Acute and chronic effects on skeletal muscle from alphavirus infection

Ross River (RRV) and Chikungunya (CHIKV) viruses are emerging pathogens that target the musculoskeletal system and a major health concern as they cause explosive outbreaks in humans. RRV and CHIKV are mosquito-borne enveloped RNA viruses that cause severe arthralgia, arthritis, myalgia and myopathy that typically resolves within weeks of infection, although a significant fraction of RRV and CHIKV patients develop debilitating chronic disease. While the etiology of virally-induced arthralgia and arthritis has been intensely studied, the mechanisms underlying myalgia and myopathy are poorly understood. Our collaborative research uniquely combines the expertise of a skeletal muscle biology lab (Gabrielle Kardon) and a viral pathogenesis lab (Deborah Lenschow) to determine how RRV and CHIKV affect muscle structure and function to cause myopathy and test if and how infection of myogenic cells drives acute and chronic disease. Using new mouse models of RRV and CHIKV disease, recombinant versions of RRV and CHIKV to track infected cells, and mouse genetic alleles to label and manipulate myogenic cells we will test two hypotheses. First, we will test whether infection and cytopathic destruction of myofibers and a protracted regenerative response are the cause of acute myopathy. Second, we will test whether mechanically compromised myofibers and functionally and transcriptionally altered muscle stem stems are major causes of virally-induced chronic myopathy. Our research will elucidate the mechanisms causing the acute and chronic myopathy that are key aspects of increasingly common and debilitating RRV and CHIKV disease. In addition, our studies, which include comparison to regeneration following hypercontraction (BaCl2) injury, will provide important insights into the mechanistic differences between skeletal muscle recovery after pathogenic and acute sterile injury.