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Microbes & Immunity Host receptors in immunogenic cell death

number of receptors using mechanisms that are strikingly appears to function by inhibiting the activity of a pro-
similar yet significantly distinct. 13 death member of the Bcl2 protein family, whereas ShdA
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functions by maintaining the integrity of the bacterial
3.1. Highly regulated cell death: Apoptosis phagosome (Figure 2).
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Apoptosis is a highly regulated form of cell death In light of the immune-defense functions of apoptosis,
commonly observed in normal development and during pathogens have evolved a wide array of strategies to
pathogen infections. This process is a multifaceted counteract and inhibit apoptosis, thereby ensuring
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orchestration involving a series of messengers and their successful replication within host cells: (1) some
enzymes, including members of the caspase family and bacterial species synthesize proteins that specifically
mitochondrial-associated proteins without discharging engage with and proteolytically cleave vital elements of
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cellular components into the extracellular milieu. Hence, the host’s apoptotic pathways. An illustration of this is
apoptosis is considered to proceed without eliciting the AIP56 toxin secreted by Photobacterium damselae
an inflammatory response. Therefore, it is considered subsp. piscicida, which catalyzes the cleavage of NF-κB
immunologically silent, distinct from the inflammatory p65, consequently inhibiting the NF-κB-dependent
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cell death pyroptosis. Characteristics of infected cells transcription of pro-inflammatory genes. (2) Certain
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undergoing apoptosis include DNA fragmentation, nuclear bacterial pathogens prevent apoptosis by modulating
condensation, cytoplasmic blebbing, cell shrinkage, and 95,96
the formation of apoptotic bodies. Induction of apoptosis autophagy. For example, Salmonella Typhimurium can
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facilitates the removal of infected cells, thus preventing the switch the fate of host cells by triggering autophagy and
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spread of pathogens into deep tissues. preventing infected cells from undergoing apoptosis.
This is achieved by the leakage of amino acids from the
The induction of apoptosis by infection occurs through pores formed by its T3SS1, which activates acute starvation
multiple distinct pathways: (1) caspases are proteases stress, triggering the eIF2α/ATF4-mediated autophagy
that are activated in a cascade manner upon specific pathway. (3) Many bacteria can inhibit the initiation of
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apoptotic stimuli, such as LPS and Fas ligand (FasL). apoptosis by inducing the transcription of anti-apoptotic
More precisely, the interaction between FasL derived from genes. For example, L. pneumophila infection induces
Helicobacter pylori and its cognate Fas receptor (CD95) the activation of the MAP kinase pathway in a Dot/Icm-
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and tumor necrosis factor receptor 1 (TNFR1), triggers dependent manner, resulting in increased expression of
the assembly of death-inducing signaling complex (DISC), anti-apoptotic proteins. (4) Effector proteins secreted
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resulting in the activation of caspases. (2) Infection- by some bacteria directly hijack constitutes of apoptotic
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induced apoptosis can also occur through the impairment pathways. As an illustration, L. pneumophila effector SidF
of mitochondrial integrity, accompanied by the release selectively antagonizes the activities of two pro-apoptotic
of pro-apoptotic factors. For example, the toxin EspC Bcl2 members, thereby impeding the apoptosis of infected
secreted by M. tuberculosis triggers the permeabilization cells. In summary, bacterial pathogens employ complex
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of the outer mitochondrial membrane (MOMP), allowing approaches with multiple effectors to manipulate host
2+
the release of cytochrome c, calcium ions (Ca ), and other apoptosis pathways to counteract elimination caused by cell
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apoptogenic factors into the cytoplasm. Cytochrome death. These balancing acts between apoptosis induction
c then activates caspase-9, which initiates the intrinsic and inhibition highlight the evolutionary mechanisms
apoptotic pathway. (3) Recent studies showed that pathogens adapt to thrive within hosts.
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infections by L. pneumophila lead to extensive apoptosis
in specialized phagocytes, such as dendritic cells. From Investigating the mechanisms of apoptosis in response
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a molecular perspective, infections by these pathogens tip to pathogen infections holds substantial clinical relevance,
the balance between the pro-apoptotic and anti-apoptotic as it elucidates the intricacies of the host’s anti-bacterial
constituents of the Bcl-2 protein family, leading to the immune response and identifies potential therapeutic
initiation of the MOMP and subsequent activation of targets for other diseases, including inflammatory bowel
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caspase-3-mediated apoptosis. Intriguingly, infections disease and cancers. Recent studies suggest that chronic
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of L. pneumophila in permissive macrophages did not infections can precipitate sustained inflammation, in part
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exhibit obvious apoptosis, suggesting that L. pneumophila due to the suppression of apoptosis in immune cells.
possesses mechanisms to prevent infected macrophages Modulating apoptotic pathways in these cells can attenuate
from apoptotic cell death. This hypothesis gained inflammation and facilitate the resolution of chronic
experimental support when it was observed that infections infections. Moreover, the dysregulation of apoptosis is a
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by L. pneumophila strains lacking sdhA or sidF elicited defining characteristic of cancer. By deciphering the
enhanced induction of apoptosis in macrophages. SidF ways in which pathogens modulate apoptotic processes,
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Volume 1 Issue 2 (2024) 34 doi: 10.36922/mi.4264