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  • Review Article
  • Published:

Poxvirus tropism

Nature Reviews Microbiology volume 3, pages 201–213 (2005)Cite this article

Abstract

Despite the success of the WHO-led smallpox eradication programme a quarter of a century ago, there remains considerable fear that variola virus, or other related pathogenic poxviruses such as monkeypox, could re-emerge and spread disease in the human population. Even today, we are still mostly ignorant about why most poxvirus infections of vertebrate hosts show strict species specificity, or how zoonotic poxvirus infections occur when poxviruses occasionally leap into novel host species. Poxvirus tropism at the cellular level seems to be regulated by intracellular events downstream of virus binding and entry, rather than at the level of specific host receptors as is the case for many other viruses. This review summarizes our current understanding of poxvirus tropism and host range, and discusses the prospects of exploiting host-restricted poxvirus vectors for vaccines, gene therapy or tissue-targeted oncolytic viral therapies for the treatment of human cancers.

Key Points

  • Poxvirus host range varies markedly ? some viruses, such as variola and molluscum contagiosum virus (both of which are human-specific), exhibit strict species tropism, whereas others such as cowpox virus are able to infect multiple host species.

  • Members of four of the eight genera of chordopoxviruses can zoonotically infect man. For example, monkeypox virus can cause severe smallpox-like disease in humans that clinically resembles variola virus.

  • The species tropism that is exhibited by many poxviruses in terms of causing disease is frequently quite different from the range of cultured cells that can be infected by these viruses.

  • Specific host-cell receptors do not mediate the distinction between cells that are permissive as opposed to non-permissive for poxvirus infection. Rather, restrictive host cells fail to support the full replication cycle of the infecting poxvirus at a point downstream of binding and entry.

  • A variety of poxviral host-range genes have been identified that contribute to the control of permissive versus non-permissive infection of cultured mammalian cells. The gene products of these host-range genes regulate the ability of the virus to complete its cytoplasmic replication cycle.

  • The development of host-restricted vaccines, like modified vaccinia Ankara (MVA), that do not replicate in humans but that retain potent immunogenicity, will provide safer platforms for recombinant vaccines.

  • Another advance has been the development of poxvirus-based oncolytic vectors that replicate preferentially in human tumour cells.

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Figure 1: Examples of host-restricted poxviruses.
Figure 2: All poxviruses are morphologically similar.
Figure 3: Poxvirus replication cycle.
Figure 4: Intracellular signalling events modulate poxvirus tropism.
Figure 5: Origin of modified vaccinia Ankara strain.

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Acknowledgements

The author holds a Canada Research Chair in Molecular Virology, and is supported by operating grants from the Canadian Institutes of Health Research and the NCIC of Canada. The help of D. Hall in preparing the manuscript and the critical feedback from M. Stanford and M. Barry are gratefully appreciated.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Western Ontario, and Robarts Research Institute, Siebens-Drake Building, Room 133, 1400 Western Road, London, N6G 2V4, Ontario, Canada

    Grant McFadden

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Competing interests

I am co-founder of a biotechnology company (VIRON Therapeutics) which is developing anti-inflammatory proteins derived from viruses. However, the corporate agenda for this company is unrelated to this particular review.

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DATABASES

Entrez

Cowpox virus

Ectromelia virus

molluscum contagiosum virus

myxoma virus

vaccinia virus

variola virus

Infectious Disease Information

Monkeypox

SARS

smallpox

SwissProt

Nck

N-WASP

SPI-1

WIP

FURTHER INFORMATION

Poxvirus Bioinformatics Resouce Center

WHO smallpox slide set

Grant McFadden's laboratory

Glossary

ZOONOSIS

The infection of a novel host species, usually humans, by an animal virus that normally does not use man as a reservoir host.

PERMISSIVE HOST

A host species that manifests overt disease when exposed to a specific virus.

RESTRICTIVE CELLS

Cells that do not allow completion of the virus life cycle when exposed to a specific virus.

GLYCOSAMINOGLYCANS

A group of polysaccharides with repeating disaccharide units that are linked to proteoglycans located at the surface of most mammalian cells.

TOLL-LIKE RECEPTORS

(TLRs). Surface receptors that are pattern-recognition sentinels for recognizing pathogen infection and inducing innate antimicrobial responses.

ACTIN-TAIL POLYMERIZATION

A motility mechanism that assists the extrusion of certain pathogens, such as poxviruses, to facilitate infection of neighbouring cells.

MITOGENIC STIMULATION

The process by which many poxviruses express growth factor homologues that can trigger neighbouring cells from quiescence into an inappropriate S-phase that increases virus replication levels.

DENDRITIC CELLS

Cells of the immune system with characteristic tree-like projections. They participate in the recognition of pathogens and initiate the early phases of the host antiviral responses.

MOLECULAR CHAPERONE

Host proteins that assist in the folding or trafficking of host (and possibly viral) proteins.

SERPIN

Serine proteinase inhibitor, designed to bind and inhibit specific target proteinases. Poxviruses are the only viruses to express active members of this superfamily.

CATHEPSIN G

A host serine proteinase that can form inhibitory complexes with the poxviral SPI-1 serpin.

TH1 IMMUNE RESPONSE

A host response to a pathogen that is skewed to the preferential activation of cell-mediated pathways, especially cytotoxic T-cells. By contrast, TH2 immune responses are skewed towards the activation of humoral patyhways, especially antibodies.

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McFadden, G. Poxvirus tropism. Nat Rev Microbiol 3, 201–213 (2005). https://doi.org/10.1038/nrmicro1099

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