Listeria monocytogenes: The Impact of Cell Death on Infection and Immunity

Abstract

Listeria monocytogenes has evolved exquisite mechanisms for invading host cells and spreading from cell-to-cell to ensure maintenance of its intracellular lifecycle. As such, it is not surprising that loss of the intracellular replication niche through induction of host cell death has significant implications on the development of disease and the subsequent immune response. Although L. monocytogenes can activate multiple pathways of host cell death, including necrosis, apoptosis, and pyroptosis, like most intracellular pathogens L. monocytogenes has evolved a series of adaptations that minimize host cell death to promote its virulence. Understanding how L. monocytogenes modulates cell death during infection could lead to novel therapeutic approaches. In addition, as L. monocytogenes is currently being developed as a tumor immunotherapy platform, understanding how cell death pathways influence the priming and quality of cell-mediated immunity is critical. This review will focus on the mechanisms by which L. monocytogenes modulates cell death, as well as the implications of cell death on acute infection and the generation of adaptive immunity.

Keywords: CD8+ T-cells; Listeria monocytogenes; apoptosis; cell death; cell-mediated immunity; necrosis; pyroptosis.

Figure 1

Induction of necrosis by L. monocytogenes and implications on immunity and virulence. LLO can induce traditional necrosis; as such, L. monocytogenes has evolved mechanisms to avoid lytic activity of LLO outside the vacuole, including an acidic pH optimum and ubiquitin-mediated degradation. Strains of L. monocytogenes-induced to express active LLO in the cytosol lead to membrane pore formation and osmotic lysis. In addition, L. monocytogenes induces programmed necrosis. Multiple proposed pathways exist, including a RIPK3-mediated pathway leading to pore formation by MLKL and an IRF3 dependent pathway that occurs by a yet undefined mechanism. Induction of necrosis ultimately leads to a host-protective neutrophil-mediated clearance of L. monocytogenes and an impaired cell-mediated immune response. Impaired immunity is at least in part mediated by diminished numbers of cross-presenting dendritic cells, as well as lower CD86 expression.

Figure 2

Mechanism and effects of pyroptosis during L. monocytogenes infection. L. monocytogenes can activate the NLRC4, AIM2, and NLRP3 inflammasomes through flagellin, bacterial DNA release, and LLO-mediated pore formation, respectively. Inflammasome activation results in caspase-1 autoproteolysis followed by cytokine and eicosanoid release, and the induction of the lytic form of cell death called pyroptosis. Importantly, as this leads to the loss of the intracellular niche, L. monocytogenes has evolved strategies to avoid inflammasome activation. It represses flagellin during infection through MogR, regulates expression and activity of LLO, and prevents release of bacterial DNA through genes designed to combat cell wall stress (yvcK, oat, pgd). Activation of inflammasomes results in decreased bacterial virulence, potentially through direct bacterial pore formation by GSDMD, bacterial trapping in pore-induced intracellular traps, and potential redundant mechanisms of extracellular killing. Additionally, inflammasome activation impairs cell-mediated immunity through a suboptimal inflammatory milieu associated with proinflammatory cytokines, eicosanoids, and pyroptosis-released DAMPS.

Figure 3

Mechanism and impact of apoptosis during L. monocytogenes infection. (A) Direct infection of hepatocytes with L. monocytogenes leads to apoptosis, potentially through a TNFα and/or Bcl-2 family member-mediated mechanism. Induction of apoptosis through either pathway ultimately leads to caspase-3 activation. Hepatocyte apoptosis is host-protective through release of chemoattractants and subsequent neutrophil-mediated L. monocytogenes killing. The complete impact on cell-mediated immunity, if any, is unknown. (B) In contrast to hepatocytes, L. monocytogenes-mediated lymphocyte killing is independent of direct infection. Lymphocyte apoptosis is instead induced through sublytic concentrations of LLO and/or type I IFN from infected phagocytes. Type I IFN produced after STING activation leads to antigen-independent preactivation of T cells as indicated by CD69 expression, potentially sensitizing them to apoptotic capabilities of LLO. Uptake of apoptotic bodies by secondary phagocytes leads to increased bacterial virulence though IL-10 production, as well as diminished cell-mediated immunity, through both IL-10-dependent and potentially IL-10-independent mechanisms.

Figure 3

Mechanism and impact of apoptosis during L. monocytogenes infection. (A) Direct infection of hepatocytes with L. monocytogenes leads to apoptosis, potentially through a TNFα and/or Bcl-2 family member-mediated mechanism. Induction of apoptosis through either pathway ultimately leads to caspase-3 activation. Hepatocyte apoptosis is host-protective through release of chemoattractants and subsequent neutrophil-mediated L. monocytogenes killing. The complete impact on cell-mediated immunity, if any, is unknown. (B) In contrast to hepatocytes, L. monocytogenes-mediated lymphocyte killing is independent of direct infection. Lymphocyte apoptosis is instead induced through sublytic concentrations of LLO and/or type I IFN from infected phagocytes. Type I IFN produced after STING activation leads to antigen-independent preactivation of T cells as indicated by CD69 expression, potentially sensitizing them to apoptotic capabilities of LLO. Uptake of apoptotic bodies by secondary phagocytes leads to increased bacterial virulence though IL-10 production, as well as diminished cell-mediated immunity, through both IL-10-dependent and potentially IL-10-independent mechanisms.