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

Gopal, R and Monin, L and Slight, S and Uche, U and Blanchard, E and A. Fallert Junecko, B and Ramos-Payan, R and Stallings, CL and Reinhart, TA and Kolls, JK and Kaushal, D and Nagarajan, U and Rangel-Moreno, J and Khader, SA (2014) Unexpected Role for IL-17 in Protective Immunity against Hypervirulent Mycobacterium tuberculosis HN878 Infection. PLoS Pathogens, 10 (5). ISSN 1553-7366

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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. © 2014 Gopal et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Gopal, Rrag100@pitt.eduRAG100
Monin, Llem83@pitt.eduLEM83
Slight, S
Uche, Uunu1@pitt.eduUNU1
Blanchard, E
A. Fallert Junecko, B
Ramos-Payan, R
Stallings, CL
Reinhart, TAreinhar@pitt.eduREINHAR
Kolls, JKjkk23@pitt.eduJKK23
Kaushal, D
Nagarajan, U
Rangel-Moreno, J
Khader, SA
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 January 2014
Date Type: Publication
Journal or Publication Title: PLoS Pathogens
Volume: 10
Number: 5
DOI or Unique Handle: 10.1371/journal.ppat.1004099
Schools and Programs: School of Medicine > Infectious Diseases and Microbiology
School of Medicine > Pediatrics
Refereed: Yes
ISSN: 1553-7366
Date Deposited: 01 Jul 2014 16:30
Last Modified: 02 Aug 2020 12:56


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