Live Variola Virus Considerations for Continuing Research (2009) / Chapter Skim
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9 Discovery Research
9 Discovery Research
Pages 123-130
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From page 123... ...
Given that variola exclusively infects humans under natural conditions and has adapted to specifically modulate the human immune system, much could be learned about human biology from studies with this virus. As variola proteins that dampen or manipulate a particular immune response are identified, these viral proteins, or portions thereof, become candidate novel therapeutics for autoimmune or inflammatory diseases in which the host response is aberrant or overactive.
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From page 124... ...
systems biology and smallpox Pathogenesis While some progress has been made since 1999 toward elucidating the pathogenesis of smallpox and characterizing viral immunomodulatory activities, much more remains to be learned. The synthesis of molecular biology, genomics, and computational biology, or "systems biology," offers promising approaches for understanding smallpox pathogenesis, human immunology, and other aspects of host defense and for identifying novel therapeutic targets and strategies.
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From page 125... ...
Bearing this in mind, it is possible that some variola proteins will require analysis in the context of live infection of human cells or through coexpression experiments with a number of other viral protein partners. Subversion and modulation of human immune responses At the time of the 1999 IOM report, it was known that poxviruses encode the largest number of putative immunomodulatory proteins of any group of mammalian viruses (Barry and McFadden, 1997)
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From page 126... ...
Although functional analysis of related immunomodulatory proteins from other orthopoxviruses can provide insight into the activities of their variola-encoded counterparts, this approach may not always provide an accurate understanding of the virulence factors of variola. For instance, direct comparison of the variola-encoded complement inhibitor SPICE with similar evasion proteins encoded by vaccinia (VCP)
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From page 127... ...
Variations in the expression of various immunomodulatory proteins could explain the dramatic differences in pathogenesis and mortality rates that are associated with these two forms of smallpox, as well as with different strains of variola major. In addition to evading host T cell responses, poxviruses are known to subvert antiviral innate immune responses, including the attenuation of type I interferon, proinflammatory cytokines, and chemokine production.
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From page 128... ...
Moreover, some viral proteins may have multiple, unrelated functions or may function primarily in a complex or in concert with other viral or host cell proteins, and thus may fail to demonstrate the relevant phenotype if expressed in the wrong cell type or in the absence of a productive variola virus infection. Many viral immunomodulatory proteins act with high specificity against a particular immune function or pathway and do so at very low doses (femtomolar to nanomolar)
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From page 129... ...
Live virus would also be needed for the use of systems biology approaches in an improved nonhuman primate model with the goal of identifying novel therapeutic targets. With more than 40 strains of variola now having been sequenced, there is ample opportunity to study specific variola proteins, and thereby advance understanding of host–pathogen interactions and develop potential new therapeutic drugs.
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From page 130... ...
2008. RIG-I mediates the co-induc tion of tumor necrosis factor and type I interferon elicited by myxoma virus in primary human macrophages.
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