Cytosolic Recognition of Microbes and Pathogens: Inflammasomes in Action

Abstract

Infection is a dynamic biological process underpinned by a complex interplay between the pathogen and the host. Microbes from all domains of life, including bacteria, viruses, fungi, and protozoan parasites, have the capacity to cause infection. Infection is sensed by the host, which often leads to activation of the inflammasome, a cytosolic macromolecular signaling platform that mediates the release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 and cleavage of the pore-forming protein gasdermin D, leading to pyroptosis. Host-mediated sensing of the infection occurs when pathogens inject or carry pathogen-associated molecular patterns (PAMPs) into the cytoplasm or induce damage that causes cytosolic liberation of danger-associated molecular patterns (DAMPs) in the host cell. Recognition of PAMPs and DAMPs by inflammasome sensors, including NLRP1, NLRP3, NLRC4, NAIP, AIM2, and Pyrin, initiates a cascade of events that culminate in inflammation and cell death. However, pathogens can deploy virulence factors capable of minimizing or evading host detection. This review presents a comprehensive overview of the mechanisms of microbe-induced activation of the inflammasome and the functional consequences of inflammasome activation in infectious diseases. We also explore the microbial strategies used in the evasion of inflammasome sensing at the host-microbe interaction interface.

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

“…Several bacterial molecules can serve as signal 2 during activation of NAIPs (Figure ) (Hayward et al, ; Evavold & Kagan, 2019). Bacterial flagellin and evolutionarily conserved rod and needle proteins of the type 3 secretion system (T3SS) injectisome of some Gram‐negative bacteria are recognised by the NAIPs, leading to the assembly of the NLRC4 inflammasome in macrophages (Miao, Mao, et al, ; Zhao et al, ).…”

“…Several bacterial molecules can serve as signal 2 during activation of NAIPs ( Figure 1) (Hayward et al, 2018;Evavold & Kagan, 2019).…”

“…IL-1α and HMGB1) help promote inflammation, neutrophil recruitment and an adequate adaptive immune response (Mantovani, Dinarello, Molgora, & Garlanda, 2019), while pyroptosis eliminates intracellular bacterial replicative niches . The antibacterial function of inflammasomes is illustrated by the ability of various inflammasome sensor proteins to recognise and respond to bacterial ligands (Eldridge & Shenoy, 2015;Hayward et al, 2018), and the increased susceptibility to infection shown by mice with deletions in inflammasome components (Man, Karki, & Kanneganti, 2017;Lacey & Miao, 2019). Although inflammasomes have been best studied in myeloid cells, several inflammasome components, such as caspase-4/11 and pro-IL-18, are also expressed in IECs (Man, 2018;Winsor, Krustev, Bruce, Philpott, & Girardin, 2019).…”

Role reversal: adaptive immunity instructs inflammasome activation for anti‐viral defence

“…Adenoviruses are non‐enveloped dsDNA viruses that commonly cause respiratory infections in humans. Previous studies observed that adenovirus infection of myeloid cells could cause inflammasome activation, but the mechanism and nature of the inflammasome sensor involved were not clearly defined (Hayward et al , ; Labzin et al , ). Notably, the impact of anti‐adenovirus antibodies, which are likely to be present in a natural infection, on macrophage sensing of adenovirus was unknown.…”

“…Select cytosolic PRRs such as NLRP3 and AIM2 form inflammasomes, protein complexes which mediate the activation of the zymogen protease caspase-1. Caspase-1 cleaves the pro-inflammatory cytokines pro-IL-1b and pro-IL-18, triggering their secretion, and also cleaves gasdermin-D resulting in plasma membrane pore formation and inflammatory cell death called pyroptosis (Broz & Dixit, 2016;Hayward et al, 2018). Inflammasome-dependent secretion of IL-1b and IL-18 drives both innate and adaptive immune responses (Evavold & Kagan, 2018;Hayward et al, 2018).…”