STAT2 dependent Type I Interferon response promotes dysbiosis and luminal expansion of the enteric pathogen Salmonella Typhimurium

The mechanisms by which the gut luminal environment is disturbed by the immune system to foster pathogenic bacterial growth and survival remain incompletely understood. Here, we show that STAT2 dependent type I IFN signaling contributes to the inflammatory environment by disrupting hypoxia enabling the pathogenic S. Typhimurium to outgrow the microbiota. Stat2-/- mice infected with S. Typhimurium exhibited impaired type I IFN induced transcriptional responses in cecal tissue and reduced bacterial burden in the intestinal lumen compared to infected wild-type mice. Although inflammatory pathology was similar between wild-type and Stat2-/- mice, we observed decreased hypoxia in the gut tissue of Stat2-/- mice. Neutrophil numbers were similar in wild-type and Stat2-/- mice, yet Stat2-/- mice showed reduced levels of myeloperoxidase activity. In vitro, the neutrophils from Stat2-/- mice produced lower levels of superoxide anion upon stimulation with the bacterial ligand N-formylmethionyl-leucyl-phenylalanine (fMLP) in the presence of IFNα compared to neutrophils from wild-type mice, indicating that the neutrophils were less functional in Stat2-/- mice. Cytochrome bd-II oxidase-mediated respiration enhances S. Typhimurium fitness in wild-type mice, while in Stat2-/- deficiency, this respiratory pathway did not provide a fitness advantage. Furthermore, luminal expansion of S. Typhimurium in wild-type mice was blunted in Stat2-/- mice. Compared to wild-type mice which exhibited a significant perturbation in Bacteroidetes abundance, Stat2-/- mice exhibited significantly less perturbation and higher levels of Bacteroidetes upon S. Typhimurium infection. Our results highlight STAT2 dependent type I IFN mediated inflammation in the gut as a novel mechanism promoting luminal expansion of S. Typhimurium.

[1]  E. Liverani,et al.  Protein Kinase C-Delta (PKC&dgr;) Tyrosine Phosphorylation is a Critical Regulator of Neutrophil-Endothelial Cell Interaction in Inflammation , 2019, Shock.

[2]  Andrew Y. Koh,et al.  Precision editing of the gut microbiota ameliorates colitis , 2018, Nature.

[3]  C. Lebrilla,et al.  Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion , 2017, Science.

[4]  H. Andrews-Polymenis,et al.  Respiration of Microbiota-Derived 1,2-propanediol Drives Salmonella Expansion during Colitis , 2017, PLoS pathogens.

[5]  Fachao Zhi,et al.  Lower Level of Bacteroides in the Gut Microbiota Is Associated with Inflammatory Bowel Disease: A Meta-Analysis , 2016, BioMed research international.

[6]  Fariborz Soroush,et al.  A novel microfluidic assay reveals a key role for protein kinase C δ in regulating human neutrophil–endothelium interaction , 2016, Journal of leukocyte biology.

[7]  Fabian Rivera-Chávez,et al.  Energy Taxis toward Host-Derived Nitrate Supports a Salmonella Pathogenicity Island 1-Independent Mechanism of Invasion , 2016, mBio.

[8]  C. Lebrilla,et al.  Depletion of Butyrate-Producing Clostridia from the Gut Microbiota Drives an Aerobic Luminal Expansion of Salmonella. , 2016, Cell host & microbe.

[9]  D. Golenbock,et al.  Type I Interferon Transcriptional Signature in Neutrophils and Low-Density Granulocytes Are Associated with Tissue Damage in Malaria. , 2015, Cell reports.

[10]  M. Wolfson,et al.  Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-δ Inhibitory Peptide: Impact on Indirect Lung Injury , 2015, The Journal of Pharmacology and Experimental Therapeutics.

[11]  Tracy K. Teal,et al.  Intestinal microbial communities associated with acute enteric infections and disease recovery , 2015, Microbiome.

[12]  G. Ramachandran,et al.  Salmonella Typhimurium Co-Opts the Host Type I IFN System To Restrict Macrophage Innate Immune Transcriptional Responses Selectively , 2015, The Journal of Immunology.

[13]  Courtney R. Plumlee,et al.  Different STAT Transcription Complexes Drive Early and Delayed Responses to Type I IFNs , 2015, The Journal of Immunology.

[14]  A. Bäumler,et al.  Now you see me, now you don't: the interaction of Salmonella with innate immune receptors , 2015, Nature Reviews Microbiology.

[15]  K. Błaszczyk,et al.  STAT2/IRF9 directs a prolonged ISGF3-like transcriptional response and antiviral activity in the absence of STAT1 , 2015, The Biochemical journal.

[16]  K. Błaszczyk,et al.  STAT 2 / IRF 9 directs a prolonged ISGF 3-like transcriptional response and antiviral activity in the absence of STAT 1 , 2015 .

[17]  E. Tuomanen,et al.  Type I Interferon Protects against Pneumococcal Invasive Disease by Inhibiting Bacterial Transmigration across the Lung , 2013, PLoS pathogens.

[18]  Myeong Sup Lee,et al.  Negative Regulation of Type I IFN Expression by OASL1 Permits Chronic Viral Infection and CD8+ T-Cell Exhaustion , 2013, PLoS pathogens.

[19]  R. Goldin,et al.  Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis , 2013, Proceedings of the National Academy of Sciences.

[20]  Sanjai J. Parikh,et al.  Host-Derived Nitrate Boosts Growth of E. coli in the Inflamed Gut , 2013, Science.

[21]  L. Engstrand,et al.  Intestinal microbial profiles in extremely preterm infants with and without necrotizing enterocolitis , 2013, Acta paediatrica.

[22]  D. Monack,et al.  Noncanonical Inflammasomes: Caspase-11 Activation and Effector Mechanisms , 2013, PLoS pathogens.

[23]  Fatema Z. Chowdhury,et al.  STAT2: A shape-shifting anti-viral super STAT. , 2013, JAK-STAT.

[24]  B. Finlay,et al.  Neutrophil Elastase Alters the Murine Gut Microbiota Resulting in Enhanced Salmonella Colonization , 2012, PloS one.

[25]  D. Ganea,et al.  Microbial Amyloids Induce Interleukin 17A (IL-17A) and IL-22 Responses via Toll-Like Receptor 2 Activation in the Intestinal Mucosa , 2012, Infection and Immunity.

[26]  Timothy L. Tickle,et al.  Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment , 2012, Genome Biology.

[27]  Kamila Belhocine,et al.  Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1 , 2012, Nature.

[28]  D. Monack,et al.  Innate immune response to Salmonella typhimurium, a model enteric pathogen , 2012, Gut microbes.

[29]  Liping Zhao,et al.  Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers , 2011, The ISME Journal.

[30]  Jinfeng Liu,et al.  Non-canonical inflammasome activation targets caspase-11 , 2011, Nature.

[31]  Sunny Shin,et al.  Dissection of a type I interferon pathway in controlling bacterial intracellular infection in mice , 2011, Cellular microbiology.

[32]  D. Monack,et al.  Molecular mechanisms of inflammasome activation during microbial infections , 2011, Immunological reviews.

[33]  P. Kovarik,et al.  Type I Interferon Production Induced by Streptococcus pyogenes-Derived Nucleic Acids Is Required for Host Protection , 2011, PLoS pathogens.

[34]  C. Schindler,et al.  STAT2 Mediates Innate Immunity to Dengue Virus in the Absence of STAT1 via the Type I Interferon Receptor , 2011, PLoS pathogens.

[35]  Courtney R. Plumlee,et al.  Mouse STAT2 restricts early dengue virus replication. , 2010, Cell host & microbe.

[36]  J. Roth,et al.  Gut inflammation provides a respiratory electron acceptor for Salmonella , 2010, Nature.

[37]  D. Vargas-Inchaustegui,et al.  Type I IFN Receptor Regulates Neutrophil Functions and Innate Immunity to Leishmania Parasites , 2010, The Journal of Immunology.

[38]  T. Vary,et al.  Regulation of TNF‐induced oxygen radical production in human neutrophils: role of δ‐PKC , 2010, Journal of leukocyte biology.

[39]  C. Bevins,et al.  Life in the inflamed intestine, Salmonella style. , 2009, Trends in microbiology.

[40]  N. Pace,et al.  Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. , 2008, Cell host & microbe.

[41]  Samuel I. Miller,et al.  Salmonellae interplay with host cells , 2008, Nature Reviews Microbiology.

[42]  J. Johndrow,et al.  The Type I IFN Response to Infection with Mycobacterium tuberculosis Requires ESX-1-Mediated Secretion and Contributes to Pathogenesis1 , 2007, The Journal of Immunology.

[43]  R. Preissner,et al.  Legionella pneumophila Induces IFNβ in Lung Epithelial Cells via IPS-1 and IRF3, Which Also Control Bacterial Replication* , 2006, Journal of Biological Chemistry.

[44]  U. Gophna,et al.  Differences between Tissue-Associated Intestinal Microfloras of Patients with Crohn's Disease and Ulcerative Colitis , 2006, Journal of Clinical Microbiology.

[45]  E. Purdom,et al.  Diversity of the Human Intestinal Microbial Flora , 2005, Science.

[46]  D. Jack,et al.  Gamma Interferon Enhances Internalization and Early Nonoxidative Killing of Salmonella enterica Serovar Typhimurium by Human Macrophages and Modifies Cytokine Responses , 2005, Infection and Immunity.

[47]  E. Zúñiga,et al.  Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling. , 2005, Immunity.

[48]  E. Proietti,et al.  Type I IFN Protects Permissive Macrophages from Legionella pneumophila Infection through an IFN-γ-Independent Pathway1 , 2004, The Journal of Immunology.

[49]  S. Falkow,et al.  Salmonella typhimurium Persists within Macrophages in the Mesenteric Lymph Nodes of Chronically Infected Nramp1 + / + Mice and Can Be Reactivated by IFNγ Neutralization , 2004, The Journal of experimental medicine.

[50]  M. Hensel,et al.  Role of Neutrophils in Murine Salmonellosis , 2004, Infection and Immunity.

[51]  M. Dion,et al.  A new oxygen-regulated operon in Escherichia coli comprises the genes for a putative third cytochrome oxidase and for pH 2.5 acid phosphatase (appA) , 1991, Molecular and General Genetics MGG.

[52]  A. Mócsai,et al.  G-protein-coupled receptor signaling in Syk-deficient neutrophils and mast cells. , 2003, Blood.

[53]  Michael Weiden,et al.  Inhibition of Response to Alpha Interferon by Mycobacterium tuberculosis , 2003, Infection and Immunity.

[54]  J. Doré,et al.  Alterations of the dominant faecal bacterial groups in patients with Crohn's disease of the colon , 2003, Gut.

[55]  R. Wilson,et al.  Complete genome sequence of Salmonella enterica serovar Typhimurium LT2 , 2001, Nature.

[56]  F. Fang,et al.  Periplasmic superoxide dismutase protects Salmonella from products of phagocyte NADPH-oxidase and nitric oxide synthase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[57]  J. Shea,et al.  Simultaneous identification of bacterial virulence genes by negative selection. , 1995, Science.

[58]  S. Miller,et al.  Transepithelial signaling to neutrophils by salmonellae: a novel virulence mechanism for gastroenteritis , 1995, Infection and immunity.

[59]  F. Heffron,et al.  Ethanolamine utilization in Salmonella typhimurium: nucleotide sequence, protein expression, and mutational analysis of the cchA cchB eutE eutJ eutG eutH gene cluster , 1995, Journal of bacteriology.

[60]  T. Atlung,et al.  Role of the transcriptional activator AppY in regulation of the cyx appA operon of Escherichia coli by anaerobiosis, phosphate starvation, and growth phase , 1994, Journal of bacteriology.

[61]  P. Mäkelä,et al.  The role of IFN-γ in murine Salmonella typhimurium infection , 1990 .

[62]  J. Galán,et al.  Cloning and molecular characterization of genes whose products allow Salmonella typhimurium to penetrate tissue culture cells. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[63]  J. Lindenmann,et al.  Virus interference. I. The interferon. By A. Isaacs and J. Lindenmann, 1957. , 1987, Journal of interferon research.

[64]  J. Lindenmann,et al.  Virus interference. I. The interferon , 1957, Proceedings of the Royal Society of London. Series B - Biological Sciences.