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MacDonald and her colleagues study positive-strand RNA viruses in the Alphavirus and Flavivirus genera to gain insights into viruses and the hosts they infect. Sindbis virus, an alphavirus, causes severe, untreatable illness including arthritis and encephalitis. The zinc-finger antiviral protein (ZAP) is a host factor with powerful inhibitory activity against several pathogens, including Sindbis, hepatitis B, HIV, and Ebola viruses. While ZAP’s antiviral mechanism is not fully elucidated, it belongs to a family of enzymes called poly ADP-ribose polymerases (PARPs), blocks translation of the incoming Sindbis virus genome, and promotes degradation of retrovirus and filovirus genomic RNA. MacDonald’s group has shown that ZAP synergizes with an innate immune defense molecule called interferon and requires the enzyme TRIM25 for full activity. The group is studying two new ZAP isoforms to determine their biological activity against a panel of viruses. They are also studying the role of poly-ADP-ribosylation in limiting Sindbis virus replication.

Recently, MacDonald’s group begin studying the tick-borne Powassan virus, a flavivirus that can cause severe encephalitis and is transmitted by the same tick that transmits Lyme disease. These studies aim to determine host factors required for infection, to develop a vaccine, and to identify, clone, and characterize human monoclonal antibodies with potent neutralization capacity for possible therapeutic or diagnostic use. In collaboration with Charles M. Rice, MacDonald is also investigating the mechanisms of attenuation in the live, attenuated yellow fever virus vaccine strain. Knowledge gained will help improve the vaccine’s safety and aid the development of vaccines against other flaviviruses.