Pneumonia is a public health concern that is especially important at the 2 ends of the age spectrum. For children, pneumonia is the most common cause of death worldwide and of hospitalization in the US. Pneumonia rates plummet in early childhood and remain low for decades, until they begin rising around the fifth decade and escalate ever after. For older Americans, pneumonia confers a significantly higher risk of death compared to all other common causes of hospitalization, and half of all infectious disease hospitalizations and deaths are due to pneumonia. There is little known about the naturally acquired protection against pneumonia in most older children and young adults.
We aim to elucidate this trough between the peaks of pneumonia susceptibility, to better define the immune mechanisms preventing pneumonia during late childhood and much of adulthood. We posit that heterotypic immunity, adaptive immune responses to related but not identical organisms, drives lung defense for most human-microbe interactions in the lung. For bacterial pneumonia, we propose that lung resident memory CD4+ T cells with polyfunctional Th17 phenotype are determinative, enhancing the antibacterial activities of resident alveolar macrophages and recruited neutrophils to more effectively eliminate pathogens in the deep lung. We have developed mouse models of infection-elicited heterotypic immunity against pneumococcus in the lungs, which will empower mechanistic investigations of these defenses. We will complement these studies with the first ever examinations of antibacterial responses by CD4+ T cells from human lung tissue. To test our central hypothesis that lung resident memory Th17 cells provide heterotypic immune defense against bacterial pneumonia, we will pursue 3 specific aims: (1) we will determine whether heterotypic immunity improves lung responses to bacteria via IL- 17 enhancement of phagocyte function, using mouse models of infection-elicited heterotypic protection and deletion or blockade of IL-17 signaling; (2) we will determine whether lungs contain specialized resident memory cells that drive local heterotypic antibacterial protection, using mouse models and ex vivo analyses of cells collected from fresh human lungs to investigate functional activities of resident memory CD4+ T cells; and (3) we will test whether lung heterotypic protection against pneumonia is prolonged by repeated stimulation and whether that protection declines during aging, using both mouse models and human lung patient samples. Elucidating these mechanisms protecting the lung from infection will be critical for guiding future efforts to identify subjects developing susceptibility, to counter susceptibilit, to strategize vaccine design, and to develop new therapies based on stimulating antibacterial activities from lung-resident CD4+ T cells.
Pneumonia represents a major public health concern that is particularly prominent in children and in the elderly. Here we propose that this age-dependent disparity in lung host defense is attributable to the presence and function of resident memory CD4+ T cells, which are guided by prior exposures to related but not identical bacteria. By elucidating the immunological properties that confer protection between the 2 ends of the age spectrum, we aim to identify novel targets for clinical intervention.
