The inflammasomes: molecular effectors of host resistance against bacterial, viral, parasitic, and fungal infections

Abstract

The inflammasomes are large multi-protein complexes scaffolded by cytosolic pattern recognition receptors (PRRs) that form an important part of the innate immune system. They are activated following the recognition of microbial-associated molecular patterns or host-derived danger signals (danger-associated molecular patterns) by PRRs. This recognition results in the recruitment and activation of the pro-inflammatory protease caspase-1, which cleaves its preferred substrates pro-interleukin-1β (IL-1β) and pro-IL-18 into their mature biologically active cytokine forms. Through processing of a number of other cellular substrates, caspase-1 is also required for the release of "alarmins" and the induction and execution of an inflammatory form of cell death termed pyroptosis. A growing spectrum of inflammasomes have been identified in the host defense against a variety of pathogens. Reciprocally, pathogens have evolved effector strategies to antagonize the inflammasome pathway. In this review we discuss recent developments in the understanding of inflammasome-mediated recognition of bacterial, viral, parasitic, and fungal infections and the beneficial or detrimental effects of inflammasome signaling in host resistance.

Keywords: Nod-like receptors; caspases; infection; inflammasome; inflammation; innate immunity.

Figure 1

Regulation of the inflammasomes by host factors and pathogen effectors. Inflammasomes are activated in a two-step process beginning with PRR-mediated induction of inflammasome components and pro-IL-1β production through NF-kB, followed by a second signal that activates the inflammasome and caspase-1 catalysis. This process can be regulated at multiple steps by host proteins that function as positive regulators (green) or inhibitors (orange) or targeted by pathogen effectors (red). Host COPs and POPs, the poxvirus proteins M13L and gp013L, and the anti-apoptotic factors Bcl-2 and Bcl-X_L inhibit inflammasome assembly. Caspase-1 activation is inhibited by caspase-12, and multiple pathogen effectors, while murine caspase-11 and human caspase-5 are required for caspase-1 activation in response to certain stimuli. Type I IFN is required for AIM2 inflammasome activation in response to cytosolic DNA. The IL-1β and IL-18 pathways are also highly regulated. Endogenous IL-1 receptor antagonist (RA) prevents IL-1 signaling by binding to the IL-1 receptor, while the vaccinia virus proteins B15R and Molluscum contagiosum poxvirus MC53L and MC54L can bind and inhibit IL-1 and IL-18, respectively.

Figure 2

Microbial activation of the inflammasomes. Pathogenic microorganisms activate the inflammasomes through multiple agonists and pathways. S. typhimurium, L. pneumophila, and M. tuberculosis reside within the host cell phagosome and are capable of activating inflammasomes through secreted flagellin, effectors, or undefined NLRP3 agonists. F. tularensis and L. monocytogenes, which escape the phagosome activate AIM2 that senses cytosolic DNA. B. anthracis lethal toxin activates the NLRP1 inflammasome. C. albicans and hemozoin activate NLRP3 through SYK signaling. Viral-mediated inflammasome activation is heavily dependent on the detection of nucleic acids by NLRP3, AIM2, and RIG-I. Dotted lines indicate signaling through an unknown mechanism.