The Recombinant BCG ΔureC::hlyVaccine Targets the AIM2 Inflammasome to Induce Autophagy and Inflammation

Abstract

rBCG stimulates AIM2 inflammasome activation and autophagy, suggesting that these cell-autonomous functions should be exploited for improved vaccine design.

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

“…With a more detailed understanding of ligand-PRR interactions and the resulting immune responses of vaccine strains, a more targeted design of recombinant live vaccines becomes feasible. In line with this, we have recently elucidated that activation of the AIM2 inflammasome contributes to the superior protection afforded by a recombinant BCG strain compared with that seen with conventional BCG vaccination (63). Here, we show that rapid IL-18 secretion that significantly contributes to early protective immunity against TB depends on ESAT-6-mediated NLRP3, but not AIM2, inflammasome activation.…”

Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice

“…These studies corroborated our previous findings of Th1-predominant protective immunity in live attenuated parasite-immunized and WT-challenged mice and dogs (40)(41)(42)(43). It is worth mentioning here that the macrophage-mediated immune response plays a key role in vaccine protection, as recently observed by various groups working with vaccine candidates, such as recombinant BCG, live attenuated West Nile virus, and live attenuated measles virus, against tuberculosis, WNV infection, and measles, respectively; the response manipulates the macrophage population and provides improved protection by enhancing the macrophage effector response (32)(33)(34). Therefore, it is likely that the abundance of classically activated macrophages (M1) in live attenuated parasiteinfected mice could serve as a biomarker for effective Leishmania vaccines (40)(41)(42)(43).…”

“…Of interest, such a polarization of T cells by proinflammatory (M1) macrophages was associated with induction of protection in several vaccine studies, including studies of recombinant Mycobacterium bovis BCG, attenuated West Nile virus (WNV), and live attenuated measles virus (32)(33)(34). These studies have shown that the aforementioned vaccine candidates manipulate the macrophages to enhance proinflammatory responses and yield improved protection against tuberculosis or WNV or measles virus infection.…”

Inflammasome and Autophagy Regulation: A Two-way Street

“…Another mechanism by which autophagy regulates inflammasome activation is through p62-dependent deg-has now been confirmed in two separate models (13,52). In the first model, AIM2 activation by host-derived dsDNA led to increased autophagic flux in hepatocytes after redox stress induced by hypoxia with reoxygenation (13).…”

“…In contrast, in hepatocytes, AIM2-dependent regulation of autophagy was mediated by caspase-1, suggesting that mechanisms of AIM2-mediated autophagy regulation may differ between immune and nonimmune cell types (53,54). In the second model, Saiga et al demonstrated that following infection of recombinant bacillus CalmetteGuerin, a live attenuated vaccine against tuberculosis, autophagy induction was partially dependent on AIM2 in macrophages (52). Therefore, it seems that activation of AIM2 inflammasome, by either microbial or endogenous self-DNA, triggers host adaptive autophagy responses designed to limit excessive inflammation and restore cellular homeostasis.…”