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This laboratory is interested in delineating the factors that are involved in virus virulence and pathogenesis of viral infections at mucosal surfaces. Current work in my laboratory is focused on rotavirus which initiates localized mucosal infection of the gastrointestinal tract. Rotavirus is the major viral pathogen of diarrhea in young children and is responsible worldwide for approximately one million deaths annually. Intense research efforts are underway to understand the pathogenesis of this virus and to develop effective vaccines.

We are investigating rotavirus virulence and host range restriction using animal models. The role of individual rotavirus genes or their protein products in pathogenesis are being defined. Recently, a licensed rotavirus vaccine approved for use in humans was withdrawn from the market because of an association with intussusceptions. We have developed the first animal model to study rotavirus-associated intussusception and have shown directly that rotavirus can contribute to intussusception. We are seeking to understand the molecular mechanisms of how rotavirus contributes to intussusception.

The application of molecular biology techniques to vaccine development has opened a new realm of vaccine possibilities. Co-expression of rotavirus structural proteins in the baculovirus expression system results in self-assembly of rotavirus virus-like particles (VLPs). VLPs are particulate, non-replicating antigens that may provide a safe and efficacious vaccine. VLPs administered intramuscularly, orally or intranasally with adjuvants induce protection from rotavirus infection in several animal models. VLPs composed of different combinations of structural proteins are being used to define the viral proteins necessary for protective immunity. To understand how VLPs induce immunity, we are examining the interaction of VLPs at mucosal sites, the role of antibody in immunity and the ability of VLPs to induce different T and B cell subsets and cytokines.

The studies with rotavirus will provide important basic information on rotavirus pathogenesis and mucosal immunity and may provide a safe effective subunit rotavirus vaccine. Success with this approach will be generalized to determine if the rotavirus VLPs or specific proteins from other viruses that possess tropisms for cells in the gastrointestinal tract can be used to target oral or intranasal vaccines to enhance mucosal immunization with non-replicating antigens.

Recent Publications (PubMed)

Crawford SE, Estes MK, Ciarlet M, Barone C, O’Neal CM, Cohen J, and Conner ME. 1999. Induction of heterotypic neutralizing antibodies by rotavirus-like particles. J. Virol. 73:4813-4822.

O’Neal CM, Harriman GR, and Conner ME. 2000. Protection of the villus epithelial cells of the small intestine from rotavirus infection does not require IgA. J. Virol. 74:4102-4109.

Ciarlet M, Estes MK, and Conner ME. 2000. Simian rhesus rotavirus (RRV) is a unique heterologous (non-lapine) rotavirus strain capable of productive replication and horizontal transmission in rabbits. J. Gen. Virol., 81:1237-1249.

Ciarlet M, Conner ME, and Estes MK. 2002. Group A rotavirus infection and age-dependent diarrheal disease in rats: a new animal model to study rotavirus gastrointestinal pathophysiology and pathogenesis. J. Virol. 76:41-57.

Blutt S, Warfield, Lewis D, and Conner ME. 2002, Early respone to rotavirus infection involves massive B cell activation. J. Immunol. 168:5716-5721.

Blutt SE. , Kirkwood CD, Parreno V , Warfield KL, Ciarlet M, Estes MK. , Bok K, Bishop RF, Conner ME. 2003. Rotavirus Antigenemia/Viremia: A Common Event? Lancet, In press.