Unexpected Role for IL-17 in Protective Immunity against Hypervirulent Mycobacterium tuberculosis HN878 Infection

PLoS Pathogens

Beth A. Fallert Junecko¹  Jay K. Kolls¹  Shabaana A. Khader²  Christina L. Stallings²  Todd A. Reinhart³  Leticia Monin⁴  Uzodinma Uche⁴  Samantha Slight⁴  Emmeline Blanchard⁴  Radha Gopal⁴  Javier Rangel-Moreno⁵  Rosalio Ramos-Payan⁶  Deepak Kaushal⁷  Uma Nagarajan⁸ 

[1] Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America;Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, United States of America;Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, Missouri, United States of America;Department of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America;Department of Pediatrics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America;Faculty of Biological and Chemical Sciences, Autonomous University of Sinaloa, Culiacan, Sinaloa, Mexico;Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America;Tulane National Primate Center, New Orleans, Louisiana, United States of America

关键词: Mycobacterium tuberculosis;    T cells;    Macrophages;    Lymphoid follicles;    Tuberculosis;    Immunity;    Cell-mediated immunity;    Infectious disease immunology;   

DOI  :  10.1371/journal.ppat.1004099

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world's population. Among these infections, clinical isolates belonging to the W-Beijing appear to be emerging, representing about 50% of Mtb isolates in East Asia, and about 13% of all Mtb isolates worldwide. In animal models, infection with W-Beijing strain, Mtb HN878, is considered “hypervirulent” as it results in increased mortality and causes exacerbated immunopathology in infected animals. We had previously shown the Interleukin (IL) -17 pathway is dispensable for primary immunity against infection with the lab adapted Mtb H37Rv strain. However, it is not known whether IL-17 has any role to play in protective immunity against infection with clinical Mtb isolates. We report here that lab adapted Mtb strains, such as H37Rv, or less virulent Mtb clinical isolates, such as Mtb CDC1551, do not require IL-17 for protective immunity against infection while infection with Mtb HN878 requires IL-17 for early protective immunity. Unexpectedly, Mtb HN878 induces robust production of IL-1β through a TLR-2-dependent mechanism, which supports potent IL-17 responses. We also show that the role for IL-17 in mediating protective immunity against Mtb HN878 is through IL-17 Receptor signaling in non-hematopoietic cells, mediating the induction of the chemokine, CXCL-13, which is required for localization of T cells within lung lymphoid follicles. Correct T cell localization within lymphoid follicles in the lung is required for maximal macrophage activation and Mtb control. Since IL-17 has a critical role in vaccine-induced immunity against TB, our results have far reaching implications for the design of vaccines and therapies to prevent and treat emerging Mtb strains. In addition, our data changes the existing paradigm that IL-17 is dispensable for primary immunity against Mtb infection, and instead suggests a differential role for IL-17 in early protective immunity against emerging Mtb strains.

【 授权许可】

CC BY