Defining a Minimal Sequential Infection Model to Mature Mouse Immune Responses

About This Grant

PROJECT SUMMARY Recent studies with ‘dirty’ or microbially experienced mice suggest that one crucial difference between mouse models and humans is the history of infection and microbial exposure. Laboratory mice lack the diversity of microbial exposure experienced by their wild mice counterparts and humans. When SPF mice are exposed to microbes found in wild mice their immune responses change and start to more closely mimic the human immune response, indicating that infections are important for maturing the immune response. Because exposing laboratory mice to wild mice is not feasible for many researchers, new mouse models are needed to bridge the gap between mouse and human immune research. We developed a model of sequential infection, where mice are infected with a series of three viruses and an intestinal parasite starting early in life. We showed that mice with sequential infections have different response to vaccination and have blood transcriptional signatures that more closely mimic wild mice and humans. Therefore, we hypothesize that exposure of laboratory mice to a defined and small number of viral and parasitic infections will be sufficient to recapitulate many aspects of other dirty mouse models. We propose to determine which aspects of the immune response of mice exposed to wild mice are recapitulated by our sequential infected mice. We will also determine the contribution of specific pathogens to the alterations in the mouse immune response and test whether the order of infections changes the outcome of the sequential infection model. The conclusion of these experiments will be a well-defined and simple microbial-experienced model that can be reproduced by other investigators. In addition, we will have defined the contribution of specific mouse pathogens to immune system maturity. These experiments will enhance the translatability of mouse models to human preclinical research.