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Principal Investigator: BRIAN M WARD
Organization: UNIVERSITY OF ROCHESTER
Fiscal Year: 2024
Award: $385,000
Funding agency: National Institute of Allergy and Infectious Diseases
Poxviruses are a large family of DNA viruses with several members capable of infecting and causing disease in humans. Whereas the most notorious member, variola virus, is the causative agent of smallpox and was eradicated from natural infection, there are still concerns about a clandestine release during a biological attack. In addition, other members of the family, such as monkeypox virus, have raised concern about epizootic infections that are capable of causing epidemics. For these reasons several poxviruses are listed as Category A priority pathogens by NIH/NIAID. Poxviruses produce two infectious forms, intracellular mature virus (IMV) and extracellular virus (EV). EV are formed by the intracellular envelopment of IMV and are critical for cell-to-cell spread, systemic infection, and pathogenesis. The long-term goal of our research is to understand the molecular mechanisms employed by orthopoxviruses to envelope, transport, and release infectious EV. Only 9 viral proteins are known to be unique to the EV form. Whereas some functions have be assigned to these 9 proteins, none of them have been shown to be a matrix- like protein and make a direct connection with the IMV form of the virus to coordinate envelopment. The immediate goal of this application is to better define the role of the putative matrix protein F13 in intracellular envelopment of EV and its relationship with the other EV glycoproteins. We propose 3 aims to better understand the function of F13: 1) Interrogate interactions between F13 and IMV surface proteins. We hypothesize that F13 acts as a matrix protein and provides a link between the outer EV membrane and the inner IMV particle and facilitates interactions with IMV at the site of intracellular envelopment, the TGN. In this aim we will further characterize interactions between F13 and IMV surface proteins. 2) Uncover cellular and viral proteins that interact with the putative matrix protein F13. We will use BioID to identify viral and cellular proteins that interact with F13 during specific stages of envelopment. 3). Determine the relationship between F13, glycoprotein content, EV cell binding, and non fusogenic dissolution for virus entry. We will utilize a panel of recombinant viruses to determine how F13 controls glycoprotein content and how this effects cell binding and entry of EV. The results obtained from these studies will provide greater insight into the molecular mechanism poxviruses use to produce infectious EV, spread cell-to-cell, and cause disease in their hosts. This information will in turn inform intelligent decisions in designing recombinant poxvirus vectors for both vaccines and oncolytic platforms.
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