A gastrointestinal rotavirus infection mouse model for immune modulation studies. Part 2
Mice provide a reliable animal model for studying the immune responses during a primary rotavirus infection, although the kinetics of rotavirus infections in mice differs slightly from what is observed in humans. Unlike infant mice which are susceptible to symptomatic infection with rotavirus only during the first 15 days of life, human infants can suffer from multiple rotavirus infections up to the age of five years. There are even many reports of adult rotavirus infection, particularly in the elderly. Aside from these differences, studies of rotavirus infection in mice can provide valuable information on the induction of immune responses by the virus. Sheridan et al. was one of the first to describe a mouse model studying rotavirus-specific immunity. Their findings indicate that (i) infection occurs in all age groups but diarrheal disease is observed in neonatal animals only and that (ii) re-infection of adult animals is associated with suppression of virus-specific cell-mediated immunity.
Despite many years of research, the immune correlates of protection from rotavirus infection and disease are still not completely understood. The mouse model has been extensively used to investigate the contribution of different components of the immune system necessary for protection. These studies have suggested that both humoral- and cell-mediated immunity are important in the resolution of ongoing rotavirus infection and in protection against subsequent re-infection. In more detail, studies have shown that B cells were essential for long-term protection against rotavirus. CD4+ T cells were pivotal for the development of approximately 90% of the rotavirus-specific intestinal IgA. Their presence seems to be critical for the establishment of protective long-term memory responses and IgA antibody in serum and stool samples correlates best with protection against re-infection. CD8+ T cells appeared to be involved in providing partial protection against re-infection.
The original neonatal mouse model has been developed in order to determine the effects of an immature immune system on responses to candidate vaccines. In the present study, this model has been modified to a sensitive gastrointestinal viral infection and illness model in infant mice for testing nutritional compounds for their antiviral and/or immunomodulatory activity. Therefore, neonatal mice were inoculated with a rhesus rotavirus strain (RRV) at an early age for immune induction and later challenged with epizootic-diarrhea infant-mouse (EDIM) virus. Protection due to intervention with the nutritional supplement Gastrogard-R® was determined by reduction of diarrhea and protection against later EDIM challenge, measured by rotavirus fecal-shedding. Associations between protection and both humoral (antibody) and cellular (T cell) responses were examined.
Gastrogard-R® is prepared from the colostrum of hyperimmunised cows and contains high antibody titers against four human rotavirus serotypes, as measured in a virus neutralisation test. It is used as prophylactic treatment of ‘at risk’ children aged one month to three years to prevent diarrhea due to rotavirus infection and the efficacy of treatment was established in a clinical trial in children aged 3 to 15 months.
The purpose of this study was to demonstrate a modified gastro-intestinal viral re-infection model for studying the effects of nutritional intervention on clinical symptoms as well as the development of immune responses and protection against subsequent viral infection.