TRIM2 is Essential for the Proper Neurological Functioning and it is Antiviral Against Arenaviruses
thesisposted on 01.12.2020, 00:00 by Güliz Otkiran Clare
Arenaviruses are single-stranded RNA viruses that can infect and cause disease in humans. It is important to study arenavirus biology as hemorrhagic fever-causing arenavirus infection is associated with a high mortality rate and can lead to neurological complications in infected humans. A siRNA screen previously performed in our lab identified novel antiviral host factors that may play a role in viral entry. Importantly, one factor identified in the RNAi screen, TRIM2 (Tripartite Motif Containing 2), was shown to be antiviral against New World Arenaviruses (NWAs) when tested with murine leukemia virus (MLV) pseudotyped with glycoproteins from NWAs and with the replication-competent Junín virus vaccine strain Candid 1 (JUNV C1). In vitro and in vivo studies carried out in our lab using Trim2-knockout mice showed that TRIM2, at minimum, requires its Filamin domain for its antiviral activity. Trim2-knockout mice carried an ataxic phenotype and the underlying neurological conditions were investigated in this mouse model which can be used to study Charcot-Marie-Tooth (CMT) disease (a degenerative nerve disease that may be related to TRIM2). TRIM2 was investigated by using several different strains of arenaviruses. It was found that it plays a role in restricting NWAs but does not affect the Old World Arenaviruses (OWAs). The results found by using replication-competent viruses overlapped with the results found by using the pseudotyped viruses. The other two factors found in the screen were CLDN2 (Claudin-2) and SSU72 (SSU72 Homolog, RNA Polymerase II CTD Phosphatase). In this study, CLDN2 and SSU72 were further analyzed for their effects on NWA and OWA infections. They have the potential for being broad antiviral factors. The findings in this study might shed light upon a broader discovery for future studies with a greater range of emerging viruses.