A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

Abstract

Tuberculosis remains the most hazardous bacterial infection worldwide. The causative agent, Mycobacterium tuberculosis, is a facultative intracellular pathogen of resting MU. IFN-c secreted by natural killer, CD4 Th 1 and CD8 T cells upon instruction by IL-12 and -18 activates MU to restrict mycobacterial growth. Production of both cytokines is induced by TLR signalling in DC and MU. Mice deficient for the TLR adaptor, MyD88, are highly susceptible to M. tuberculosis infection. Shared usage of MyD88 by signalling cascades for TLR and receptors for IL-1 and IL-18 prompted us to revisit the role of IL-18 during experimental infection with M. tuberculosis. We show that mice deficient for IL-18 and MyD88 but not for IL-18 receptor promptly succumbed to M. tuberculosis infection in contrast to WT or TLR-2/-4 double KO mice indicating that lack of IL-18 contributes to the high susceptibility of MyD88 KO mice to M. tuberculosis. Without IL-18, the protective Th1 response was decreased and hence, mycobacterial propagation was favoured. Neutrophildriven lung immunopathology concomitant with unrestrained growth of tubercle bacilli are most likely responsible for the premature death of IL-18 KO mice. Thus, IL-18 plays a decisive role in protective immunity against tuberculosis.Key words: IFN-c . IL-18 . Mouse . Neutrophils . Tuberculosis IntroductionDespite more than 125 years of research and development, tuberculosis (TB) remains the most hazardous bacterial infection worldwide with approximately 2 million people dying of the disease annually [1]. The risk of disease is increased by immunocompromising conditions such as AIDS emphasizing that T-cell immunity protects latently infected individuals against active TB. The innate immune response to Mycobacterium tuberculosis instructs acquired immunity in the initial stage, and executes effector mechanisms in the chronic stage.M. tuberculosis is usually transmitted via aerosols and establishes stable infection in the lung. There, M. tuberculosis is engulfed by MF and DC, which serve as host cells for mycobacterial survival and propagation. Binding of mycobacterial ligands to TLR-2, -4 and -9 promotes release of chemokines and proinflammatory cytokines, expression of adhesion molecules and attraction of MF, DC and PMN. Two crucial MF-and DCderived cytokines, , induce NK-cell activity and bias immunity towards a Th1 cell response characterized by profound 396IFN-g production, which is considered critical for protection against M. tuberculosis [2]. Activated MF express anti-mycobacterial molecules such as nitric oxide synthase (NOS)-2 (also known as inducible NOS) and LRG47 as well as cytokines such as TNF-a, which promotes granuloma formation within the infected tissue to sequester the bacilli from dissemination [2].Despite the prevailing assumption that resistance to M. tuberculosis infection depends on microbe sensing through TLR, their importance for mounting a protective immune response against M. tuberculosis remains controversial. While some groups found that TLR-mediated...

ESAT-6–dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo

“…Lung lobes were collected aseptically, fixed overnight with 4% w/v paraformaldehyde, and embedded in paraffin. Tissues were cut at 2-μm thickness and stained with Giemsa, TB Fluor (Merck), or anti-iNOS Ab (Thermo Scientific) according to standard protocols described elsewhere (28).…”

“…Secretion of bioactive IL-18 requires proteolytic cleavage from its biologically inactive precursor pro-IL-18 through caspase-1 (26), which in turn depends on the upstream assembly and activation of inflammasomes through the engagement of cytosolic pattern recognition receptors (PRRs) (26). Intriguingly, not only have deficiencies in caspase-1 and IL-18 (27,28) been implicated in impaired immunity to Mtb, but a deficiency in a PRR that is required for the upstream activation of caspase-1 has been implicated as well (29). These results point to an important host-protective role for the caspase-1/IL-18/IFN-γ axis and suggest that strategies aimed at targeting cytosolic PRRs beyond adjuvant immunotherapy (30) could serve as a means of inducing IL-18-mediated IFN-γ production to control Mtb infections.…”

Type 2 Diabetes Mellitus Coincident with Pulmonary Tuberculosis Is Associated with Heightened Systemic Type 1, Type 17, and Other Proinflammatory Cytokines

“…In addition, IL-18 has also been shown to play a role in protective immunity to tuberculosis (27). Similarly, IL-12 is also known to be crucial in immunity to tuberculosis both in mouse models and human infections (28,29).…”

Toll-Like Receptor 9 Is Required for Full Host Resistance to Mycobacterium avium Infection but Plays No Role in Induction of Th1 Responses

“…In the case of M. tuberculosis infection models, IL-1 and IL-18 may be those molecules, as shown by the increased susceptibility of IL-1R KO, IL-1␤ KO, and IL-18 KO mice to tuberculosis (7,18,22,26). IL-1R KO mice were already studied with regard to susceptibility to M. avium by Feng and colleagues (6) and shown not to differ from the respective controls.…”