Unexpected role for IL-17 in protective immunity against hypervirulent Mycobacterium tuberculosis HN878 infection.

Radha Gopal,Leticia Monin,Javier Rangel-Moreno,Uzodinma Uche,Emmeline Blanchard,Rosalio Ramos-Payan,Deepak Kaushal,Uma Nagarajan,Shabaana A Khader,Samantha Slight,Jay K Kolls,Christina L Stallings,Todd A Reinhart,Beth A Fallert Junecko

doi:10.1371/journal.ppat.1004099

Abstract

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.

Highlights

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world’s population
We report here that while IL-17 is dispensable for protection against infection with lab adapted Mtb strains such as H37Rv, or less virulent Mtb clinical isolates such as Mtb CDC1551, IL-17 is required for early protective immunity against Mtb HN878 infection
The dependence on IL-17 to drive protective immunity against Mtb HN878 is due to the differential ability to induce high levels of IL-1b through a TLR-2-dependent mechanism, driving potent IL-17 responses, induction of the chemokine CXCL-13 and localization of T cells within lung lymphoid follicles for maximal macrophage activation and Mtb control

Summary

Introduction

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world’s population. Most infected people with latent TB remain asymptomatic, they have ,10% lifetime risk of developing into active TB. Among these infections, clinical isolates being typed as belonging to the W-Beijing strain appear to be increasingly prevalent. Infection with Mtb HN878 isolate, the best studied of the W-Beijing isolates, is thought to be ‘‘hypervirulent’’ as it results in increased mortality and causes severe immunopathology in infected animals [8,9]. Studies suggest that M.bovis Bacille Calmette-Guerin (BCG) vaccination may be less protective against W-Beijing genotype Mtb strains [4], contributing to its successful recent worldwide emergence

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