Microbial Inhibitors of Apoptosis

Abstract

Infection with microbial agents (bacteria, fungi, viruses and parasites) is a challenge to a host cell. The host cell's response to infection is complex and entails changes in the activity of a number of intracellular signalling pathways, commonly including the apoptotic machinery. Microbes, if they have evolved the capacity to infect mammals or other complex hosts, have to be able to deal with such defence systems. The lifestyle of microbes varies substantially – viruses, for instance, depend on an intact cell, whereas many bacteria grow on surfaces and are not sensitive to host cell apoptosis. What we know about microbial interference with host cell apoptosis is in accordance with these lifestyles. Viruses often directly target and inhibit the apoptosis machinery with specific proteins, whereas other microbes frequently also interfere with host apoptosis, but this interaction is more frequently indirect.

Key Concepts

  • Microbes (bacteria, fungi, viruses and parasites) can vary widely in terms of growth requirements and intimacy of association with host cells.
  • Apoptosis may be induced in cells infected with microbes as a defence mechanism.
  • A number of viruses carry genes whose products can directly interfere with the host cell's apoptosis apparatus.
  • Activation of host cells by microbes may enhance survival of the host cell or a responding immune cell.
  • Activation of antiapoptotic pathways in immune cells by microbial components is a regulatory mechanism of the immune response.

Keywords: apoptosis; virus; bacteria; host; immune system

Figure 1. The interaction between microbes and human host cells is determined by the microbial lifestyle. Viruses are intracellular parasites. They need parts of the cellular machinery for their replication and are vulnerable to apoptosis by the host cell. In the groups of bacteria and parasites there are different lifestyles. Some bacteria can grow only within the host cell and undergo differentiation into specialised forms before they can be transmitted between host cells and between hosts (obligate intracellular bacteria, e.g. Chlamydiae). Other bacterial genera can grow or at least live both inside and outside host cells (Listeria, Salmonella, Legionella and others; facultative intracellular bacteria). Apoptosis of the host cell usually does not vitally affect these bacteria although it may have indirect consequences such as through its effect on the immune response. Some bacteria are at least mainly extracellular, for instance, Streptococci and Escherichia coli. Apoptosis inhibition for these bacteria is least likely but may occur through the activation of prosurvival pathways. Among the groups of protozoan parasites, the lifestyles are similar to the ones discussed for bacteria.
Figure 2. Activation of prosurvival pathways by microbial agents. Cellular receptors (shown as two groups, the transmembrane Toll‐like receptors, TLR, and the cytosolic receptors, encompassing a number of different groups) can sense microbial components. These ligands are typically recognised by their structural composition but may vary considerably in actual molecular identity (e.g. TLR4 recognises bacterial lipopolysaccharide from many different bacteria that vary in terms of fatty acid and polysaccharide structure). Signalling through these receptors causes, among other events, the activation of prosurvival pathways, such as the MAPK, NF‐κB and PI3K pathways. In most cases, these pathways induce prosurvival genes that make the cell less susceptible to proapoptotic stimuli; modification of proteins such as ubiquitination and proteasomal degradation by the E3‐ligase βTrCP has also been reported. The mechanism acts upstream of the initiation of mitochondrial apoptosis. The precise nature of these genes in a given situation is largely unknown, but some candidates are shown.
Figure 3. Direct antiapoptotic effects by microbial proteins. Direct attack of the host cell's apoptosis machinery by microbial inhibitors is largely the domain of viruses. The biggest group of known viral apoptosis inhibitors is the family of proteins with similarity to Bcl‐2‐like prosurvival proteins (vBcl‐2s), which block the activation of Bax/Bak at or upstream of mitochondria. This strategy is used by a number of different viruses such as poxviruses, herpesviruses and adenoviruses. The viral proteins CrmA/SPI‐2 and vFLIP can, at least in experimental conditions, block death receptor‐induced apoptosis. Both may have different biological functions, as CrmA can also inhibit caspase‐1 (which may be more important because this blocks the release of proinflammatory mediators) as well as the effector of cytotoxic T cells, granzyme B and vFLIP may interfere with NF‐κB activation. The inhibitors vIAP and p35/p49 are only known in insect‐infecting baculoviruses where vIAPs probably prevent the activation of initiator caspases, whereas p35 as a pseudosubstrate blocks active caspases. CPAF is a bacterial protein with documented autonomous antiapoptotic activity. CPAF indirectly induces the degradation of BH3‐only proteins in Chlamydia‐infected cells and contributes to making them resistant to apoptosis. The Anaplasma protein Ats‐1 has been found to be transported into mitochondria and to have an antiapoptotic effect.
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Further Reading

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Häcker, Georg(Nov 2016) Microbial Inhibitors of Apoptosis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021984.pub2]