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  • Review Article
  • Published:

Cytokine determinants of viral tropism

Nature Reviews Immunology volume 9, pages 645–655 (2009)Cite this article

Key Points

  • Viral tropism is the ability of a given virus to productively infect a particular cell (cellular tropism), tissue (tissue tropism) or host species (host tropism). Various host innate immune antiviral cytokines, in particular the interferons (IFNs) and tumour necrosis factor (TNF), have a role in mediating viral tropism at these different levels.

  • Type I IFNs have a key role in determining the tropism of various viruses. These IFNs probably mediate their effects through the induction of interferon-stimulated genes; however, the exact genes that determine tropism for each virus have not been fully characterized.

  • Type II IFN has a more limited role in determining viral tropism, contributing mainly in the central nervous system.

  • The ability of type III IFNs to dictate viral tropism is largely determined by the tissue-specific expression of the type III IFN receptor. Type III IFNs probably have a major role in determining viral tropism in tissues and cells of epithelial origin.

  • TNF influences viral tropism through altering the expression of cell surface receptors required for viral infection. TNF can alter viral tropism in both a positive and negative manner.

  • Pro-inflammatory cytokines, particularly the IFNs, might be good therapeutic agents against various viruses that are capable of causing zoonotic infections. However, a better understanding of the mechanisms involved in these treatments is needed.

  • Defects in the IFN and TNF responsiveness of cancer cells can be exploited to create tumour-specific viral infections in an approach known as viral oncolysis. The synergistic responses of multiple cytokines might have a key role in this phenomenon.

Abstract

The specificity of a given virus for a cell type, tissue or species — collectively known as viral tropism — is an important factor in determining the outcome of viral infection in any particular host. Owing to the increased prevalence of zoonotic infections and the threat of emerging and re-emerging pathogens, gaining a better understanding of the factors that determine viral tropism has become particularly important. In this Review, we summarize our current understanding of the central role of antiviral and pro-inflammatory cytokines, particularly the interferons and tumour necrosis factor, in dictating viral tropism and how these cytokine pathways can be exploited therapeutically for cancer treatment and to better counter future threats from emerging zoonotic pathogens.

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Figure 1: Levels of viral tropism.
Figure 2: Cytokine-mediated regulation of viral tropism.
Figure 3: Cytokine-mediated viral tropism in tumour tissues.

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Acknowledgements

This work was supported by the University of Florida College of Medicine, USA.

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Author notes

  1. Mohamed R. Mohamed, Masmudur M. Rahman and Eric Bartee: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Academic Research Building, Room R4-295, Gainesville, Florida 32610, USA.,

    Grant McFadden, Mohamed R. Mohamed, Masmudur M. Rahman & Eric Bartee

Authors
  1. Grant McFadden
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  2. Mohamed R. Mohamed
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Correspondence to Grant McFadden.

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Glossary

Antiviral state

An intracellular state in which virus replication is blocked, restricting the spread of virus to neighbouring cells. By signalling through the type I IFN receptor, IFNs activate the inducible expression of hundreds of genes that together establish the antiviral state.

Zoonotic infection

The ability of a given virus to cross the host species barrier from its current or long-term evolutionary host to humans, causing disease.

Oncolytic virotherapy

The treatment of cancer by using a virus specifically tailored to infect cancer cells while leaving normal cells unharmed. The engineering of such viruses involves ensuring that the viruses can replicate only inside cancer cells, lysing the cells when they exit, and ensuring a high dosage at the site of the tumour.

Interferon-stimulated genes

(ISGs). Genes that are induced or expressed as a result of IFN action and encode proteins such as: PKR, a dsRNA-activated kinase that phosphorylates eIF2α with a consequent blockade of the translation of most cellular and viral mRNAs; oligoadenylate synthases, which produce 2'-5' oligoadenylates, which in turn activate the latent nuclease RNase L, resulting in the degradation of both viral and host RNA transcripts; and myxovirus resistance proteins, which possibly interfere with viral assembly and trafficking in the cell.

Plasmacytoid dendritic cell

An immature dendritic cell with a morphology that resembles that of a plasma cell. Plasmacytoid dendritic cells produce type I IFNs (that is, IFNα and IFNβ) in response to viral infection.

IFN-stimulated gene factor 3 (ISGF3) complex

An IFN-induced signal transduction and transcription activation complex. ISGF3 is assembled from three proteins, STAT1, STAT2 and interferon-regulatory factor 9. Of these components, STAT2 provides a fundamental and essential transcription activation function.

Oligodendrocyte

A type of glial cell that creates the myelin sheath that insulates axons and improves the speed and reliability of signal transmission by neurons.

Alveolar type II (ATII) epithelial cell

ATII cells are cuboidal in shape, with short microvilli along their apical surface. They secrete a pulmonary surfactant that decreases the surface tension of the alveolar surface, allowing the alveoli to expand during inspiration and preventing their collapse during expiration.

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McFadden, G., Mohamed, M., Rahman, M. et al. Cytokine determinants of viral tropism. Nat Rev Immunol 9, 645–655 (2009). https://doi.org/10.1038/nri2623

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