The theme of this grant is to understand how arenaviruses (and viruses in general) trigger the innate immune system in ways that lead to either pathology or immunity. Our overall objective is to understand the complex relationship between viral infection, viral-induced pathology and the generation of immunity. Our underlying hypothesis is that these events are controlled by two classes of molecules with adjuvant-like properties: One class is viral proteins that stimulate the immune system by binding toll-like receptors and the other class is endogenous adjuvant molecules generated by injured cells of the host. The major emphasis is on defining these immunostimulatory molecules/adjuvants and their receptors and then to understand how they might be exploited to modify the course of infection and to develop more effective vaccines. We believe that the results of our proposed experiments will identify new adjuvants that will be useful for generating effective vaccines to arenaviruses and many other pathogens. We will achieve our goals through a collaborative effort between the three component projects, which are highly interactive and complementary. The goal of Project 1 (P.I., Rock) is to elucidate the structure and function of a novel set of adjuvant molecules that are produced by the host when cells are injured, e.g. during a viral infection. The goal of Project 3 (P.I., Finberg) is to identify novel immunostimulatory molecules that are part of the arenavirus itself, determine how they affect immunity and disease and assess their potential to function as adjuvants. The goal of Project 2 (P.I., Golenbock) is to identify the receptors for these immunostimulators/ adjuvants and determine how these receptors function, with a major focus Toll like receptor 2 (because this molecule appears to be unquestionably linked to arenavirus pathogenesis). The interplay between the endogenous adjuvants, viral immunostimulatory molecules, and Toll Like receptors will be examined as a collaborative effort between the three component projects.
| Rock, Kenneth L (2009) Pathobiology of inflammation to cell death. Biol Blood Marrow Transplant 15:137-8 |
| Zhou, Shenghua; Halle, Annett; Kurt-Jones, Evelyn A et al. (2008) Lymphocytic choriomeningitis virus (LCMV) infection of CNS glial cells results in TLR2-MyD88/Mal-dependent inflammatory responses. J Neuroimmunol 194:70-82 |
| Wang, Jennifer P; Bowen, Glennice N; Padden, Carolyn et al. (2008) Toll-like receptor-mediated activation of neutrophils by influenza A virus. Blood 112:2028-34 |
| Rock, Kenneth L; Kono, Hajime (2008) The inflammatory response to cell death. Annu Rev Pathol 3:99-126 |
| Kono, Hajime; Rock, Kenneth L (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8:279-89 |
| Wang, Jennifer P; Kurt-Jones, Evelyn A; Finberg, Robert W (2007) Innate immunity to respiratory viruses. Cell Microbiol 9:1641-6 |
| Finberg, Robert W; Wang, Jennifer P; Kurt-Jones, Evelyn A (2007) Toll like receptors and viruses. Rev Med Virol 17:35-43 |
| Ha, Unhwan; Lim, Jae Hyang; Jono, Hirofumi et al. (2007) A novel role for IkappaB kinase (IKK) alpha and IKKbeta in ERK-dependent up-regulation of MUC5AC mucin transcription by Streptococcus pneumoniae. J Immunol 178:1736-47 |
| Visintin, Alberto; Halmen, Kristen A; Khan, Naseema et al. (2006) MD-2 expression is not required for cell surface targeting of Toll-like receptor 4 (TLR4). J Leukoc Biol 80:1584-92 |
| Mann, Paul B; Wolfe, Daniel; Latz, Eicke et al. (2005) Comparative toll-like receptor 4-mediated innate host defense to Bordetella infection. Infect Immun 73:8144-52 |
