Pyroptosis in defense against intracellular bacteria

Abstract

Pathogenic microbes invade the human body and trigger a host immune response to defend against the infection. In response, host-adapted pathogens employ numerous virulence strategies to overcome host defense mechanisms. As a result, the interaction between the host and pathogen is a dynamic process that shapes the evolution of the host's immune response. Among the immune responses against intracellular bacteria, pyroptosis, a lytic form of cell death, is a crucial mechanism that eliminates replicative niches for intracellular pathogens and modulates the immune system by releasing danger signals. This review focuses on the role of pyroptosis in combating intracellular bacterial infection. We examine the cell type specific roles of pyroptosis in neutrophils and intestinal epithelial cells. We discuss the regulatory mechanisms of pyroptosis, including its modulation by autophagy and interferon-inducible GTPases. Furthermore, we highlight that while host-adapted pathogens can often subvert pyroptosis, environmental microbes are effectively eliminated by pyroptosis.

Keywords: Autophagy; Environmental pathogen; Guanylate-binding protein; Host-adapted pathogen; Intracellular bacteria; Pyroptosis.

Figure 1.. Inflammasome activation induces pyroptosis.

Inflammasomes are multiprotein complexes located in the cytosol that trigger the activation of caspase-1. Typically, an inflammasome comprises an inflammasome sensor and often the protein adaptor ASC. Inflammasome sensors are responsible for detecting various cellular disturbances, including microbial contaminants or danger signals. Upon polymerization, inflammasome sensors often recruit ASC, leading to the formation of ASC specks. Inflammasomes either directly or via ASC recruit pro-caspase-1 and trigger its activation. Once activated, caspase-1 cleaves GSDMD into its active form, N-terminal GSDMD (N-GSDMD). N-GSDMD polymerizes and forms pores in the plasma membrane, resulting in pyroptosis. NINJ1, a transmembrane protein, facilitates plasma membrane rupture in pyroptosis and other types of lytic cell death. Furthermore, caspase-1 also cleaves pro-IL-1β and pro-IL-18, generating active IL-1β and IL-18, respectively. These pro-inflammatory cytokines can be released from the GSDMD pores, along with other inflammatory cellular components. In parallel, caspase-4/5/11, are activated by cytosolic LPS. This activation leads to the cleavage of GSDMD, ultimately inducing pyroptosis. Notably, caspase-4/5 but not caspasae-11 can cleave pro-IL-18 into its mature form.

Figure 2.. Interplay of autophagy and pyroptosis.

A. Autophagy is a cellular process that captures and degrades a variety of cellular materials, including damaged organelles, self-proteins, and pathogen-derived molecules. This process is initiated by the formation of a double-membrane structure called a phagophore, which expands and engulfs the targeted material to form an autophagosome. The autophagosome fuses with a lysosome to form an autolysosome, where the materials are degraded. Autophagy plays a role in inhibiting inflammasome activation by removing damaged mitochondria, mitochondrial DNA, cytosolic PAMPs, and inflammasome pathway components. B. In response to Burkholderia cenocepacia infection, the inflammasome can be activated by bacterial effectors that are secreted through the bacterial secretion system. Once activated, the inflammasome cleaves GSDMD, which then targets mitochondria to mediate the release of mitochondrial ROS (mtROS). mtROS can directly target cytosolic bacteria or promote the clearance of bacteria through xenophagy, a selective form of autophagy.

Figure 3.. Regulation of pyroptosis by GBPs.

GBPs exhibit diverse mechanisms to activate inflammasomes in response to bacterial infections. GBPs can target bacteria in vacuoles or cytosol, as well as bind to released PAMPs such as LPS. GPBs facilitate caspase-4 activation in response to cytosolic free LPS or LPS packaged in outer membrane vesicles (OMVs). GBP-mediated caspase-4 activation can also occur by recruiting the caspase to the bacterial surface or by promoting the release of LPS into the cytosol. Additionally, GBPs, in conjunction with IRGB10, promote AIM2 inflammasome activation by facilitating bacterial lysis and liberation of bacterial DNA. Furthermore, GBP1 can activate the NLRP3 inflammasome during C. trachomatis infection by hydrolyzing GTP into GMP, which is then catabolized to uric acid that activates the NLRP3 inflammasome. However, it is unclear whether the uric acid concentration is sufficient for crystallization within the infected cell.

Figure 4.. Activation mechanisms of gasdermins.

Pyroptosis is triggered through the cleavage of gasdermin proteins, which involves both inflammasome-dependent and inflammasome-independent pathways. Gasdermin D (GSDMD), the prototype of gasdermins, can be activated by inflammatory caspases, including caspase-1/4/5/11, through the inflammasome-dependent pathway. Gasdermins can also divert apoptotic signaling towards pyroptosis through their cleavage. Caspase-8, traditionally known as an initiator of apoptosis, can induce pyroptosis by cleaving GSDMD under specific conditions. Caspase-8 can also cleave GSDMC, which is primarily expressed in epithelial tissues, leading to pyroptosis. Caspase-3 cleaves GSDME, transitioning from caspase-3-mediated apoptosis to pyroptosis. Furthermore, granzyme B, produced by cytotoxic lymphocytes, can directly cleave GSDME, resulting in pyroptosis independent of caspase-3. Granzyme A, another protease produced by cytotoxic lymphocytes, activates GSDMB, triggering pyroptosis in target cells. In addition to host-derived proteases, pathogen-derived factors can also activate gasdermins. For instance, the cysteine protease virulence factor SpeB produced by Streptococcus pyogenes cleaves GSDMA, inducing pyroptosis in keratinocytes.