New world rodent-borne hemorrhagic fever arenaviruses (NWA) such as Jun?n virus have about a 30% mortality rate. Although an effective Jun?n virus vaccine has decreased disease incidence, sporadic cases of this as well as the other known and novel NWAs for which there are no vaccines or effective therapeutics still occur. Because they are transmitted by aerosols, these Category A arenaviruses are also potential bioterrorism agents. We recently performed a siRNA screen with pseudotyped viruses bearing the Jun?n glycoprotein to find host genes involved in entry that could serve as therapeutic targets. We identified a number of genes not previously implicated in virus infection, including TRIM2, a member of the tripartite motif (TRIM) family that includes well-known members of the host's intrinsic defense against viral infections. We showed that TRIM2 is an anti-viral entry host factor. In addition to their antiviral activity, TRIM proteins are involved in a wide range of biological functions including cell proliferation, ubiquitinylation, apoptosis and a variety of human pathologies. Here we will investigate the likely novel mechanism by which TRIM2 restricts NWA infection by carrying out the following aims:
Aim 1 : Characterize which steps of Jun?n virus infection are affected by TRIM2.
Aim 2 : Determine how TRIM2 restricts Jun?n virus infection.
Aim 3 : Determine if TRIM2 restricts Jun?n virus infection in vivo. These studies will allow us to define the potentially unique mechanism by which TRIM2 restricts NWA infection and will allow us to develop critical reagents for future in vivo studies of TRIM2 in virus infection and in normal development.
New World Arenaviruses (NWA) are single-stranded RNA viruses that cause viral hemorrhagic fevers in humans with high mortality and a better understanding of how host factors influence infection is important to our ability to prevent and treat infection. We recently discovered a new host factor, TRIM2 that blocks virus infection by restricting entry of NWAs into cells. This proposal will build upon this finding and use mouse and cell culture models to determine how TRIM2 works to inhibit infection, with the ultimate goal of finding anti-viral therapies.