Thursday, November 21, 2024
11/21/2024
Pneumonia results from uncontrolled lung inflammation and injury often triggered by viral/bacterial pathogen insults. Pneumococci, instigating agents of bacterial pneumonia, are independently pathogenic causing lower respiratory tract infections and hospitalizations in adults, including those with chronic pulmonary conditions like asthma. Pneumococci are also opportunistic pathogens particularly synergizing with respiratory viruses, like influenza A virus (IAV), to cause severe morbidity and excess mortality. Our prior work established that IAV infection during heightened eosinophilic allergic inflammation was host protective, recapitulating clinical data from the 2009 Swine Flu pandemic. Using a laboratory model we developed to investigate mechanisms by which this protection occurred, we identified novel functions for eosinophils as direct mediators of antiviral immunity during early and late phases of IAV infection. Importantly, eosinophilic asthma was also host protective during co-infection with IAV and Streptococcus pneumoniae (Spn), an outcome that was lost in eosinophil deficient mice. Further preliminary data show that eosinophils, a) internalize Spn in large numbers, b) kill intracellular and extracellular Spn, c) undergo physiologic and phenotypic alterations in response to Spn uptake. These data led to our central hypothesis that eosinophils in allergic airways promote anti-bacterial immunity against Spn through direct and indirect mechanisms to reduce the bacterial load and safeguard the host. The two overlapping aims to be investigated in this project are: (1) To determine mechanisms and outcomes of interactions between eosinophils and Spn, and (2) To elucidate pathways by which eosinophil-Spn interactions impact surrounding leukocytes important in mucosal host defense during co-infection. This project is significant because we propose to identify basic immune mechanisms in pulmonary host defense against a prominent human pathogen with an innovative approach of investigating eosinophils as a regulator of local innate immunity and mediator of host protection rather than as an end-stage effector cell. These studies will have a broad impact on eosinophil biology, on our appreciation of host-pathogen interactions in allergic asthma and may offer novel therapeutic targets to treat bacterial co-infections during influenza in allergic hosts.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
