Monkeypox Genetics - Identification of Virulence Factors Grant uri icon

abstract

  • Monkeypox virus (MPV) is a serious and emerging pathogen that causes smallpox-like disease in humans, but smallpox vaccination is not fully protective from disease. Our long term goal is to identify the MPV genes and mechanisms that make this virus so virulent in primates/humans. We and others have identified 2 clades of MPV, one high and one low virulence in man and nonhuman primates. Isolates of both clades have been sequenced and candidate genes responsible for these virulence differences postulated. One possibility is that only the high virulence MPV clade members can replicate in certain key cell types, and indeed one major identified gene difference is a known poxvirus host range/replication gene. We propose to investigate the genetic differences between the high and low virulence MPV clades. In the first year of this study, we will construct fluorescently-tagged recombinant high and low-virulence monkeypox isolates and determine their ability to replicate in a spectrum of animal and human cell lines and primary cells in vitro. This will identify host range/tropism differences between the clades, possibly identify surrogate in vitro assays for virulence, and produce the tagged viruses required for future studies in nonhuman primates where candidate virulence genes will be deleted or swapped for in vivo virulence studies. Identifying specific MPV genes important for human virulence is an important step in understanding all poxvirus infections of humans, and should facilitate the design of effective treatment strategies and potentially drug development. It also has the potential to shed light on the actual pathologic mechanisms of MPV disease, including potentially the basis for the presumptive "cytokine storm" that some believe mediates poxvirus virulence in man.

date/time interval

  • July 2008 - February 2009