Inflammasome activation by Gram-positive bacteria: Mechanisms of activation and regulation

Abstract

The inflammasomes are intracellular multimeric protein complexes consisting of an innate immune sensor, the adapter protein ASC and the inflammatory caspases-1 and/or -11 and are important for the host defense against pathogens. Activaton of the receptor leads to formation of the inflammasomes and subsequent processing and activation of caspase-1 that cleaves the proinflammatory cytokines IL-1β and IL-18. Active caspase-1, and in some instances caspase-11, cleaves gasdermin D that translocates to the cell membrane where it forms pores resulting in the cell death program called pyroptosis. Inflammasomes can detect a range of microbial ligands through direct interaction or indirectly through diverse cellular processes including changes in ion fluxes, production of reactive oxygen species and disruption of various host cell functions. In this review, we will focus on the NLRP3, NLRP6, NLRC4 and AIM2 inflammasomes and how they are activated and regulated during infections with Gram-positive bacteria, including Staphylococcus spp., Streptococcus spp. and Listeria monocytogenes.

Keywords: Gram-positive bacteria; autophagy; inflammasome; mechanisms of activation; regulation.

Figure 1

Inflammasome activation by Gram-positive bacteria. Activation of the inflammasome typically starts by priming (signal 1) through TLR activation resulting in the transcriptional upregulation of inflammasome components such as Asc, Nlrp3, Nlrc4, IL-1β and IL-18. Activation (signal 2) is initiated by a variety of PAMPs from Listeria monocytogenes, Streptococcus spp. and Staphylococcus spp., such as lipoteichoic acid (LTA), DNA and flagellin. LTA activates the NLRP6 inflammasome, DNA activates the AIM2 inflammasome and flagellin activates the NLRC4 inflammasome. Listeria monocytogenes, Streptococcus spp. and Staphylococcus spp. express pore forming toxins (PFTs) that are inserted into the plasma membrane to facilitate access to the host cytosol. K+ efflux and Ca+ influx through these pores and the P2X5 receptor (a member of the P2X purinergic receptor family of ligand-gated cation channels) results in activation of the NLRP3 inflammasome. In addition to PAMP activation and ion fluxes, the inflammasome is also activated by damage-associated molecular patterns (DAMPs) such as lysosomal rupture and production of mitochondrial reactive oxygen species (mtROS) that activates the NLRP3 inflammasome. Sensing of PAMPs and DAMPs by the NLR initiates the formation of the inflammasome consisting of ASC and Caspase-1, which in turn cleaves pro-IL-1β and pro-IL-18. Gasdermin D (GSDMD) is also cleaved and inserts into the membrane, forming pores leading to the release of the proinflammatory cytokines IL-1β and IL-18 and the induction of pyroptosis.

Figure 2

Mechanisms of autophagy/NLRP3 inflammasome by Gram-positive bacteria interaction. Autophagy can inhibit NLRP3 inflammasome activation by reducing ASC, increasing NLRP3 phosphorylation, and eliminating ROS. Activated Caspase-1 directly cleaves TRIF, thereby diminishing TRIF-mediated autophagy. The M protein of S. pyogenes binds the CD46 receptor to facilitate internalization, and subsequently S. pyogenes escapes from the phagosome via streptolysin O (SLO)-dependent pore formation. In the host cytosol, streptococcal pyrogenic exotoxin B (SpeB) degrades the autophagy adapter proteins p62, NDP52 and NBR1, and NAD-glycohydrolase (Nga) disrupts LC3 formation thereby inhibiting phagosome formation and escape from autophagy allowing for S. pyogenes cytosolic replication. LLO, listeriolysin O, pore-forming acts to damage and disrupt the vacuole membrane. Surface protein A (ActA) recruits the host Arp2/3 complex and Ena/VASP to the bacterial surface, which disguises the bacteria from autophagic recognition. Phosphatidylinositol-specific phospholipase C (Plc) A and B expressed by L. monocytogenes interfere with the production of phosphatidylinositol 3-phosphate (PI3P), a phospholipid required for phagosome formation. Escape from autophagy allows for L. monocytogenes replicating within the host cytosol and cell-to-cell spread.