The aim of the proposed research is to elucidate the reason(s) for reduced CD8 T cell responses in the nasal- associated lymphoid tissue (NALT) of the aged following influenza virus infection. Influenza viruses are very contagious and cause an average of 36,000 deaths and 226,000 hospitalizations in yearly epidemics. The elderly particularly are at risk with influenza ranking as the fifth leading cause of death. A progressive decline in the immune response with aging is associated with reduced efficacy of vaccination in the elderly. In addition, the continuous emergence of new influenza virus strains reduces the effective period of the protection provided by immunization. T cells generated to conserved viral components are crucial in resolving influenza virus infection, can protect from antigenically disparate challenges, and their presence in the elderly is highly correlated with vaccine efficacy. Thus, vaccine strategies that mimic natural infection and induce T cell responses to conserved epitopes, such as cold-adapted live attenuated influenza virus (LAIV), would be advantageous. However, the commercially available LAIV 'Flumist'is not licensed in the elderly, due to a lack of studies. LAIV is administered via the nasal mucosa and replicates only in the upper respiratory tract, and the NALT could play a crucial role in the induction of immune response. Little is known about the immunological events following either nasal vaccination or infection. We show in preliminary studies that experimental LAIV immunization of the aged results in impaired T cell responses in the NALT. We hypothesize that the mucosal environment of the NALT is crucial for influenza virus immunity, but that changes with age affect the ability to mount an appropriate CD8 T cell immune response. The decrease in T cell number in aged NALT could have several reasons: reduced capability of nasal DCs to induce CD8 T cells, changes in the NALT environment, deficiencies in aged CD4 T cell help to CD8 T cells, or changes in the aged CD8 T cells'capability to migrate into the nasal mucosa. Our goals are to elucidate the induction of the T cell effector response in the NALT in response to LAIV. We will determine how and what dendritic cells induce CD8 T cells and how the NALT environment affects CD8 T cell immunity. Furthermore, we will identify the chemokine and adhesion receptor expression profile required for CD8 T cell entry into the NALT, the level of CD4 T cell help needed, and how both are affected with age. The proposed studies are crucial towards understanding the mechanism(s) of how CD8 T cell immunity is generated in the NALT following intranasal vaccination or natural infection in the aged. In addition, they will provide important insights into the 'normal'immune response in the NALT, i.e. how do (memory) T cells circulate through the body as part of their surveillance function. Novel findings into the immunological events in the aged NALT after infection could lead to the identification of strategies for improvement of vaccines to respiratory viruses for the elderly, which are the fastest growing segment of the population in developed countries.

Public Health Relevance

Influenza viruses cause significant annual illness and death in the elderly with recurrent seasonal epidemics and sporadic devastating pandemics. The goal of the proposed research is to investigate the responses that underlie the development of immunity in the nasal mucosa after influenza virus immunization. Findings from the proposed studies will provide crucial information that could lead to the identification of strategies for improvement of nasal vaccines.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Aging Systems and Geriatrics Study Section (ASG)
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Fuldner, Rebecca A
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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Bradley, Linda M; Douglass, Mia F; Chatterjee, Dhrubamitra et al. (2012) Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling. PLoS Pathog 8:e1002641