Virus-induced cellular signaling
Upon infection SV40 elicits multiple signaling in the host, which facilitate its endocytosis, cellular trafficking, and propagation cycle. We specifically focus on signaling induced by the viral capsid proteins prior to nuclear entry and viral gene expression. We found that upon infection SV40 elicits complex signaling networks, including pro-apoptotic signaling and survival pathway. Intriguingly these two opposing pathways are robustly balanced, as the cells neither apoptose nor proliferate. Regulation of this balance is presently a major interest. Under investigation.
Our basic research leads to medical applications
Medical applications stem from basic research
Survival pathway and other signaling cascades induced by recombinant empty capsids lead to protection against Acute Kidney Injury (AKI) in mouse and rat preclinical models. As these pathways are common to other organs, the same strategy may be applicable to a range of clinical conditions. Development of such medical applications is underway.
The tumor suppressor p53 functions in viral host defense by modulating viral transcription.
We found that p53 is activated in SV40-infected cells as part of the host defense response. p53 commonly functions in host defense by leading infected cells towards apoptosis. However, in the case of SV40, p53 aborts the infection by repressing T-antigen expression. This system provides a unique and simple experimental model to investigate the molecular basis of p53 tumor suppression activity.
Nuclear entry of the infecting virus
The infecting virus activates caspase-6 and 10 by an unknown mechanism. This novel caspase pathway leads to dramatic deformation of the nuclear envelope, which facilitates nuclear entry of viral genome. We plan to use this experimental system to study the structure of the nuclear envelope and the mechanism that protects its integrity.
Basic laws that govern protein assemblages
Cellular proteins commonly function in assemblages, such as transcription complex, replication complex or signaling complexes. Some of these complexes are transient and some more stable. We investigate SV40 capsid assembly in vitro as a model for the formation of such assemblages. Our interest is in protein-protein and protein-nucleic acids interactions that lead to assembly, and in forces that keep the assembled particles together.