Microbial Inhibitors of Apoptosis

Georg Häcker, Technische Universität München, Munich, Germany

Published online: September 2009

DOI: 10.1002/9780470015902.a0021984

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 more indirectly.

Key concepts:

  • Microbes (bacteria, fungi, viruses and parasites) can vary widely in terms of growth requirements and intimacy of association with host cells.
  • Apoptosis is commonly induced in cells infected with microbes.
  • In infections with obligate intracellular agents, apoptosis can be a defence mechanism of the host cell.
  • A number of viruses carry genes whose products can directly interfere with the host cell's apoptosis apparatus.
  • Many cells become activated when encountering microbial agents, and this activation may entail the triggering of pro-survival pathways in the host 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 specialized 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 pro-survival pathways. Among the groups of protozoan parasites the lifestyles are similar to the ones discussed for bacteria.
Figure 2. Activation of pro-survival pathways by microbial agents. Cellular receptors (shown are by way of example of two groups, the Toll-like receptors, TLR, and the nod-like receptors, NLR) can sense microbial components. These ligands are typically recognized by their structural composition but may vary considerably in actual molecular identity (e.g. TLR4 recognizes 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 pro-survival pathways, such as the NFB and PI3K pathways. In most cases, these pathways induce pro-survival genes that make the cell less susceptible to pro-apoptotic stimuli; modification of proteins such as bad phosphorylation 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 pro-survival 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 pro-inflammatory mediators) and vFLIP may interfere with NFB 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 the only bacterial protein whose autonomous antiapoptotic activity is well-documented. CPAF indirectly induces the degradation of BH3-only proteins in Chlamydia-infected cells and makes them resistant to apoptosis.
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Related Sub-Topics:

Immunodeficiency | Infection | Mechanisms of Cell Death, Senescence and Metabolism | Medical Microbiology | Biosynthesis
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Article Title: Microbial Inhibitors of Apoptosis
 
How to Cite close
Häcker, Georg(Sep 2009) Microbial Inhibitors of Apoptosis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021984]