pan Sham", "Emily Yi Shan Yu", "Muhammet F. Gulen", "Ganive Bhinder", "Martin Stahl", "Justin M. Chan", "Lara Brewster", "Vijay Morampudi", "Deanna L. Gibson", "Michael R. Hughes", "Kelly M. McNagny", "Xiaoxia Li", "Bruce A. Vallance"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003539.g007", "stats"=>{"downloads"=>2, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IL_1R_signaling_is_required_for_the_exaggerated_IEC_responses_in_Sigirr_8722_8722_mice_/767998", "title"=>"IL-1R signaling is required for the exaggerated IEC responses in <i>Sigirr −/−</i> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-08 03:28:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1147649"], "description"=>"<p>WT and <i>Sigirr−/−</i> mice were used to generate BM chimeric mice, which were then infected for 10 days with <i>C. rodentium</i>. Similar to <i>Sigirr −/−</i> mice, <i>Sigirr −/−</i> + WT BM mice displayed significantly heavier (A) pathogen burdens compared to WT mice. The ceca of <i>Sigirr −/−</i> + WT BM mice displayed (B) severe macroscopic and (C) histologic damage with significantly (D) greater pathology scores compared to WT and WT + <i>Sigirr−/−</i> BM mice. <i>Sigirr −/−</i> + WT BM mice exhibit higher levels of IEC proliferation as revealed by (E and F) Ki-67 staining. Pathogen counts represent mucosal associated bacteria. Results are pooled from 2 independent infections with n = 3–4 per group. Error bars = SEM, (Student t test (Figure A and D), One way ANOVA with Bonferroni posttest for (Figure F), *P<0.05, **P<0.01). Images were taken at 200× magnification.</p>", "links"=>[], "tags"=>["immunology", "immunity", "Immune defense", "Immune tolerance", "Immunity to infections", "immunoregulation", "Innate immunity", "Immune response", "Gastroenterology and hepatology", "Bacterial and foodborne illness", "Gastrointestinal infections", "Inflammatory bowel disease", "derived", "cells", "mediate", "sigirr-dependent", "mucosal"], "article_id"=>767995, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ho Pan Sham", "Emily Yi Shan Yu", "Muhammet F. Gulen", "Ganive Bhinder", "Martin Stahl", "Justin M. Chan", "Lara Brewster", "Vijay Morampudi", "Deanna L. Gibson", "Michael R. Hughes", "Kelly M. McNagny", "Xiaoxia Li", "Bruce A. Vallance"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003539.g004", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Non_BM_derived_cells_mediate_SIGIRR_dependent_mucosal_responses_/767995", "title"=>"Non-BM derived cells mediate SIGIRR-dependent mucosal responses.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-08 03:28:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1147648"], "description"=>"<p>Immunostaining for the proliferation marker (A) Ki-67 (red) revealed <i>Sigirr −/−</i> mice exhibit increased IEC proliferation in cecal tissues by D4 pi. (B) At D4, D6 and D10 pi, there are significantly more proliferating IEC in <i>Sigirr −/−</i> mice compared to WT mice. (C) WT and <i>Sigirr −/−</i> mice experience similar levels of barrier permeability following infection. (D) <i>Sigirr −/−</i> mice carry significantly higher gene transcript levels for antimicrobial peptides and chemokines compared to WT mice following cecal loop surgery. Results are representative of 4 independent infections with n = 3–4 per group. Error bars = SEM, (Student t test (Figure B and C), Mann-Whitney t test (Figure D), *P<0.05, **P<0.01).</p>", "links"=>[], "tags"=>["immunology", "immunity", "Immune defense", "Immune tolerance", "Immunity to infections", "immunoregulation", "Innate immunity", "Immune response", "Gastroenterology and hepatology", "Bacterial and foodborne illness", "Gastrointestinal infections", "Inflammatory bowel disease", "stronger", "inflammatory", "responses"], "article_id"=>767994, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ho Pan Sham", "Emily Yi Shan Yu", "Muhammet F. Gulen", "Ganive Bhinder", "Martin Stahl", "Justin M. Chan", "Lara Brewster", "Vijay Morampudi", "Deanna L. Gibson", "Michael R. Hughes", "Kelly M. McNagny", "Xiaoxia Li", "Bruce A. Vallance"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003539.g003", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sigirr_8722_8722_mice_exhibit_stronger_inflammatory_responses_during_C_rodentium_infection_/767994", "title"=>"<i>Sigirr −/− mice</i> exhibit stronger inflammatory responses during <i>C. rodentium</i> infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-08 03:28:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1147651"], "description"=>"<p>WT and <i>Sigirr −/−</i> mice were intra-peritoneally injected twice with anakinra (1 mg/mouse) each day for 6 days, or with PBS during <i>C. rodentium</i> infection. Anakinra treatment did not impact on pathogen burdens in infected mice (A) however treatment with anakinra ameliorated macroscopic ulceration in infected <i>Sigirr −/−</i> mice (B–C) along with reducing edema and improving epithelial integrity (D–E). Immunostaining for the proliferation marker Ki-67 demonstrated treatment with anakinra reduced the elevated IEC proliferation observed in <i>Sigirr −/−</i> mice (F). Pathogen counts represent mucosal associated bacteria. Results are pooled from 2 independent infections each with n = 3–4 per group. Error bars = SEM, (Student t test (Figure A, C), *P<0.05, **P<0.01). Images were taken at 200× magnification.</p>", "links"=>[], "tags"=>["immunology", "immunity", "Immune defense", "Immune tolerance", "Immunity to infections", "immunoregulation", "Innate immunity", "Immune response", "Gastroenterology and hepatology", "Bacterial and foodborne illness", "Gastrointestinal infections", "Inflammatory bowel disease", "exaggerated", "colitis", "seen", "mice", "attenuated", "il-1r", "antagonist"], "article_id"=>767997, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ho Pan Sham", "Emily Yi Shan Yu", "Muhammet F. Gulen", "Ganive Bhinder", "Martin Stahl", "Justin M. Chan", "Lara Brewster", "Vijay Morampudi", "Deanna L. Gibson", "Michael R. Hughes", "Kelly M. McNagny", "Xiaoxia Li", "Bruce A. Vallance"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003539.g006", "stats"=>{"downloads"=>2, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_exaggerated_colitis_seen_in_the_Sigirr_8722_8722_mice_is_attenuated_by_treatment_with_the_IL_1R_antagonist_anakinra_/767997", "title"=>"The exaggerated colitis seen in the <i>Sigirr −/−</i> mice is attenuated by treatment with the IL-1R antagonist anakinra.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-08 03:28:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1147650"], "description"=>"<p>WT, <i>Sigirr −/−</i>, <i>Myd88/Sigirr −/−</i>, <i>Tlr2/Sigirr −/−</i>, and <i>Tlr4/Sigirr −/−</i> mice were infected by <i>C. rodentium</i> for 6 and 10 days. (A) <i>Myd88/Sigirr −/−</i> mice required euthanization by D8 pi whereas the other mouse groups survived the infection. (B) All mice on a <i>Sigirr −/−</i> background carried significantly heavier pathogen burdens and (C) showed more severe colitis compared to WT mice at D6 and D10 pi. (C–D) Immunostaining for the proliferation marker Ki-67 demonstrated infected <i>Sigirr−/−</i>, <i>Tlr2/Sigirr −/−</i> and <i>Tlr4/Sigirr −/−</i> display elevated IEC proliferation compared to WT mice. (E) phospho STAT-3 staining is restored in <i>Tlr2/Sigirr −/−</i> mice, while (F) the heightened barrier disruption seen in infected <i>Tlr2−/−</i> mice is normalized in <i>Tlr2/Sigirr −/−</i> mice. Pathogen counts represent mucosal associated bacteria. Results are pooled from 2–3 independent infections, each with n = 3–4 per group. Error bars = SEM, (Student t test (Figure B, D) and one way ANOVA (Figure D), *P<0.05, **P<0.01). Images were taken at 200× magnification.</p>", "links"=>[], "tags"=>["immunology", "immunity", "Immune defense", "Immune tolerance", "Immunity to infections", "immunoregulation", "Innate immunity", "Immune response", "Gastroenterology and hepatology", "Bacterial and foodborne illness", "Gastrointestinal infections", "Inflammatory bowel disease", "infected"], "article_id"=>767996, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ho Pan Sham", "Emily Yi Shan Yu", "Muhammet F. Gulen", "Ganive Bhinder", "Martin Stahl", "Justin M. Chan", "Lara Brewster", "Vijay Morampudi", "Deanna L. Gibson", "Michael R. Hughes", "Kelly M. McNagny", "Xiaoxia Li", "Bruce A. Vallance"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003539.g005", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MyD88_signaling_is_required_for_the_survival_of_infected_Sigrr_8722_8722_mice_/767996", "title"=>"MyD88 signaling is required for the survival of infected <i>Sigrr −/−</i> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-08 03:28:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1147647"], "description"=>"<p><i>Sigirr −/−</i> mice exhibited (A) rapid weight loss by D4 pi. At both D6 and D10 pi, (B–C) their ceca displayed severe damage, with loss of stool contents and focal ulcers. (D) Cecal tissues from <i>Sigirr −/−</i> mice had significantly higher pathology scores at D6 and D10 pi compared to WT mice. Plating revealed <i>Sigirr −/−</i> mice carried significantly higher pathogen burdens than WT mice in (E) cecal and colonic tissues, but their burdens were similar in (F) liver or spleens. Pathogen counts represent mucosal associated bacteria. Results are pooled from 2 independent infections with n = 3–4 per group. Error bars = SEM, (Two-way ANOVA (Figure A), Student t test (Figure D, E, and F, *P<0.05, **P<0.01). Images were taken at 200× magnification.</p>", "links"=>[], "tags"=>["immunology", "immunity", "Immune defense", "Immune tolerance", "Immunity to infections", "immunoregulation", "Innate immunity", "Immune response", "Gastroenterology and hepatology", "Bacterial and foodborne illness", "Gastrointestinal infections", "Inflammatory bowel disease", "mice", "colitis"], "article_id"=>767993, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ho Pan Sham", "Emily Yi Shan Yu", "Muhammet F. Gulen", "Ganive Bhinder", "Martin Stahl", "Justin M. Chan", "Lara Brewster", "Vijay Morampudi", "Deanna L. Gibson", "Michael R. Hughes", "Kelly M. McNagny", "Xiaoxia Li", "Bruce A. Vallance"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003539.g002", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sigirr__mice_suffer_more_severe_colitis_during_C_rodentium_infection_/767993", "title"=>"<i>Sigirr</i> −/− mice suffer more severe colitis during <i>C. rodentium</i> infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-08 03:28:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1147646"], "description"=>"<p><i>Myd88</i> −/−, <i>Myd88</i> flox and IEC-<i>Myd88</i> −/− mice were infected for 6 days with <i>C. rodentium</i>. Infected IEC-<i>Myd88</i> −/− mice carried similar (A) pathogen burdens, (B) levels of serum FD4, and (C–D) similar mucosal damage as <i>Myd88</i> flox mice. Moreover all of these readouts are significantly greater in <i>Myd88</i> −/− mice, as compared to <i>Myd88</i> flox and IEC-<i>Myd88</i> −/− mice. Pathogen counts represent mucosal associated bacteria. Results are pooled from 2 independent infections with n = 3–4 mice per group. Error bars = SEM, (Student t test *P<0.05, ** P<0.01). Images were taken at 200× magnification.</p>", "links"=>[], "tags"=>["immunology", "immunity", "Immune defense", "Immune tolerance", "Immunity to infections", "immunoregulation", "Innate immunity", "Immune response", "Gastroenterology and hepatology", "Bacterial and foodborne illness", "Gastrointestinal infections", "Inflammatory bowel disease", "iec"], "article_id"=>767992, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ho Pan Sham", "Emily Yi Shan Yu", "Muhammet F. Gulen", "Ganive Bhinder", "Martin Stahl", "Justin M. Chan", "Lara Brewster", "Vijay Morampudi", "Deanna L. Gibson", "Michael R. Hughes", "Kelly M. McNagny", "Xiaoxia Li", "Bruce A. Vallance"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003539.g001", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MyD88_signaling_in_IEC_is_not_required_for_protection_against_C_rodentium_infection_/767992", "title"=>"MyD88 signaling in IEC is not required for protection against <i>C. rodentium</i> infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-08 03:28:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1147655", "https://ndownloader.figshare.com/files/1147656", "https://ndownloader.figshare.com/files/1147657", "https://ndownloader.figshare.com/files/1147658", "https://ndownloader.figshare.com/files/1147659"], "description"=>"<div><p>Enteric bacterial pathogens such as enterohemorrhagic <i>E. coli</i> (EHEC) and <i>Salmonella</i> Typhimurium target the intestinal epithelial cells (IEC) lining the mammalian gastrointestinal tract. Despite expressing innate Toll-like receptors (TLRs), IEC are innately hypo-responsive to most bacterial products. This is thought to prevent maladaptive inflammatory responses against commensal bacteria, but it also limits antimicrobial responses by IEC to invading bacterial pathogens, potentially increasing host susceptibility to infection. One reason for the innate hypo-responsiveness of IEC is their expression of Single Ig IL-1 Related Receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and TLR signaling. To address whether SIGIRR expression and the innate hypo-responsiveness of IEC impacts on enteric host defense, <i>Sigirr</i> deficient (−/−) mice were infected with the EHEC related pathogen <i>Citrobacter rodentium</i>. <i>Sigirr −/−</i> mice responded with accelerated IEC proliferation and strong pro-inflammatory and antimicrobial responses but surprisingly, <i>Sigirr −/−</i> mice proved dramatically more susceptible to infection than wildtype mice. Through haematopoietic transplantation studies, it was determined that SIGIRR expression by non-haematopoietic cells (putative IEC) regulated these responses. Moreover, the exaggerated responses were found to be primarily dependent on IL-1R signaling. Whilst exploring the basis for their susceptibility, <i>Sigirr −/−</i> mice were found to be unusually susceptible to intestinal <i>Salmonella</i> Typhimurium colonization, developing enterocolitis without the typical requirement for antibiotic based removal of competing commensal microbes. Strikingly, the exaggerated antimicrobial responses seen in <i>Sigirr −/−</i> mice were found to cause a rapid and dramatic loss of commensal microbes from the infected intestine. This depletion appears to reduce the ability of the microbiota to compete for space and nutrients (colonization resistance) with the invading pathogens, leaving the intestine highly susceptible to pathogen colonization. Thus, SIGIRR expression by IEC reflects a strategy that sacrifices maximal innate responsiveness by IEC in order to promote commensal microbe based colonization resistance against bacterial pathogens.</p></div>", "links"=>[], "tags"=>["immunology", "immunity", "Immune defense", "Immune tolerance", "Immunity to infections", "immunoregulation", "Innate immunity", "Immune response", "Gastroenterology and hepatology", "Bacterial and foodborne illness", "Gastrointestinal infections", "Inflammatory bowel disease", "signalling", "microbiota", "colonization", "enteric", "bacterial"], "article_id"=>768001, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ho Pan Sham", "Emily Yi Shan Yu", "Muhammet F. Gulen", "Ganive Bhinder", "Martin Stahl", "Justin M. Chan", "Lara Brewster", "Vijay Morampudi", "Deanna L. Gibson", "Michael R. Hughes", "Kelly M. McNagny", "Xiaoxia Li", "Bruce A. Vallance"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003539.s001", "https://dx.doi.org/10.1371/journal.ppat.1003539.s002", "https://dx.doi.org/10.1371/journal.ppat.1003539.s003", "https://dx.doi.org/10.1371/journal.ppat.1003539.s004", "https://dx.doi.org/10.1371/journal.ppat.1003539.s005"], "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SIGIRR_a_Negative_Regulator_of_TLR_IL_1R_Signalling_Promotes_Microbiota_Dependent_Resistance_to_Colonization_by_Enteric_Bacterial_Pathogens_/768001", "title"=>"SIGIRR, a Negative Regulator of TLR/IL-1R Signalling Promotes Microbiota Dependent Resistance to Colonization by Enteric Bacterial Pathogens", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-08-08 03:28:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/1147653"], "description"=>"<p>(A) <i>Sigirr −/−</i> mice were heavily colonized by 100× lower dose (LD) of <i>C. rodentium</i> by D2 pi. By D10 pi, <i>Sigirr −/−</i> mice carried 1000× heavier (B) pathogen burdens and developed severe mucosal damage compared to WT mice. (C) WT and <i>Sigirr −/−</i> mice infected by <i>S.</i> Typhimurium without streptomycin pre-treatment. By D7 pi, <i>Sigirr −/−</i> mice were heavily colonized and underwent extensive cecal injury. Pathogen counts represent mucosal associated bacteria. Results are pooled from 2–3 independent infections with n = 3 per group. Error bars = SEM, (Two-way ANOVA (Figure A), Student t test (Figures B and C), *P<0.05, **P<0.01)). Histological images were taken at 100× magnification.</p>", "links"=>[], "tags"=>["immunology", "immunity", "Immune defense", "Immune tolerance", "Immunity to infections", "immunoregulation", "Innate immunity", "Immune response", "Gastroenterology and hepatology", "Bacterial and foodborne illness", "Gastrointestinal infections", "Inflammatory bowel disease", "mice", "susceptible", "enteric"], "article_id"=>767999, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Ho Pan Sham", "Emily Yi Shan Yu", "Muhammet F. Gulen", "Ganive Bhinder", "Martin Stahl", "Justin M. Chan", "Lara Brewster", "Vijay Morampudi", "Deanna L. Gibson", "Michael R. Hughes", "Kelly M. McNagny", "Xiaoxia Li", "Bruce A. Vallance"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003539.g008", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sigirr_8722_8722_mice_are_highly_susceptible_to_enteric_infection_/767999", "title"=>"<i>Sigirr −/−</i> mice are highly susceptible to enteric infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-08 03:28:30"}

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Relative Metric

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