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[0] Fikrig, Erol [1] Innate Immune Responsiveness in the Elderly and the Immunosuppressed [2] Yale School of Medicine-Howard Hughes Medical Institute [3] NO1-AI-50031* [4] 
The growing threats of bioterrorism and emerging infectious diseases such as West Nile (WN) virus infection, SARS, and avian influenza represent a crucial challenge to health care providers, to the public health infrastructure, and to the biomedical research community. Our understanding of the immune responses to potential agents of bioterrorism remains incomplete in particularly vulnerable populations with impaired immunity, such as immunosuppressed and elderly individuals. Elucidation of the consequences of aging and immunosuppression on infection with, or vaccination against such agents is therefore essential to the development of clinical tests and interventions aimed at identifying individuals likely to be at particular risk for adverse outcomes following an attack of bioterrorism or outbreak of an emerging infectious agent. In addition, by identifying potential mechanisms for augmentation of immune responses, these new clinical approaches will also be of general benefit to global health, particularly given the potential for the use of more virulent or drug-resistant bioterror agents. This proposal will explore the hypothesis that altered innate immune responsiveness in the elderly and the immunosuppressed contributes to vaccine unresponsiveness or disease susceptibility. This premise is based upon our preliminary data, first, that individuals that respond poorly to a lipoprotein-based vaccine have defects in TLR1/2 signaling, and second, that TLR3-responsiveness contributes to susceptibility to West Nile virus infection. Here we will initially delineate innate immune responses in the elderly and immunosuppressed focusing on TLRs and a prototype TLR-dependent cytokine, macrophage migration inhibitory factor (MIF), that differ from the general population. We will then determine whether these differences alter immune responses to selected NIAID Biodefense priority pathogens, using West Nile virus infection and influenza vaccination as paradigms. These mechanistic studies will lead to new approaches for vaccine development and for the treatment of infectious diseases.
ImmPort: Immunology Database and Analysis Portal
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