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Microbes & Immunity Host receptors in immunogenic cell death

the resultant N-terminal fragment instigating pyroptosis modulate and impede host pyroptosis, highlighting the
as a countermeasure against bacterial infection. perpetual evolutionary interplay between microbial
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Interestingly, the caspase-3-GSDME axis may also be virulence and host immunity.
activated by granzyme B (GZMB) within lung alveolar
epithelial cells infected by the H7N9 virus, resulting in 3.3. The last line of defense: Necrosis
an overwhelming cytokine response and pyroptosis. (4) Necrosis is another type of cell death induced by
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Furthermore, cytotoxic T lymphocytes and natural killer pathogen infections, characterized by rupture of the
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cells possess the capability to secrete serine proteases plasma membrane, nuclear swelling, and release of
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granzymes, targeting infected cells or cancer cells. cellular contents into the extracellular space, resulting
Granzyme A (GZMA) released from these cytotoxic in inflammation independent of caspases. During
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lymphocytes cleaves Gasdermin B (GSDMB) within pathogen infections, several mechanisms can lead to
targeted cells. The N-terminal domain of GSDMB forms necrosis: (1) Certain pathogens produce toxins or enzymes
pores on membranes, leading to pyroptosis. (5) In a that directly damage host cells and lead to necrosis. For
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separate mechanism, the AIM2 inflammasome detects example, the alpha-toxin of S. aureus causes the formation
and binds to cytosolic dsDNA signatures from invading of pores in the plasma membrane, resulting in cell swelling
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bacteria, thereby inducing AIM2 oligomerization, which and lysis. (2) Besides, the replication of bacteria in host
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in turn recruits the adaptor ASC. This complex then cells leads to altered homeostasis and the accumulation of
recruits pro-caspase-1, paving the way for inflammasome misfolded proteins, resulting in endoplasmic reticulum
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assembly and the induction of pyroptosis. 68 (ER) stress and subsequent necrosis. (3) Moreover,
pathogen infections can induce necrosis through the
Intriguingly, the proteolytically cleaved form of production of reactive oxygen species (ROS). For
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GSDMD possesses the ability to directly lyse bacteria by example, the uracil released by the Bacillus thuringiensis
assembling pores in the bacterial cell membrane. More promotes mitochondrial dysfunction and the activation
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specifically, this happens when its N-terminal fragment of NADPH oxidases, which then leads to the production
binds with cardiolipin, a phospholipid localized in the of ROS. ROS subsequently induces oxidative stress and
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cell membranes of bacterial species such as Staphylococcus damages cellular components, resulting in necrosis. (4)
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aureus and Bacillus megaterium. 117 Finally, cellular Ca dysregulation during infections also
2+
2+
To counter the damage caused by pyroptosis, triggers necrosis in infected cells, the disruption of Ca
2+
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bacterial pathogens have evolved effective strategies to homeostasis leads to an influx of Ca into the cytoplasm.
2+
inhibit the activation of pyroptosis within infected host Excessive cytoplasmic Ca levels can activate various
cells: (1) Among these, Yersinia pestis capitalizes on enzymes that perturb cellular processes and ultimately lead
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the functionalities of its effectors YopK and YopM. While to necrotic cell death. 135
YopK inhibits the recognition of its T3SS by the NLRC4 The consequences of pathogen-induced necrosis are
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inflammasome, YopM inhibits the activation of the pyrin usually detrimental to both the infecting organisms and
inflammasome. This dual action ultimately hinders the hosts. Cellular contents released upon cellular damage
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caspase-1 activation, effectively suppressing the initiation or inflammation can lead to the activation of autoimmune
of pyroptosis. (2) L. pneumophila, for instance, employs responses and the amplification of inflammation, thereby
its effector SdhA to maintain the structural integrity of its exacerbating tissue destruction as well as broader systemic
replicative vacuole, thus preventing the leakage of DNA effects.
into the host cytoplasm, which will avoid pyroptosis
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caused by AIM2 activation and by IFN-I induction. (3) 3.4. Lysosomal cell death triggered by microbes
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Furthermore, S. flexneri, implicated in bacillary dysentery, Lysosomes are membrane-bound organelles containing
inhibits LPS-induced pyroptosis through its effector various hydrolytic enzymes involved in intracellular
OspC3. OspC3 catalyzes arginine ADP-riboxanation degradation and cell recycling. During bacterial
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on caspase-4/-11, halting the proteolytic processing of infections, lysosomes can exhibit both beneficial and
GSDMD and subsequent pyroptosis. Similar to Shigella detrimental effects on infected cells depending on the
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OspC3, the effector CopC, secreted by Chromobacterium magnitude of lysosomal perturbations. Concurrently,
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violaceum, also possesses ADP-riboxanase activity. Once lysosomes contribute to host defenses by fusing with
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specifically interacting with host calmodulin (CaM), CopC phagosomes to degrade the engulfed bacteria. This
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mediates arginine ADP-riboxanation of apoptotic caspases process aids in the eradication of intracellular pathogens
encompassing caspase-7/-8/-9. Collectively, bacterial and prompts immune reactions. However, microbial
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pathogens deploy a myriad of effectors to intricately infections can compromise lysosomal membrane integrity,
Volume 1 Issue 2 (2024) 36 doi: 10.36922/mi.4264