To model crossreacting T-memory of virus-infected mice

描述（由申请人提供）：本项目旨在开发宿主反应的IMMSIM模型，以充分发挥其作为感染研究的支持和预测工具的潜力。这项工作是由数学建模者和免疫学家进行的多学科合作，他们研究痘病毒和沙病毒家族的病毒，这两种病毒都属于a类，因此模拟器可能会在当前NIAID生物防御研究协议的框架中引起兴趣。两个问题是理解抗病毒反应的核心：T细胞激活的多阈值机制，以及T细胞记忆的可变克隆层次。去年在这两个领域都取得了突破，对保护战略产生了重要影响。随着新的T细胞特征的纳入，该模型应测试可靠性，以再现实验结果和假设，其预测应通过特别的体内或体外实验的手段来挑战。

DESCRIPTION (provided by applicant): This project seeks to develop the IMMSIM model of host responses to its full potential as a supporting and predictive tool for infection research. This effort is carried out by a multidisciplinary cooperation of mathematical modelers and immunologists working with viruses of the pox and arenavirus families, which both belong to the A category, and hence the simulator may become of interest in the frame of the current NIAID Biodefense Research protocols. Two issues are central for the understanding of anti-virus responses: the multi-threshold mechanism of T cell activation, and the changeable clonal hierarchy of T cell memory. In both areas breakthroughs have been made in the last year, with important consequences for protection strategies. With the new T cell features incorporated, the model shall be tested for reliability in reproducing bench results and hypotheses, and its predictions shall be challenged by means of ad hoc in vivo or in vitro experiments. The study will focus on: a) the nature of clonal dominance and clonal attrition, asking whether the signal for induced apoptosis is originated by competition of local resources (antigen, lymphokines) or by global population constraints; b) the reasons for the apparent asymmetry of the effects of crossreactions, when two viral infections are enacted in opposite order; and c) the possible advantage of using heterologous (but not B-crossreacting) instead of homologous vaccines, in order to avoid neutralization by circulating antibodies and thus to reach a more predictable protection.