Research in the McCormick lab is focused on understanding host antiviral stress responses (e.g. autophagy, stress granules) and the tactics employed by viruses to overcome these defenses. We are primarily focused on two viruses: influenza A virus and a cancer-causing herpesvirus known as KSHV.

Influenza A virus (IAV): Influenza A virus (IAV) polymerase complexes function in the nucleus of infected cells, generating mRNAs that bear 5’ caps and poly(A) tails which are exported to the cytoplasm and translated by host machinery. Host antiviral defenses include mechanisms that detect the stress of virus infection and arrest cap-dependent mRNA translation, which normally results in the formation of cytoplasmic aggregates of translationally stalled mRNA-protein complexes known as stress granules (SGs). We discovered that IAV encodes three proteins, NS1, NP, and PA-X, which prevent SG formation. Ongoing work is focused on detailed characterization of the mechanism of action of these viral countermeasures. Interestingly, we identified a window of opportunity early in infection when the virus is quite sensitive to stress-induced translation arrest and SG formation. By better understanding these virus-host interactions, we hope to identify new host-directed targets for therapeutic intervention.

Kaposi’s sarcoma-associated herpesvirus (KSHV): Our KSHV program encompasses two distinct phases of the infectious cycle, latency and lytic replication.
LATENCY: Acute oncogenic stress can activate autophagy and facilitate permanent arrest of the cell cycle through a failsafe mechanism known as oncogene-induced senescence (OIS). We discovered that tandemly expressed KSHV v-cyclin and v-FLIP proteins coordinate an attack on OIS. v-cyclin deregulates the cell cycle, triggers DDRs and, if left unchecked, can promote autophagy and senescence. However, during latency v-FLIP blocks v-cyclin-induced autophagy and senescence. Together, these data reveal a coordinated viral gene expression program that usurps autophagy, blocks senescence and facilitates the proliferation of KSHV-infected cells. Ongoing work is focused on the role of viral microRNAs (the K-miRs) in OIS control.
LYTIC REPLICATION: A hallmark of Kaposi’s sarcoma is the elaboration of pro-inflammatory cytokines and angiogenic factors by KSHV-infected endothelial cells (ECs). We discovered the mechanisms whereby KSHV proteins increase the production of these host factors by stabilizing the AU-rich-element-containing mRNAs that encode them. We demonstrated that signal transduction pathways subverted by these viral proteins are central nodes of control for stress responses, cytoskeletal dynamics, cell migration and secretion. These proteins are likely key contributors to viral reprogramming of ECs, capable of eliciting many of the phenotypes characteristic of KS tumor cells, and strongly contributing to the post-transcriptional control of EC gene expression and secretion. Ongoing work is focused on understanding how host stress responses affect reactivation from latency, viral replication and release of infectious progeny.