An innate granuloma eradicates an environmental pathogen using Gsdmd and Nos2

Granulomas often form around pathogens that cause chronic infections. Here, we discover a novel granuloma model in mice. Chromobacterium violaceum is an environmental bacterium that stimulates granuloma formation that not only successfully walls off but also clears the infection. The infected lesion can arise from a single bacterium that replicates in the presence of a neutrophil swarm. Bacterial replication ceases when macrophages organize around the infection and form a granuloma. This granuloma response is accomplished independently of adaptive immunity that is typically required to organize granulomas. The C. violaceum-induced granuloma requires at least two separate defense pathways, gasdermin D and iNOS, to maintain the integrity of the granuloma architecture. These innate granulomas successfully eradicate C. violaceum infection. Therefore, this new C. violaceum-induced granuloma model demonstrates that innate immune cells successfully organize a granuloma and thereby eradicate infection by an environmental pathogen.

[1]  Yang Yu,et al.  A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin , 2022, Science.

[2]  Nathaniel J. Moorman,et al.  Caspase-7 activates ASM to repair gasdermin and perforin pores , 2022, Nature.

[3]  J. Weiss,et al.  Mycobacterium tuberculosis Induces Irg1 in Murine Macrophages by a Pathway Involving Both TLR-2 and STING/IFNAR Signaling and Requiring Bacterial Phagocytosis , 2022, Frontiers in Cellular and Infection Microbiology.

[4]  Zilin Li,et al.  Calmodulin Binding Activates Chromobacterium CopC Effector to ADP-Riboxanate Host Apoptotic Caspases , 2022, mBio.

[5]  Q. Zhu,et al.  Pathogen hijacks programmed cell death signaling by arginine ADPR-deacylization of caspases. , 2022, Molecular cell.

[6]  E. Miao,et al.  Innate Sensors Trigger Regulated Cell Death to Combat Intracellular Infection. , 2022, Annual review of immunology.

[7]  E. Radaelli,et al.  Inflammatory monocytes promote pyogranuloma formation to counteract Yersinia blockade of host defense , 2022, bioRxiv.

[8]  G. Takaesu,et al.  GRIM‐19 is a target of mycobacterial Zn2+ metalloprotease 1 and indispensable for NLRP3 inflammasome activation , 2021, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  G. Atwal,et al.  Single-cell RNA transcriptome landscape of hepatocytes and non-parenchymal cells in healthy and NAFLD mouse liver , 2021, iScience.

[10]  Sara B Ellinwood,et al.  Mycobacterium tuberculosis inhibits the NLRP3 inflammasome activation via its phosphokinase PknF , 2021, PLoS pathogens.

[11]  G. Du,et al.  Chrysomycin A Attenuates Neuroinflammation by Down-Regulating NLRP3/Cleaved Caspase-1 Signaling Pathway in LPS-Stimulated Mice and BV2 Cells , 2021, International journal of molecular sciences.

[12]  Raphael Gottardo,et al.  Integrated analysis of multimodal single-cell data , 2020, Cell.

[13]  A. Sher,et al.  PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques , 2020, Science Immunology.

[14]  Yan Xie,et al.  Mycobacterial EST12 activates a RACK1–NLRP3–gasdermin D pyroptosis–IL-1β immune pathway , 2020, Science Advances.

[15]  Y. Saeys,et al.  Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver , 2020, Immunity.

[16]  R. Adigun,et al.  Cell Liquefactive Necrosis , 2020 .

[17]  Xiaodu Wang,et al.  Mycobacterial PPE13 activates inflammasome by interacting with the NATCH and LRR domains of NLRP3 , 2020, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  J. Galán,et al.  Itaconate is an effector of a Rab GTPase cell-autonomous host defense pathway against Salmonella , 2020, Science.

[19]  B. Mishra,et al.  Granulocytes act as a niche for Mycobacterium tuberculosis growth , 2020, Mucosal Immunology.

[20]  S. Oliveira,et al.  NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection , 2020, Frontiers in Immunology.

[21]  B. Robertson,et al.  Genetic and pharmacological inhibition of inflammasomes reduces the survival of Mycobacterium tuberculosis strains in macrophages , 2020, Scientific Reports.

[22]  A. Prasse,et al.  The NLRP3 inflammasome pathway is activated in sarcoidosis and involved in granuloma formation , 2020, European Respiratory Journal.

[23]  H. Stenmark,et al.  Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection , 2019, bioRxiv.

[24]  J. Mecsas.  Unraveling neutrophil– Yersinia interactions during tissue infection , 2019, F1000Research.

[25]  Marie Nguyen,et al.  The Ultimate qPCR Experiment: Producing Publication Quality, Reproducible Data the First Time. , 2019, Trends in biotechnology.

[26]  D. Kaushal,et al.  The current state of animal models and genomic approaches towards identifying and validating molecular determinants of Mycobacterium tuberculosis infection and tuberculosis disease , 2019, Pathogens and disease.

[27]  M. Artyomov,et al.  Itaconate: the poster child of metabolic reprogramming in macrophage function , 2019, Nature Reviews Immunology.

[28]  O. Tirosh,et al.  iNOS as a metabolic enzyme under stress conditions. , 2019, Free radical biology & medicine.

[29]  P. Fallon,et al.  Schistosoma “Eggs-Iting” the Host: Granuloma Formation and Egg Excretion , 2018, Front. Immunol..

[30]  Michael Y. Gerner,et al.  Alveolar Macrophages Provide an Early Mycobacterium tuberculosis Niche and Initiate Dissemination. , 2018, Cell host & microbe.

[31]  Kimberly M. Davis,et al.  All Yersinia Are Not Created Equal: Phenotypic Adaptation to Distinct Niches Within Mammalian Tissues , 2018, Front. Cell. Infect. Microbiol..

[32]  L. Ramakrishnan,et al.  The Formation and Function of Granulomas. , 2018, Annual review of immunology.

[33]  D. Russell,et al.  Growth of Mycobacterium tuberculosis in vivo segregates with host macrophage metabolism and ontogeny , 2018, The Journal of experimental medicine.

[34]  Maxim N. Artyomov,et al.  Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection , 2018, The Journal of experimental medicine.

[35]  Leland McInnes,et al.  UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction , 2018, ArXiv.

[36]  J. Lakshmanan,et al.  Cell-specific regulation of iNOS by AMP-activated protein kinase in primary rat hepatocytes. , 2018, The Journal of surgical research.

[37]  Yue Zhang,et al.  CCR2+ Inflammatory Monocytes Are Recruited to Yersinia pseudotuberculosis Pyogranulomas and Dictate Adaptive Responses at the Expense of Innate Immunity during Oral Infection , 2017, Infection and Immunity.

[38]  J. F. da Silva Neto,et al.  Chromobacterium violaceum Pathogenicity: Updates and Insights from Genome Sequencing of Novel Chromobacterium Species , 2017, Front. Microbiol..

[39]  D. Green,et al.  RIPK1-dependent apoptosis bypasses pathogen blockade of innate signaling to promote immune defense , 2017, The Journal of experimental medicine.

[40]  B. Corleis,et al.  M. tuberculosis-Induced Necrosis of Infected Neutrophils Promotes Bacterial Growth Following Phagocytosis by Macrophages. , 2017, Cell host & microbe.

[41]  S. Fortune,et al.  Heterogeneity in tuberculosis , 2017, Nature Reviews Immunology.

[42]  Chuan Qin,et al.  Animal Models for Tuberculosis in Translational and Precision Medicine , 2017, Front. Microbiol..

[43]  I. Brodsky,et al.  NAIP‐NLRC4 Inflammasomes Coordinate Intestinal Epithelial Cell Expulsion with Eicosanoid and IL‐18 Release via Activation of Caspase‐1 and ‐8 , 2017, Immunity.

[44]  L. Ramakrishnan,et al.  A Zebrafish Model of Mycobacterium leprae Granulomatous Infection , 2017, bioRxiv.

[45]  Xinchun Chen,et al.  Nitric oxide prevents a pathogen permissive granulocytic inflammation during tuberculosis , 2017, Nature Microbiology.

[46]  B. Pritt,et al.  Histopathologic review of granulomatous inflammation , 2017, Journal of clinical tuberculosis and other mycobacterial diseases.

[47]  M. V. van Zelm,et al.  Immunopathogenesis of granulomas in chronic autoinflammatory diseases , 2016, Clinical & translational immunology.

[48]  K. Boini,et al.  Activation of NLRP3 inflammasomes in mouse hepatic stellate cells during Schistosoma J. infection , 2016, Oncotarget.

[49]  Charles H. Yoon,et al.  Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq , 2016, Science.

[50]  M. Mann,et al.  Inflammatory signaling in human Tuberculosis granulomas is spatially organized , 2016, Nature Medicine.

[51]  P. Kaye,et al.  Lessons from other diseases: granulomatous inflammation in leishmaniasis , 2015, Seminars in Immunopathology.

[52]  S. Holland,et al.  Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium. , 2015, Immunity.

[53]  L. Lamps.  Hepatic Granulomas: A Review With Emphasis on Infectious Causes. , 2015, Archives of pathology & laboratory medicine.

[54]  Kimberly M. Davis,et al.  Community behavior and spatial regulation within a bacterial microcolony in deep tissue sites serves to protect against host attack. , 2015, Cell host & microbe.

[55]  I. Orme,et al.  The formation of the granuloma in tuberculosis infection. , 2014, Seminars in immunology.

[56]  Jin Hee Kim,et al.  Microenvironments in Tuberculous Granulomas Are Delineated by Distinct Populations of Macrophage Subsets and Expression of Nitric Oxide Synthase and Arginase Isoforms , 2013, The Journal of Immunology.

[57]  L. Schlesinger,et al.  Mini Review Article , 2022 .

[58]  Hardy Kornfeld,et al.  Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome–dependent processing of IL-1β , 2012, Nature Immunology.

[59]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[60]  K. Takeda,et al.  Critical role of AIM2 in Mycobacterium tuberculosis infection. , 2012, International immunology.

[61]  Philip S Crosier,et al.  Neutrophils exert protection in the early tuberculous granuloma by oxidative killing of mycobacteria phagocytosed from infected macrophages. , 2012, Cell host & microbe.

[62]  Jian Ye,et al.  Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction , 2012, BMC Bioinformatics.

[63]  L. Ramakrishnan.  Revisiting the role of the granuloma in tuberculosis , 2012, Nature Reviews Immunology.

[64]  J. Tschopp,et al.  Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis , 2012, European journal of immunology.

[65]  Patrick S. Aranda,et al.  Bleach gel: A simple agarose gel for analyzing RNA quality , 2012, Electrophoresis.

[66]  T. Miki,et al.  The Chromobacterium violaceum type III effector CopE, a guanine nucleotide exchange factor for Rac1 and Cdc42, is involved in bacterial invasion of epithelial cells and pathogenesis , 2011, Molecular microbiology.

[67]  M. Braunstein,et al.  Granuloma Formation and Host Defense in Chronic Mycobacterium tuberculosis Infection Requires PYCARD/ASC but Not NLRP3 or Caspase-1 , 2010, PloS one.

[68]  T. Miki,et al.  Chromobacterium pathogenicity island 1 type III secretion system is a major virulence determinant for Chromobacterium violaceum‐induced cell death in hepatocytes , 2010, Molecular microbiology.

[69]  N. Hacohen,et al.  Mycobacterium tuberculosis protein ESAT‐6 is a potent activator of the NLRP3/ASC inflammasome , 2010, Cellular microbiology.

[70]  D. Underhill,et al.  Faculty Opinions recommendation of Caspase-1 independent IL-1beta production is critical for host resistance to mycobacterium tuberculosis and does not require TLR signaling in vivo. , 2010 .

[71]  L. Kobzik,et al.  Immunopathology and Infectious Diseases Dominant Role of the sst 1 Locus in Pathogenesis of Necrotizing Lung Granulomas during Chronic Tuberculosis Infection and Reactivation in Genetically Resistant Hosts , 2010 .

[72]  S. Ehlers,et al.  Mycobacterium tuberculosis prevents inflammasome activation. , 2008, Cell host & microbe.

[73]  Ronald N Germain,et al.  Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas. , 2008, Immunity.

[74]  David G. Russell,et al.  Who puts the tubercle in tuberculosis? , 2007, Nature Reviews Microbiology.

[75]  L. H. Hogan,et al.  Characterization of the Histoplasma capsulatum-Induced Granuloma , 2006 .

[76]  D. van Soolingen,et al.  Differential pattern of cytokine expression by macrophages infected in vitro with different Mycobacterium tuberculosis genotypes , 2005, Clinical and experimental immunology.

[77]  C. Nathan,et al.  The Proteasome of Mycobacterium tuberculosis Is Required for Resistance to Nitric Oxide , 2003, Science.

[78]  Joel V Weinstock,et al.  Granulomas in schistosome and mycobacterial infections: a model of local immune responses. , 2003, Trends in immunology.

[79]  Ilkka Julkunen,et al.  Infection of Human Macrophages and Dendritic Cells with Mycobacterium tuberculosis Induces a Differential Cytokine Gene Expression That Modulates T Cell Response1 , 2001, The Journal of Immunology.

[80]  M. Su,et al.  Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. , 1995, Science.

[81]  T. Casale,et al.  Chronic granulomatous disease of childhood and Chromobacterium violaceum infections in the southeastern United States. , 1982, Annals of internal medicine.