Evolution of antiviral breadth in Mx GTPases

Abstract

As obligate parasites, viral pathogens coopt host resources and subvert cellular processes to promote their own replication. In response, host organisms have evolved numerous countermeasures to thwart viral infection. However, the molecular basis for how host antiviral defenses overcome the daunting challenge of viral diversity and the highly adaptive nature of viral pathogens is poorly understood. Viral pathogens and their infected hosts are engaged in a constant battle to gain evolutionary dominance. Such host-virus "arms races" drive the rapid evolution of genes in conflict to gain a fitness advantage through recurrent innovation. Herein, I leverage evolutionary signatures of these adaptive processes to gain insight into molecular mechanisms by which the broad-acting antiviral protein MxA overcomes the challenge of viral pathogen diversity. This evolution-guided approach identified and allowed the characterization of multiple surfaces on MxA that function as independent modules to define target recognition and antiviral specificity. These studies provide an evolutionary and molecular basis for MxA antiviral breadth, and suggest general principles by which cell-intrinsic immunity can tip the balance against rapidly evolving RNA viruses.