Abstract
Host cell death programs are fundamental processes that shape cellular homeostasis, embryonic development, and tissue regeneration. Death signaling and downstream host cell responses are not only critical to guide mammalian development, they often act as terminal responses to invading pathogens. Here, we briefly review and contrast how invading pathogens and specifically Staphylococcus aureus manipulate apoptotic, necroptotic, and pyroptotic cell death modes to establish infection. Rather than invading host cells, S. aureus subverts these cells to produce diffusible molecules that cause death of neighboring hematopoietic cells and thus shapes an immune environment conducive to persistence. The exploitation of cell death pathways by S. aureus is yet another virulence strategy that must be juxtaposed to mechanisms of immune evasion, autophagy escape, and tolerance to intracellular killing, and brings us closer to the true portrait of this pathogen for the design of effective therapeutics and intervention strategies.
Highlights
Human innate immune defenses substantially contribute to microbial clearance during infection [1, 2]
S. aureus-mediated demolition of host tissues and immune cells involves all key mechanisms by which programmed host cell death can occur, including immunologically silent apoptosis and highly inflammatory signaling pathways such as pyroptosis
Does S. aureus gain any advantage by provoking both non- and pro-inflammatory cell death programs? This answer may depend on the environment where the pathogen proliferates as distinct host defense arsenals may be triggered in different organ tissues
Summary
Human innate immune defenses substantially contribute to microbial clearance during infection [1, 2]. Pore-forming toxin-mediated apoptosis involves potassium efflux from damaged cells and caspase-2initiated cell death, or breakdown of the mitochondrial membrane potential, leading to the release of apoptogenic factors (e.g., cytochrome c) and activation of intrinsic death signaling pathway [31,32,33, 36]. Multiple other studies revealed that S. aureus pore-forming toxins contribute to this phenomenon, and trigger the formation of the NLRP3 inflammasome, cytokine release, pyroptosis, or pyroptotic-like cell death (Table 1).
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