Margaret R. MacDonald, M.D., Ph.D.Research Associate Professor
Virology and Infectious Disease
Dr. MacDonald uses the well-studied RNA virus Sindbis to gain insights into the associations between virus and host. The Sindbis virus is a member of the Alphavirus genus within the Togaviridae family, a large group of enveloped, positive-strand RNA viruses that can cause severe, untreatable illness in humans and animals. Studies carried out by members of Dr. MacDonald’s team use Sindbis virus to elucidate how cellular factors inhibit or contribute to viral replication, and may open up new opportunities for intervention.
Zinc-finger antiviral protein (ZAP) is a cellular factor with powerful inhibitory activity against a number of different pathogens, including Sindbis, Ebola and Marburg viruses. While its mechanism of action is not clear, overexpression of ZAP has been shown to block a step at or before translation of an incoming Sindbis virus genome and to promote the degradation of retrovirus and filovirus genomic RNA. The MacDonald group has shown that ZAP acts synergistically with another innate cellular defense, interferon. Current studies are mapping the determinants of ZAP's activity against Sindbis virus and are attempting to identify viral and cellular factors involved in its function.
While Sindbis must avoid the effects of ZAP, other host proteins may be actively recruited by the virus to aid in its replication. In collaboration with Brian Chait and with the involvement of Michael P. Rout and Charles M. Rice, Dr. MacDonald has used a proteomics approach to isolate and identify a number of host proteins that interact with a Sindbis replicase protein, nonstructural protein 3 (nsP3). Interestingly, a putative nuclear transport factor, G3BP, was among the interaction partners identified. In addition, in collaboration with Shai Shaham, a nematode model of Sindbis replication is being developed to facilitate genetic identification of such factors to further understand the roles of the cellular environment in virus replication.
Dr. MacDonald obtained a B.A. in microbiology from Oregon State University in 1979 and went on to earn her M.D. and Ph.D. degrees from Washington University in St. Louis in 1990. She continued her medical training in pediatrics and pediatric infectious disease at St. Louis Children's Hospital and Washington University. She joined The Rockefeller University in 2000 and is now a research associate professor affiliated with the Aaron Diamond AIDS Research Center and the Laboratory of Virology and Infectious Disease.