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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI054455-01
Application #
6597507
Study Section
Special Emphasis Panel (ZRG1-SSS-4 (01))
Program Officer
Gondre-Lewis, Timothy A
Project Start
2003-09-15
Project End
2005-12-31
Budget Start
2003-09-15
Budget End
2003-12-31
Support Year
1
Fiscal Year
2003
Total Cost
$140,500
Indirect Cost
Name
Hospital for Joint Diseases Ortho Institute
Department
Type
DUNS #
071036685
City
New York
State
NY
Country
United States
Zip Code
10003
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Kenney, Laurie L; Cornberg, Markus; Chen, Alex T et al. (2015) Increased Immune Response Variability during Simultaneous Viral Coinfection Leads to Unpredictability in CD8 T Cell Immunity and Pathogenesis. J Virol 89:10786-801
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Clute, Shalyn C; Naumov, Yuri N; Watkin, Levi B et al. (2010) Broad cross-reactive TCR repertoires recognizing dissimilar Epstein-Barr and influenza A virus epitopes. J Immunol 185:6753-64
Cornberg, Markus; Clute, Shalyn C; Watkin, Levi B et al. (2010) CD8 T cell cross-reactivity networks mediate heterologous immunity in human EBV and murine vaccinia virus infections. J Immunol 184:2825-38
Cheng, Yiming; Ghersi, Dario; Calcagno, Claudia et al. (2009) A discrete computer model of the immune system reveals competitive interactions between the humoral and cellular branch and between cross-reacting memory and naïve responses. Vaccine 27:833-45

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