Viruses and Apoptosis
The first thing you need to know about this topic is how to pronounce it! If you were an Ancient Greek, you may have said “ap-a-tow-sis”, but most people these days say “a-pop-tow-sis”, and everyone knows what they mean, so don’t worry about it. Apoptosis or “programmed cell death”, is a critical mechanism in tissue remodeling during embryonic development, and in cell killing by the immune system.
If you think about the immune response to infection, the first thing which might come to your mind are antibodies. These are frequently of importance in fighting invading microbes, but in the case of intracellular organisms such as viruses, parasites and some bacteria, antibodies are of limited help. In these cases, a cellular immune response is required which can detect and kill infected body cells and prevent the infection from spreading.
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There are two basics ways in which a cell can die: necrosis or apoptosis. Necrosis is the normal response of cells to injury caused by toxins or environmental stress and is marked by a non-specific changes such as:
- disruption of the plasma membrane and nuclear envelope
- rupture of membrane-bounded organelles such as mitochondria and lysosomes
- cell swelling
- random fragmentation of DNA/RNA
- influx of calcium ions into the cell and loss of membrane electrical potential
The release of cellular components from dying (necrotic) cells causes a localized inflammatory response by the cells of the immune system. This frequently leads to damage to adjacent cells/tissue – sometimes called “bystander” cell damage. In contrast to necrosis, apoptosis is a tightly regulated process controlled by complex molecular cascades, and is marked by:
- cell shrinkage
- condensation and clumping of chromatin
- a regular pattern of DNA fragmentation
- “bubbling off” of cellular contents into small membrane bounded vesicles (“blebbing”) which are subsequently phagocytosed by macrophages, preventing inflammation.
When triggered by the appropriate signals, immune effector cells such as cytotoxic T lymophocytes (CTLs) and natural killer (NK) cells release previously manufactured lytic granules stored in their cytoplasm. These act on the target cell and induce apoptosis by two mechanisms. The first of these is the release of cytotoxins such as perforin (also known as cytolysin), a peptide related to complement component C9. On release, this polymerizes to form polyperforin, which forms trans-membrane channels, resulting in permeability of the target cell membrane. Other granules contain granzymes, which are serine proteases related to trypsin. The perforin and the granzymes act collaboratively, the membrane pores formed by polyperforin allowing the entry of granzymes into the target cell. In addition, these membrane channels allow the release of intracellular calcium from the target cell, which also triggers apoptotic pathways. The second method by which CTLs (but not NK cells) can induce apoptosis is by expression of Fas ligand on their surface. This protein binds to Fas (CD95) on the surface of the target cell, triggering apoptosis by activation of cellular proteases known as caspases, which in turn trigger a cascade of events leading to apoptosis.
Apoptosis is an important response to virus infection. The regulation of apoptosis is complex, but in brief, virus infections disturb normal patterns of cellular biochemistry and frequently trigger an apoptotic response. Many different mechanisms may be involved:
- Receptor signalling: Binding of virus particles to cellular receptors may trigger signalling mechanisms resulting in apoptosis.
- PKR activation: The interferon effector PKR may be activated by some viruses.
- p53 activation: Viruses which interact with p53 may cause either growth arrest or apoptosis.
- Transcriptional disregulation: Viruses transcriptional regulatory proteins may trigger an apoptotic response.
- Foreign protein expression: Overexpression of virus proteins at late stages of the replication cycle can cause apoptosis by a variety of mechanisms.
To counteract this cellular burglar alarm, many if not most viruses have evolved mechanisms to repress apotosis:
- Bcl-2 homologs: negative regulator of apoptosis.
- Caspase inhibition
- Fas/TNF inhibition: signals blocked.
- p53 inhibition: viruses which interact with p53 have evolved proteins to counteract triggering of apoptosis.
- and many other mechanisms.
That’s a very brief overview of apoptosis and its role in cell killing by the immune system. If you want more details here are some references:
- A time to kill: viral manipulation of the cell death program. J Gen Virol. 2002 83: 1547-1564
- How apoptosis got the immune system in shape. Eur J Immunol. 2007 37: S61-70
- PubMed
Tags: Biology, Health, Immunology, Medicine, Microbiology, Podcast, Science, Virology
