Adults over the age of 65 comprise the fastest growing segment of the U.S. population. Aging increases susceptibility to most intracellular microbes (e.g. Mycobacterium, Salmonella, influenza and other viruses), likely due to waning immunity with advanced age termed 'immune senescence'. Immune senescence is characterized by impaired Th1 immunity, and efforts to reverse the responses that wane in immune senescence have been largely unsuccessful. However, recent data suggest augmenting immune responses that remain intact, even in far advanced age, may be a more achievable strategy to reduce the burden of infectious diseases in older adults. Brucella spp., important causes of disease in both human and animals, represent an exception to the rule that age increases the risk of infection due to intracellular pathogens. Scant published literature and our preliminary experiments suggest older adult mice and humans are no more susceptible to Brucella infection, and may in fact be less susceptible to this pathogen. In this proposal, we will use murine models to explore the immune mechanisms that remain intact or are enhanced with age, that allow efficient clearance of Brucella infection. Our preliminary data demonstrate marked increases in the poorly studied T cell cytokine IL-17 in response to whole Brucella organisms and specific Brucella antigens, particularly in older mice when compared to young adult mice. We suspect that the enhanced resistance of older adult mice may be due to IL-17, and the first aim of this proposal is to better define this association across the age spectrum. Very recent data have suggested IL-17 responses may be mediated by the antigen presenting cell-derived cytokine IL-23. This recently discovered feedback loop at the innate/adaptive interface may be an IL-12 independent mechanism to activate Th1 immune responses, a critical need to enhance resistance to intracellular pathogens in older adults. Initial investigations in this regard form the basis of our second aim. Finally, we will determine the clinical relevance of IL-17 in host defense by blocking the activity of this cytokine in murine models of brucellosis, and assessing the presence of IL-17 secreting memory T cells in humans with active or past Brucella infection. The data generated in this proposal will form the foundation of future R01 proposals aimed at enhancing immunity vs. intracellular pathogens in our aging population.

R21AI057952

2004-07-01

2007-06-30