Mycobacterium tuberculosis HN878 infection induces human-like B cell follicles in mice.

Specific spatial organization of granulomas within the lungs is crucial for protective anti-tuberculosis (TB) immune responses. However, only large animal models such as macaques are thought to reproduce the morphological hallmarks of human TB granulomas. In this study, we show that infection of mice with clinical "hypervirulent" Mycobacterium tuberculosis (Mtb) HN878 induces human-like granulomas composed of bacilli-loaded macrophages surrounded by lymphocytes and organized localization of germinal centers and B cell follicles. Conversely, infection with lab-adapted Mtb H37Rv resulted in granulomas that are characterized by unorganized clusters of macrophages scattered between lymphocytes. An in-depth exploration of the functions of B cells within these follicles suggested diverse roles and the activation of signaling pathways associated with antigen presentation and immune cell recruitment. These findings support the use of clinical Mtb HN878 strain for infection in mice as an appropriate model to study immune parameters associated with human TB granulomas.

[1]  M. Mitreva,et al.  A novel role for C-C motif chemokine receptor 2 during infection with hypervirulent Mycobacterium tuberculosis , 2018, Mucosal Immunology.

[2]  Astrid Gall,et al.  Ensembl 2018 , 2017, Nucleic Acids Res..

[3]  Thawfeek M. Varusai,et al.  The Reactome Pathway Knowledgebase , 2017, Nucleic Acids Res..

[4]  Maxim N. Artyomov,et al.  Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis. , 2017, JCI insight.

[5]  Jing Wang,et al.  WebGestalt 2017: a more comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit , 2017, Nucleic Acids Res..

[6]  D. Weng,et al.  IL-10-Producing B Cells Regulate T Helper Cell Immune Responses during 1,3-β-Glucan-Induced Lung Inflammation , 2017, Front. Immunol..

[7]  A. Kritski,et al.  Hypervirulent Mycobacterium tuberculosis strain triggers necrotic lung pathology associated with enhanced recruitment of neutrophils in resistant C57BL/6 mice , 2017, PloS one.

[8]  N. Hochberg,et al.  B cell responses in older adults with latent tuberculosis: Considerations for vaccine development , 2016, Global vaccines and immunology.

[9]  Min Zhang,et al.  Human B cells have an active phagocytic capability and undergo immune activation upon phagocytosis of Mycobacterium tuberculosis. , 2016, Immunobiology.

[10]  R. Hunter.  Tuberculosis as a three-act play: A new paradigm for the pathogenesis of pulmonary tuberculosis. , 2016, Tuberculosis.

[11]  Steven L Salzberg,et al.  HISAT: a fast spliced aligner with low memory requirements , 2015, Nature Methods.

[12]  C. Barry,et al.  Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses , 2015, Immunological reviews.

[13]  J. Rangel-Moreno,et al.  Immune requirements for protective Th17 recall responses to Mycobacterium tuberculosis challenge , 2014, Mucosal Immunology.

[14]  J. Kolls,et al.  Unexpected Role for IL-17 in Protective Immunity against Hypervirulent Mycobacterium tuberculosis HN878 Infection , 2014, PLoS pathogens.

[15]  Björn Usadel,et al.  Trimmomatic: a flexible trimmer for Illumina sequence data , 2014, Bioinform..

[16]  JoAnne L. Flynn,et al.  Sterilization of granulomas is common in both active and latent tuberculosis despite extensive within-host variability in bacterial killing , 2014 .

[17]  Wei Shi,et al.  featureCounts: an efficient general purpose program for assigning sequence reads to genomic features , 2013, Bioinform..

[18]  M. Selman,et al.  CXCR5⁺ T helper cells mediate protective immunity against tuberculosis. , 2013, The Journal of clinical investigation.

[19]  F. Altare,et al.  The Tuberculous Granuloma: An Unsuccessful Host Defence Mechanism Providing a Safety Shelter for the Bacteria? , 2012, Clinical & developmental immunology.

[20]  L. Denzin,et al.  H2-O, a MHC class II-like protein, sets a threshold for B-cell entry into germinal centers , 2010, Proceedings of the National Academy of Sciences.

[21]  T. Randall,et al.  In a Murine Tuberculosis Model, the Absence of Homeostatic Chemokines Delays Granuloma Formation and Protective Immunity1 , 2009, The Journal of Immunology.

[22]  J. Flynn,et al.  Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates , 2008, Infection and Immunity.

[23]  I. Orme,et al.  The Hypervirulent Mycobacterium tuberculosis Strain HN878 Induces a Potent TH1 Response followed by Rapid Down-Regulation1 , 2007, The Journal of Immunology.

[24]  J. Chan,et al.  B Cells Moderate Inflammatory Progression and Enhance Bacterial Containment upon Pulmonary Challenge with Mycobacterium tuberculosis1 , 2007, The Journal of Immunology.

[25]  J. Flynn,et al.  Characterization of the tuberculous granuloma in murine and human lungs: cellular composition and relative tissue oxygen tension , 2006, Cellular microbiology.

[26]  Susan E Wert,et al.  Expression of a Human Surfactant Protein C Mutation Associated with Interstitial Lung Disease Disrupts Lung Development in Transgenic Mice* , 2003, Journal of Biological Chemistry.

[27]  G. Kaplan,et al.  Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-α/β , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  B. Barrell,et al.  Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence , 1998, Nature.

[29]  J. Shannon,et al.  Surfactant protein C is expressed in alveolar type II cells but not in Clara cells of rat lung. , 1992, American journal of respiratory cell and molecular biology.

[30]  L. Gabbasova,et al.  Global tuberculosis report (2014) , 2014 .

[31]  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[32]  S. Kaufmann,et al.  Mycobacterium tuberculosis triggers formation of lymphoid structure in murine lungs. , 2007, The Journal of infectious diseases.

[33]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .