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

被引:220
作者
Gopal, Radha [1 ]
Monin, Leticia [1 ]
Slight, Samantha [1 ]
Uche, Uzodinma [1 ]
Blanchard, Emmeline [1 ]
Junecko, Beth A. Fallert [2 ]
Ramos-Payan, Rosalio [3 ,4 ]
Stallings, Christina L. [5 ]
Reinhart, Todd A. [2 ]
Kolls, Jay K. [6 ]
Kaushal, Deepak [7 ]
Nagarajan, Uma [8 ]
Rangel-Moreno, Javier [4 ]
Khader, Shabaana A. [1 ,5 ]
机构
[1] Univ Pittsburgh, Sch Med, Dept Pediat, Div Infect Dis, Pittsburgh, PA 15261 USA
[2] Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA 15261 USA
[3] Autonomous Univ Sinaloa, Fac Biol & Chem Sci, Culiacan, Sinaloa, Mexico
[4] Univ Rochester, Med Ctr, Dept Med, Div Allergy Immunol & Rheumatol, Rochester, NY 14642 USA
[5] Washington Univ, Dept Mol Microbiol, St Louis, MO 63110 USA
[6] Univ Pittsburgh, Childrens Hosp Pittsburgh, Richard King Mellon Fdn, Inst Pediat Res,Med Ctr, Pittsburgh, PA 15261 USA
[7] Tulane Natl Primate Ctr, New Orleans, LA USA
[8] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA
关键词
T-CELL RESPONSES; PULMONARY TUBERCULOSIS; STRAINS; EXPRESSION; INDUCTION; IL-23; MICE; VACCINATION; GENOTYPE; ABSENCE;
D O I
10.1371/journal.ppat.1004099
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
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-1 beta 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.
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页数:14
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