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MacDonald and her colleagues use 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. MacDonald’s 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. To further elucidate ZAP’s antiviral mechanism, a genome-wide screen was conducted, revealing a role for TRIM25 in ZAP action. The group is also studying two new ZAP isoforms to determine their biological activity against a panel of viruses.

Infection with the yellow fever virus, a member of the Flaviviridae family, leads to severe disease, including hemorrhagic fever and death. The live, attenuated yellow fever vaccine is a highly successful vaccine, providing life-long protection. MacDonald and her colleagues, in collaboration with Charles M. Rice, are investigating the mechanisms of attenuation of the vaccine strain. Knowledge gained will help improve the vaccine’s safety and aid the development of vaccines against other flaviviruses.