RESEARCH PROGRAM I - Interaction of Emerging Viruses with Host Cell Pathways
Program Shepherds: Robert Doms (U. of Pennsylvania, [UPenn]) and Judith M. White (U. of Virginia [UVA])
The central theme of this Research Program, which emphasizes under-studied NIAID Category A and emerging pathogens, is the analysis of virus-host interactions to detect therapeutic targets and identify and allow development of therapeutic agents.
The Research Projects will be united by utilization of innovative small molecule, proteomic and RNAi screening technologies to identify host pathways with which viral pathogens interact and to identify and characterize potential antiviral agents. Targeting cellular factors may be advantageous because this strategy may overcome the genetic diversity of viruses that have evolved to utilize a conserved cellular factor, and may make the evolution of drug resistance more difficult. Importantly, each project takes a comparative approach by studying several pathogens, which should enable identification of both commonalities and differences in how these human pathogens bind to, access, replicate and assemble in host cells. The viral pathogens include under-studied phleboviruses (Rift Valley Fever virus), two emerging paramyxoviruses (Nipah and Hendra viruses) that have caused outbreaks in Southeast Asia, and a continuation of highly successful work on variola virus topoisomerase funded during the second half of MARCE-1.
Interactions of Emerging Bunyaviruses with Host Cells
The Family Bunyaviridae consists of over 300 viruses with members of four Bunyaviridae genera (Hantavirus, Orthobunyavirus, Phlebovirus and Nairovirus) infecting humans. A number of the Hantaviruses and Rift Valley Fever virus (RVFV, a Phlebovirus) are Category A agents with RVFV being of particular concern.
Identification of Cellular Pathways involved in Rift Valley Fever Virus Infection
The emergence of epidemic arboviral diseases infecting both humans and domestic animals has led to significant world-wide morbidity and mortality. Little is known about the host factors required for the replication cycles of these viruses, and less about the innate immune pathways that restrict pathogenesis, impeding the development of antiviral treatments.
Characterization & Disruption of host protein interactions required for budding of Hendra and Nipah Viruses
Enveloped viruses are formed by a budding process that often requires participation of host proteins. Retroviruses, rhabdoviruses, and filoviruses all use similar late domain sequences within the viral proteins to recruit host factors for budding. Although paramyxoviruses generally lack the same late domain sequences used by these viruses, we have obtained evidence that paramyxoviruses, similar to other enveloped viruses, likely recruit host factors for budding. The viral protein:host protein binding interfaces used during virus budding have the potential to be effective as targets for antiviral drug design.
Inhibition of DNA Modifying Enzymes of Category A-C agents
For applications in biodefense, it is desirable for small molecule inhibitors to target multiple category A-C agents, because it is difficult and expensive to develop even one small molecule inhibitor. Relatively few clinically useful drugs are active against multiple different pathogens. Of the few that are, a substantial fraction target DNA modifying enzymes.