Dr. MacDonald’s team uses two well-studied positive-strand RNA viruses representing the Alphavirus and Flavivirus genera to gain insights into viruses and the hosts they infect. Sindbis virus is an Alphavirus genus member within the Togaviridae family, which causes severe, untreatable illness including arthritis and encephalitis. The zinc-finger antiviral protein (ZAP) is a cellular factor with powerful inhibitory activity against several pathogens, including Sindbis, hepatitis B, HIV, Ebola, and Marburg viruses. While its mechanism of action is not fully elucidated, ZAP expression blocks translation of the incoming Sindbis virus genome and promotes degradation of retrovirus and filovirus genomic RNA. The group has shown that ZAP synergizes with interferon, an innate immune defense system that creates an antiviral state. Genes synergizing with ZAP were identified by coexpressing ZAP with over 350 interferon-stimulated genes. How these factors protect cells from viral infection is being investigated. The group has recently discovered two new ZAP isoforms, which are under study to determine their biological activity against a panel of viruses.
Infection with the Flaviviridae family member yellow fever virus leads to severe disease, including hemorrhagic fever and death. Dr. MacDonald’s team identified a host protein, DNAJC14, which modulates yellow fever replication affecting the formation of the specialized membrane-associated viral structures where viral RNA replication ensues. Previously identified as a chaperone for dopamine receptor D1 transport and implicated in the replication of bovine viral diarrhea virus, DNAJC14 has been usurped by multiple Flaviviridae family members to modulate viral RNA replication. Current studies aim to understand DNAJC14’s role in Flavivirus RNA replication in order to facilitate eventual inhibitory drug development.