Pneumonia biology should be the focus of an R35 from the NHLBI. Pneumonia is a leading global burden of disease in every analysis. It kills more children worldwide and hospitalizes more US children than does any other disease. Older adults are even more affected. The incidence and risk of death from pneumonia increase throughout adulthood until becoming orders of magnitude greater than for young children. But the idea that adults have to be old and frail to get pneumonia is a counter-productive misconception. Pneumonia susceptibility is pronounced in middle age, with the median age of non-immunocompromised US adults hospitalized for pneumonia being 57 years. In addition to the directly attributable immediate morbidity and mortality, pneumonia also accelerates unhealthy aging, including exacerbations and more rapid decline of chronic pulmonary diseases, cardiovascular diseases, and more. A wide ranging assortment of viruses, bacteria, and other microbes causes pneumonia, with no one organism responsible for as much as a tenth of cases. It is not about the microbe. These are pathobionts, not pathogens. They circulate among us repeatedly or live on us continuously, growing in the lung to cause pneumonia only under exceptional circumstances. Whether pneumonia ensues depends on the quality and quantity of the host response. Pneumonia results from failures of lung defense more than from microbial virulence. We need to understand the lung defenses that normally prevent pneumonia in young healthy adults before we can identify, prevent, or reverse what goes wrong to make individuals susceptible to pneumonia. Our ongoing research program is addressing the question of lung defense against pneumonia with a long-standing and continuing focus on pulmonary inflammation and innate immunity that is now coupled with a newer emphasis on naturally acquired heterotypic adaptive immunity against respiratory pathobionts. This research program includes 2 ongoing NHLBI R01s that are defining roles of lung epithelial cells and alveolar macrophages in mediating protection against pneumonia. These 2 grants together total 26 R01-years of support from the NHLBI, and we propose unifying these distinct components of our mature and productive research program into a more integrated R35 award. During the coming years, we envision our research program (i) advancing mechanistic understanding of lung defense against pneumonia by functionally integrating the activities of lung constituents and adaptive immunity, (ii) leveraging discoveries in lung defense to generate new approaches to preventing and curing pneumonia, and (iii) forwarding the concept that pneumonia susceptibility is a chronic disease of aging, and attacking the mechanisms of susceptibility rather than (or in addition to) the acute infection has the greatest promise for diminishing the burden of this lung disease.
Abstract Pneumonia is an acute pulmonary infection that results from changes in lung defense more than from changes in microbes. This research program is elucidating the lung defense mechanisms that normally protect young healthy adults from pneumonia, so that the development of pneumonia susceptibility due to aging and other factors can be detected, prevented, and reversed.
|Dela Cruz, Charles S; Wunderink, Richard G; Christiani, David C et al. (2018) Future Research Directions in Pneumonia. NHLBI Working Group Report. Am J Respir Crit Care Med 198:256-263|
|Smith, N Ms; Wasserman, G A; Coleman, F T et al. (2018) Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia. Mucosal Immunol 11:220-235|
|Hartmann, Nadine; McMurtrey, Curtis; Sorensen, Michelle L et al. (2018) Riboflavin Metabolism Variation among Clinical Isolates of Streptococcus pneumoniae Results in Differential Activation of Mucosal-associated Invariant T Cells. Am J Respir Cell Mol Biol 58:767-776|
|Zarrella, Tiffany M; Metzger, Dennis W; Bai, Guangchun (2018) Stress Suppressor Screening Leads to Detection of Regulation of Cyclic di-AMP Homeostasis by a Trk Family Effector Protein in Streptococcus pneumoniae. J Bacteriol 200:|
|Mizgerd, Joseph P (2018) Inflammation and Pneumonia: Why Are Some More Susceptible than Others? Clin Chest Med 39:669-676|
|Quinton, Lee J; Walkey, Allan J; Mizgerd, Joseph P (2018) Integrative Physiology of Pneumonia. Physiol Rev 98:1417-1464|
|Bai, Guangchun; Vidal, Jorge E (2017) Editorial: Molecular Pathogenesis of Pneumococcus. Front Cell Infect Microbiol 7:310|
|Traber, Katrina E; Symer, Elise M; Allen, Eri et al. (2017) Myeloid-epithelial cross talk coordinates synthesis of the tissue-protective cytokine leukemia inhibitory factor during pneumonia. Am J Physiol Lung Cell Mol Physiol 313:L548-L558|
|Kasotakis, George; Galvan, Manuel; King, Elizabeth et al. (2017) Valproic acid mitigates the inflammatory response and prevents acute respiratory distress syndrome in a murine model of Escherichia coli pneumonia at the expense of bacterial clearance. J Trauma Acute Care Surg 82:758-765|
|Gutiérrez-Vázquez, Cristina; Enright, Anton J; Rodríguez-Galán, Ana et al. (2017) 3' Uridylation controls mature microRNA turnover during CD4 T-cell activation. RNA 23:882-891|
Showing the most recent 10 out of 12 publications