RESEARCH PROGRAM II - Emerging Virus Entry into Host Cells: Strategies for Inhibition
Program Shepherds: Christopher Broder (Uniformed Services University of the Health Sciences, [USUHS]) and Stuart Isaacs (UPenn)
The central theme of this Research Program is to focus on the attachment and entry of viruses into cells with the goal of teasing out and identifying the molecular details of both the viral and cellular factors involved in this process.
By attaining a thorough understanding of the factors and events comprising the viral entry process, the potential of discovering and developing novel therapeutic modalities and prevention strategies are made possible. The Research Projects will be united in part by the utilization of small molecule and RNAi screening technologies (in collaboration with Program I) to identify host targets for the development of entry inhibitors as well as to develop and validate high throughput screening assays. The projects in Program II will study the basic biology of a diverse set of RNA and DNA viruses on the NIAID Category A and C Priority Pathogens agenda, including the Filoviruses (Ebola and Marburg viruses), New World Arenaviruses (Junin and Machupo viruses), the rhabdovirus Australian bat lyssavirus, and the orthopoxviruses (variola and monkeypox viruses). These viruses comprise active research strengths within the Middle Atlantic region, and they encompass a diverse group of understudied viruses as well as agents of significant biological threat or emerging agents with bioterrorism potential.
Inhibition of Filovirus Entry into Cells
Ebola and Marburg are enveloped viruses of the family Filoviridae. As category A pathogens that cause fatal hemorrhagic fevers, they are considered to be significant biodefense threats. Currently there are no approved antiviral agents or vaccines to combat these devastating pathogens.
Identification of Cellular Pathways Involved in New World Arenavirus
The New World clade B arenaviruses (NWA), particularly Junin (JUNV) and Machupo (MACV) are associated with outbreaks of viral hemorrhagic fever in South America. JUNV and MACV infections represent zoonoses from rodents and are both transmitted through aerosols; thus, the NWAs are potential bioterrorism agents. JUNV in particular is one of only three viruses included in the recent list of agents developed by the Department of Homeland Security that represent in their assessment the most significant bioterrorism threats faced by the US.
Australian Bat Lyssavirus Tropism Entry and Host Factor Dependence
As a group, viruses have played major roles in both the number and significance of newly recognized diseases in both animals and humans. A recent example is Australian Bat Lyssavirus (ABLV). ABLV is a newly recognized rabies virus-related rhabdovirus belonging to the genus Lyssavirus and is an enveloped, single-stranded negative-sense RNA virus with an envelope G glycoprotein that is responsible for attachment, membrane fusion, and infection of host cells.
Mechanism of poxvirus entry into cells
The molecular mechanisms involved in poxvirus entry into cells remain perplexing. Our goal is to dissect these mechanisms by focusing on the envelope proteins involved in entry of three orthopoxviruses: vaccinia (VACV), variola (VARV) and monkeypox (MPXV). The accidental or intentional release of VARV, coupled with the potential of MPXV to become a more efficient human pathogen, underscore the need for further investigation of these viruses in terms of their biodefense importance and as emerging infectious agents.