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  • Review Article
  • Published:

Apoptosis in animal models of virus-induced disease

Nature Reviews Microbiology volume 7, pages 144–155 (2009)Cite this article

Key Points

  • Apoptosis occurs in a wide range of human diseases.

  • In animal models of virus-induced disease, apoptosis correlates with viral titre and can be found in areas targeted by viral infection, which indicates that viruses induce apoptosis in animal models of virus-induced disease.

  • Apoptosis correlates with disease severity, suggesting that apoptosis is a mechanism of virus-induced injury and disease.

  • Apoptosis can be triggered by the immune system or by the interaction of viral proteins with host signalling pathways.

  • Inhibition of apoptosis has mixed effects on viral titre but typically has a beneficial effect on virus-induced disease.

Abstract

Apoptosis is associated with virus-induced human diseases of the central nervous system, heart and liver, and causes substantial morbidity and mortality. Although virus-induced apoptosis is well characterized in individual cells in cell culture, virus-induced apoptosis in vivo and the role of apoptosis in virus-induced disease is not well established. This Review focuses on animal models of virus-induced diseases of the central nervous system, heart and liver that provide insights into the role of apoptosis in pathogenesis, the pathways involved and the potential therapeutic implications.

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Figure 1: Caspase-dependent apoptosis.
Figure 2: Inhibition of caspase 3, apoptosis (caspase 3 activation) and survival in reovirus-infected mice.

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Acknowledgements

Work in the authors' laboratory was supported by the National Institutes of Health (grant numbers T32AI07537, 5RO1NS050138 and 1RO1NS051403) and a VA Merit and Career Development Award. K.L.T. is supported by the Reuler–Lewin Family Professorship.

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Authors and Affiliations

  1. Department of Neurology, University of Colorado, Denver Health Sciences Programs, Anschutz Medical Campus, Aurora, 80045, Colorado, USA

    Penny Clarke & Kenneth L. Tyler

  2. Department of Immunology, University of Colorado, Denver Health Sciences Programs, Anschutz Medical Campus, Aurora, 80045, Colorado, USA

    Kenneth L. Tyler

  3. Department of Medicine, University of Colorado, Denver Health Sciences Programs, Anschutz Medical Campus, Aurora, 80045, Colorado, USA

    Kenneth L. Tyler

  4. Department of Microbiology, University of Colorado, Denver Health Sciences Programs, Anschutz Medical Campus, Aurora, 80045, Colorado, USA

    Kenneth L. Tyler

  5. Denver Vetaren's Administration, Denver, 80220, Colorado, USA

    Kenneth L. Tyler

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Correspondence to Penny Clarke.

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Glossary

Extrinsic apoptotic pathway

An apoptotic signalling pathway that is triggered by the binding of ligands to cell-surface death receptors and culminates in the activation of the initiator caspase, caspase 8.

Intrinsic apoptotic pathway

An apoptotic signalling pathway that involves the release of pro-apoptotic factors from the mitochondria and activation of the initiator caspase, caspase 9.

Cytotoxic T lymphocyte

A T lymphocyte that induces the death of pathogen-infected cells.

Oligonucleosomal DNA laddering

A generally accepted biochemical criterion of apoptosis that involves cleavage of DNA into 180 bp fragments by a caspase-activated DNase.

TUNEL

(Terminal deoxynucleotidyl transferase dUTP nick end labelling). A method used to label free ends of DNA, which increase during apoptosis owing to the action of a caspase-activated DNase.

Astrogliosis

An abnormal increase in the number of astrocytes.

Microglial proliferation

An abnormal increase in the number of microglia.

Inducible nitric oxide synthase

An enzyme involved in the generation of nitric oxide, which can result in cell death through apoptosis or necrosis.

Macrophage

A cell within tissues that originates from specific white blood cells called monocytes. Monocytes and macrophages are phagocytes that engulf and then digest cellular debris and pathogens. They also stimulate lymphocytes to respond to the pathogen.

Lymphocyte

A white blood cell from the vertebrate immune system. Lymphocytes include large granular lymphocytes, commonly known as natural killer (NK) cells, and small lymphocytes (T and B cells). NK cells are a part of the innate immune system and help defend the host from tumours and virally infected cells by releasing cytotoxic granules. T cells and B cells are the main cellular components of the adaptive immune response. B lymphocytes respond to pathogens by producing large quantities of antibodies that neutralize foreign objects, such as bacteria and viruses. T cells include helper T cells, which produce cytokines that direct the immune response, and cytotoxic T cells, which induce the death of pathogen-infected cells.

Neutrophil

The most abundant type of white blood cell in humans. Neutrophils are normally found in the bloodstream and form an essential part of the immune system. However, during the acute phase of inflammation, neutrophils migrate towards the site of inflammation, usually as a result of bacterial infection.

Fas ligand

A member of the tumour necrosis factor family of cytokines that triggers apoptosis following the binding of cell-surface receptors.

TRAIL

(Tumour necrosis factor (TNF)-related apoptosis inducing ligand). A member of the TNF family of cytokines that triggers apoptosis following the binding of cell-surface receptors.

Microglia

A type of glial cell that acts as the first and main form of active immune defence in the central nervous system.

Astrocyte

A type of non-neuronal glial cell that performs many functions, including biochemical support of endothelial cells, that form the blood–brain barrier, provision of nutrients to the nervous tissue and aiding the repair and scarring process in the brain.

Reactive oxygen species

(ROS). Highly reactive ions or very small molecules that include oxygen ions, free radicals and peroxides. During oxidative stress, increased ROS levels can result in substantial damage to cell structures.

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Clarke, P., Tyler, K. Apoptosis in animal models of virus-induced disease. Nat Rev Microbiol 7, 144–155 (2009). https://doi.org/10.1038/nrmicro2071

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