Aging is strongly associated with increased mortality and morbidity following bacterial infections, which are responsible for one third of all deaths in older adults. The two most common infections in older adults are pneumonia and urinary tract infection (UTI), both of which occur at mucosal surfaces and are prevalent across the lifespan but exhibit an age-dependent increase in disease severity. The age-dependent severity of these infections is thought to be driven by disruptions in immune responses, including decline in immune cell function (immunosenescence) and chronic low-grade inflammation (inflammaging). While age-driven alterations in adaptive immune responses are well characterized, less is known about what drives innate immunosenescence. Polymorphonuclear leukocytes (PMNs) are innate immune cells that have a critical and multi-faceted role in control of mucosal infection and subsequent return to homeostasis, and PMN function and recruitment are both dysregulated during aging, further contributing to infection susceptibility and severity. Accordingly, genetic polymorphisms that impact PMN recruitment and activation in response to infection are associated with increased infection susceptibility and severity. However, there is fundamental gap in knowledge regarding genetic traits that may be associated with protection against age-driven susceptibility to infection. The hypothesis of this proposal is that certain genetic loci will be associated with protection against severe disease following mucosal infection, and that some of these protective phenotypes may be resistant to age-driven deterioration. This hypothesis will be addressed through two specific aims.
In Aim 1, 25 CC strains and a C57BL/6J founder strain that exhibits a susceptible phenotype will be assessed for susceptibility to pneumonia (males) and UTI (females). Host survival, organ-specific bacterial burden, indicators of infection severity (such as organ pathology) and inflammatory responses will be measured to determine which phenotypes are linked for a given infection model. Linked phenotypes will be used to identify QTLs associated with disease manifestation for each infection model, and phenotypes in common between both infection models will be explored as predictors of infection severity.
In Aim 2, C57BL/6 and a subset of 3 CC strains that exhibit resistant phenotypes in youth will be aged and assessed for susceptibility to pneumonia (males) and UTI (females). The above indicators of disease manifestation will be assessed to determine if host genetics can alleviate age-driven susceptibility to mucosal infections. The proposed research is expected to yield a wealth of phenomic data, information pertaining to immune system development and function during homeostasis and in response to antigenic challenge at all stages of life, and the utility of urine and serum cytokines and chemokines as potential biomarkers to predict infection susceptibility and severity.
This proposal is designed to use Collaborative Cross mice to identify host genetic loci and innate immune responses associated with severe disease following mucosal infections. The proposal further seeks to determine the relative contribution of host genetics and age-related immune dysregulation to infection susceptibility using Streptococcus pneumoniae (the leading cause of community-acquired bacterial pneumonia in the elderly) and Proteus mirabilis (the most common cause of catheter-associated urinary tract infection in elderly nursing home residents). This study will uncover host responses that have the potential to guide treatment and prevention strategies in the vulnerable aging population.
