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

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.

Interleukin-17 limits hypoxia-inducible factor 1α and development of hypoxic granulomas during tuberculosis

“…Our data using HN878::Δpks1-15 as well as purified PGL from HN878, project PGLs as the primary inducers of IL-1β in BMDCs through TLR2, following subsequent induction of IL-17. Our data show no difference in disease progression between isotype-and anti-IL-17-treated H37Rv-infected mice, emphasizing an Mtb-straindependent protective role for IL-17 (28). These findings are consistent with the ability of PGLs to induce the chemokine CCL2 to promote the recruitment of permissive macrophages in the host (41).…”

“…While neither PIM nor ManLAM induced differential production of IL-1β (data not shown), HN878-derived total lipids and polar lipids, but not apolar lipids, induced higher protein levels of IL-1β in BMDCs, when compared with IL-1β production in BMDCs stimulated with similarly isolated derivatives from H37Rv ( Figure 4A). As previously published, total lipids obtained from BEI Resources did not induce IL-1β production in DCs (28). Furthermore, loss of IL-1β production was observed in HN878 lipid-stimulated lung cells treated with purified anti-mouse CD282 (TLR2-blocking antibody), supporting a role for TLR2 in Mtb induction of IL-1β production ( Figure 4B).…”

“…Cell wall components isolated from HN878, an emerging W-Beijing lineage strain, are potent inducers of IL-1β responses in C57BL/6J (B6) mouse lung DCs, thus mediating increased production of IL-17 in T cells (28). To delineate the molecular mechanism by which HN878 increases IL-1β production, we carried out MALDI-TOF analyses to compare the differential biomolecule expression in cell wall components between the clinical strain used in this study, HN878, and the lab-adapted strain, H37Rv, which does not effectively induce IL-17 (28). We identified 95 proteins that were increased in HN878 cell wall preparations, when compared with cell wall preparations from H37Rv (Supplemental Table 2).…”

Resuscitation-promoting factors are important determinants of the pathophysiology inMycobacterium tuberculosisinfection

“…Subsequently, activated DCs produce IL-12p70, which polarizes T-cell proliferation toward TH 1 phenotype (Choi et al, 2015;Kim et al, 2013). RpfE also induces DC IL-23p19 secretion leading to TH 17 development, which in addition to TH 1 is required for optimal protection against Mtb (Gopal et al, 2014). The induction of IL-23p17 secretion by RpfB was not tested.…”

“…TH 1 cells promote inflammatory cell recruitment and enhance Mtb killing by macrophages (Nunes-Alves et al, 2014). TH 17 cells are also important for protective immunity to Mtb, particularly in the early stages of infection (Gopal et al, 2014;Prezzemolo et al, 2014;van de Veerdonk et al, 2010). Macrophages and T-cells are key to granuloma formation, which ultimately controls primary infection but in 90% of cases fails to kill Mtb and provides a site for bacilli to latently infect the host (Ahmad, 2010;Dorhoi & Kaufmann, 2014;Ramakrishnan, 2012).…”