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Review
. 2018 Sep 12;82(4):e00015-18.
doi: 10.1128/MMBR.00015-18. Print 2018 Dec.

Cytosolic Recognition of Microbes and Pathogens: Inflammasomes in Action

Jenni A Hayward #  1 , Anukriti Mathur #  1 , Chinh Ngo  1 , Si Ming Man  2
Affiliations
Review

Cytosolic Recognition of Microbes and Pathogens: Inflammasomes in Action

Jenni A Hayward et al. Microbiol Mol Biol Rev. .

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.

Keywords: AIM2; NAIP; NLRC4; NLRP1; NLRP3; Pyrin; caspase-1; caspase-11; gasdermin; pyroptosis.

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Figures

FIG 1
FIG 1
Architecture of inflammasome complexes. (A) Formation of an inflammasome complex is initiated by an inflammasome sensor. Inflammasome sensors carry a pyrin domain (PYD) and/or a caspase activation and recruitment domain (CARD). They may also carry a leucine-rich-repeat domain (LRR), a nucleotide-binding domain (NBD), a HIN-200 domain, a B30.2 domain, a coiled-coil domain (C-C), a B-box domain (B), a function-to-find domain (FIIND), or a baculovirus inhibitor of apoptosis repeat (BIR). Other inflammasome components include the inflammasome adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and the effector protein caspase-1. A PYD-containing inflammasome sensor interacts with the PYD of ASC, allowing the CARD of ASC to interact with the CARD of caspase-1. A CARD-containing inflammasome sensor can interact with the CARD of ASC, whereby the PYD of ASC interacts with the PYD of an additional ASC. The CARD of ASC then interacts with the CARD of caspase-1. Alternatively, a CARD-containing inflammasome sensor may directly interact with caspase-1 via their respective CARDs. (B) Canonical inflammasome complexes are activated by a range of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Caspase-1 cleaves the pore-forming factor gasdermin D, whereby the N-terminal domain of gasdermin D forms pores in the host cell membrane. Caspase-1 also cleaves the proinflammatory cytokines pro-IL-1β and pro-IL-18, generating biologically active versions of these cytokines for release through the membrane pores generated by gasdermin D. The pores formed by gasdermin D also lead to lytic cell death via pyroptosis. (C) The noncanonical inflammasome is a pathway specifically activated by Gram-negative bacteria. In this pathway, lipopolysaccharides (LPS) are introduced into the cytoplasm during infection and sensed by human caspase-4 and caspase-5 and mouse caspase-11. These inflammatory caspases can also cleave gasdermin D, in a manner similar to that by caspase-1, leading to the induction of pyroptosis. The N-terminal domain of gasdermin D also induces activation of the NLRP3 inflammasome and the associated proteolytic cleavage of pro-IL-1β and pro-IL-18.
FIG 2
FIG 2
Major bacterial activators of the inflammasome. Four major groups of bacterial components trigger activation of the inflammasome. Flagellin and components of the type III secretion system (T3SS) can be injected into the cytoplasm of the host cell via the T3SS. The T3SS needle and inner rod proteins are sensed by mouse NAIP1 and NAIP2, respectively, whereas flagellin is sensed by mouse NAIP5 or NAIP6. The needle and inner rod proteins and flagellin are all sensed by human NAIP. Ligand-bound NAIPs recruit NLRC4 to the same complex to drive activation of the NLRC4 inflammasome. The bacterial nucleic acid molecules DNA and RNA can activate the AIM2 and NLRP3 inflammasomes, respectively. RNA-DNA hybrids derived from bacteria (not shown) can also activate the NLRP3 inflammasome. The cell wall components acylated lipopeptides (AcLP) might activate a putative NLRP7 inflammasome in human macrophages. Lipopolysaccharides (LPS) from the cell walls of Gram-negative bacteria activate human caspase-4 and caspase-5 and mouse caspase-11. These inflammatory caspases oligomerize and drive activation of the NLRP3 inflammasome. Pore-forming toxins produced by bacteria induce K+ efflux, a physiological aberration sensed by the NLRP3 inflammasome. Rho-inactivating toxins inactivate the host GTPase RhoA, which relieves inhibition of Pyrin, leading to activation of the Pyrin inflammasome. The protective antigen of lethal toxin generates pores on the host cell membrane, allowing lethal factor to enter the cytoplasm and mediate cleavage of NLRP1b. Cleaved NLRP1b induces formation of the NLRP1b inflammasome.
FIG 3
FIG 3
Viral activators of the inflammasome. DNA and RNA viruses carry viral PAMPs and induce physiological aberrations and host cell damage that can trigger activation of the inflammasome. DNA from double-stranded DNA (dsDNA) viruses can enter the cytoplasm and the nucleus to engage activation of the AIM2 inflammasome and the putative IFI16 inflammasome, respectively. Both DNA and RNA viruses can cause physiological aberrations in the form of cathepsin B release, production of ROS, and potassium efflux, which are signaling cues leading to activation of the NLRP3 inflammasome. RNA and viral proteins of single-stranded RNA (ssRNA) viruses and replication intermediaries of a single-stranded DNA (ssDNA) virus have been shown to trigger activation of the NLRP3 inflammasome. Host DNA release from virus-induced damage can lead to activation of the AIM2 inflammasome. There is some evidence to suggest that an ssRNA virus might activate the NLRP1 inflammasome. Double-stranded RNA (dsRNA) from a dsRNA virus has been shown to activate a putative NLRP9b inflammasome in mouse enterocytes.
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