NLRP3 Inflammasome Activation and Mitochondrial Function in the setting of Aging and HIV Infection
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Project Summary/Abstract: Both the aging and the aging HIV-infected population are characterized by increased rates of metabolic syndrome (defined by abdominal obesity, dyslipidemia, insulin resistance and hypertension). Notably, metabolic syndrome is associated with the dysregulated, age-associated pro-inflammatory environment— termed “Inflamm-aging”—characterized by elevated levels of cytokines, acute phase reactants, and clotting factors. Chronic stimulation of innate immune receptors by both pathogen-associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) is thought to contribute to age-associated chronic inflammation, but the mechanisms underlying the pathogenesis of metabolic syndrome in the context of aging and HIV disease remain an incompletely understood knowledge gap in the field. The NLRP3 (NOD- like receptor pyrin domain-containing 3) inflammasome is an intracellular protein complex, that is part of the innate immune response and mediates the caspase-1-dependent cleavage of pro-IL-1b and pro-IL-18 to their activated forms. While the NLRP3 inflammasome is activated by PAMPs, there is increasing evidence for a role of NLRP3 as a sensor of host metabolism via DAMPs, as shown by NLRP3 activation by a wide range of metabolites. Moreover, NLRP3 inflammasome activation is dependent on mitochondrial function. The NLRP3 inflammasome has been linked to the development of insulin resistance and other metabolic syndromes in mouse models, and has been minimally explored in both older adults and HIV-infected adults. The purpose of this proposal is to determine the effects of age and HIV infection on the NLRP3 inflammasome, and its relationship with mitochondrial function by comparing the following groups of subjects, young adults (21-35), and older adults (≥ 60 yrs) with and without HIV-infection. Aim 1 seeks to characterize the NLRP3 inflammasome and its relationship with mitochondrial function, in myeloid cells from peripheral blood and adipose tissue. Aim 2 seeks to characterize the metabolic pathways that are induced with activation of the NLRP3 inflammasome through RNA sequencing and CyTOF in myeloid cells from peripheral blood and adipose tissue. Data from both aims will be collected in conjunction with clinical characteristics including the components of metabolic syndrome. Our hypothesis is that increased age and HIV infection will result in dysregulated NLRP3 inflammasome function at baseline and with activation that is linked to mitochondrial dysfunction—ultimately contributing to the development of metabolic syndrome in older and HIV-infected adults. The candidate, Dr. Zapata is an Infectious Disease physician at the Yale school of medicine, who has put together an interdisciplinary mentorship committee with expertise in immunology, aging, and metabolism. This training proposal is coupled with a career development plan that includes mentorship and didactic training in Immuno-metabolism, with an additional focus on learning the analysis of sequencing data, thus providing the tools that will allow the PI to apply for an R01 award.
