Mice genetically inactivated in interleukin‐17A receptor are defective in long‐term control of Mycobacterium tuberculosis infection

Abstract

Summary Interleukin‐17A (IL‐17A), a pro‐inflammatory cytokine acting on neutrophil recruitment, is known to play an important role during Mycobacterium tuberculosis infection, but the role of IL‐17A receptor signalling in immune defence against this intracellular pathogen remains poorly documented. Here we have analysed this signalling using C57BL/6 mice genetically inactivated in the IL‐17 receptor A subunit (IL‐17RA−/−). Although early after infection bacterial growth was controlled to the same extent as in wild‐type mice, IL‐17RA−/− mice were defective in exerting long‐term control of M. tuberculosis infection, as demonstrated by a progressively increasing pulmonary bacterial burden and shortened survival time. Compared with infected wild‐type mice, IL‐17RA−/− mice showed impaired recruitment of neutrophils to the lungs at the early but not the late stage of infection. Pulmonary tumour necrosis factor‐α, IL‐6 and particularly IL‐10 levels were decreased in the absence of IL‐17RA signalling, whereas IL‐1β was increased. CD4+‐mediated and γδ‐mediated IL‐17A production was dramatically increased in IL‐17RA−/− mice (confirming part of their phenotype), whereas production of interferon‐γ and expression of the bactericidal enzyme inducible nitric oxide synthase were not affected. Collectively, our data suggest that early but not late neutrophil recruitment is essential for IL‐17A‐mediated long‐term control of M. tuberculosis infection and that a functional interferon‐γ response is not sufficient to control M. tuberculosis growth when the IL‐17RA pathway is deficient. As treatment of auto‐immune diseases with anti‐IL‐17A antibodies is actually being tested in clinical studies, our data suggest that caution should be taken with respect to possible reactivation of tuberculosis.

Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

“…Mice with genetically inactivated IL-17A receptor failed to control bacterial burden, resulting in accelerated mortality in long-term infections even though the bacterial burden was controlled during the acute phase of M. tuberculosis infection (38). Moreover, the IL-17 requirement for host protection against TB depends on the M. tuberculosis strain in mice.…”

HBHA vaccination may require both Th1 and Th17 immune responses to protect mice against tuberculosis

“…This cytokine was recently shown to play a crucial role in the formation of granulomas during M. tuberculosis infection [54] and in the establishment of a strong memory T cell response [24]. Studies performed with IL-17KO or IL-17RA-/-mice indicated that IL-17 is not essential to control mycobacterial growth, but its lack resulted in reduced survival late in the course of infection [24,25,55].…”

Quest for Correlates of Protection against Tuberculosis

“…In contrast, another study reported that mice lacking IL-17A receptor, despite being able to control acute infection, were unable to stably maintain long-term control of M. tuberculosis infection (33). The increased susceptibility was not related to deficiencies in IFN-␥ but correlated with decreased early neutrophil recruitment.…”