Rotavirus is the single most important cause of severe infantile diarrhea in the world and accounts for enormous morbidity and mortality worldwide. Susceptibility to symptomatic rotavirus infection is a function of host species and host age regardless of the immune status of the animal. Because rotavirus infection is confined to the digestive tract, it is logical to examine specific aspects of the gut which may determine whether exposure to the agent results in significant disease. A number of specific factors within the gastrointestinal tract will be examined by in vitro and in vivo methods to determine their role in host susceptibility and resistance to rotavirus infection. Enhanced gastric acid and pepsin secretion by adult, rotavirus-resistant mice inactivates rotavirus. The role of this inactivation in pathogenesis, viral transmission, and immune response in vivo will be determined by inhibiting gastric secretion in rotavirus infected mice. Murine intestinal mucins inhibit rotavirus infection in vitro. These observations will be expanded to examine in vivo infection in the murine model and to characterize the interaction of intestinal mucins with rotavirus on a molecular level. Understanding the mechanism by which mucins inhibit rotavirus replication could lead to the development of new methods of treatment or prophylaxis of rotavirus disease. The cellular basis of resistance to rotavirus will be examined in studies of rotavirus receptors and viral penetration of the cell plasma membrane. Rotavirus receptors on suckling mouse enterocytes will be purified using existing monoclonal antibodies and molecularly cloned. Mechanisms of their preferential expression in the suckling versus adult mouse will be analyzed by northern blot as well as immunochemically. In parallel studies monoclonal antibodies directed against rotavirus receptors on tissue culture cells will be developed and used for characterization, purification, and cloning of such receptors. It is anticipated that both sets of receptor experiments will ultimately prove complementary. Preliminary results have shown that rotavirus penetration f the cell plasma membrane into the cytoplasm is a critical determinant of cell permissivity for rotavirus in tissue culture. We will determine whether membrane lipid composition and/or constitutive endocytosis are important factors in inability of the virus to penetrate the plasma membrane in rotavirus resistant cells. In summary, the proposed studies will examine a number of host intestinal factors which may determine resistance to rotavirus disease. These studies may ultimately lead to improvements in the treatment and prophylaxis of viral gastroenteritis.
| Angel, J; Franco, M A; Greenberg, H B et al. (1999) Lack of a role for type I and type II interferons in the resolution of rotavirus-induced diarrhea and infection in mice. J Interferon Cytokine Res 19:655-9 |
| Angel, J; Tang, B; Feng, N et al. (1998) Studies of the role for NSP4 in the pathogenesis of homologous murine rotavirus diarrhea. J Infect Dis 177:455-8 |
| Shastri, S; Doane, A M; Gonzales, J et al. (1998) Prevalence of astroviruses in a children's hospital. J Clin Microbiol 36:2571-4 |
| Bass, D M; Upadhyayula, U (1997) Characterization of human serotype 1 astrovirus-neutralizing epitopes. J Virol 71:8666-71 |
| Bass, D M (1997) Interferon gamma and interleukin 1, but not interferon alfa, inhibit rotavirus entry into human intestinal cell lines. Gastroenterology 113:81-9 |
| Bass, D M; Baylor, M; Chen, C et al. (1995) Dansylcadaverine and cytochalasin D enhance rotavirus infection of murine L cells. Virology 212:429-37 |
