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The potential for coronaviruses to move between species and cause significant human disease was dramatically demonstrated in early 2003 with the recognition of a new human coronavirus as the cause of Severe Acute Respiratory Syndrome, or SARS. The severe disease, worldwide spread, and economic disruption caused by SARS resulted in international efforts to understand the source, emergence, and disease pathogenesis of the SARS-coronavirus (SARS-CoV). We continued studies of SARS in collaboration with Dr. Ralph Baric at the University of North Carolina, Chapel Hill using our "biosafety-level 3" (BSL3) laboratory.

Coronaviruses create "viral factories" known as replication complexes, in the host cell using viral proteins and cellular proteins and membranes. These complexes must be constructed to copy the virus genetic code before assembling new infectious virus particles. Some of the viral proteins, known as replicase proteins, serve many functions in the formation, organization, and function of replication complexes, by modifying the host cell, interacting with cellular proteins, and copying the genetic material of the virus. Among the RNA viruses, coronaviruses encode the largest and most complex array of replicase proteins and, for most of these proteins, their specific functions are unknown. Understanding how these viruses make and use these proteins during virus infection will identify targets for designing drugs and vaccines to interfere with virus growth and disease. Studies of host-cell modifications caused by coronaviruses may illuminate important new pathways used by viruses to hijack the cell or hide from host immune responses during replication.

Our lab's murine hepatitis virus (MHV) program has focused on discovering the function of replicase proteins by introducing mutations into the virus and determining the effect of these mutations on virus growth in cell culture and disease causation in mice. Recently we focused on testing the function of a viral exonuclease, which is important for genome stability, and a viral protease, which is required for processing and maturation of other viral proteins.

Recent experiments in the BSL3 lab have focused on understanding how SARS-CoV moved from animals, probably bats, into humans, and how it acquired the capacity to cause human disease. The bat viruses cannot be grown in the lab, so it is difficult to answer these questions. We have used published bat virus genome sequences to synthesize the bat virus genome and developed a strategy to grow the virus. We also tested how changes in the fidelity or error rate of copying the genetic material during replication affects the capacity of the virus to grow and survive in cells and in mice.

 



 
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Monroe Carrell Jr. Children's Hospital at Vanderbilt