Early Life Pulmonary Infection, Microbiome and Trained Innate Immunity

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Project Summary Early life respiratory syncytial virus (RSV) pulmonary infection can lead to the development of childhood wheeze and asthma. This is an important area of concern as the overall incidence of asthma has been increasing. There is a critical need to understand how early life events can predispose an individual for immunopathology later in life such as asthma. Previous work in our laboratory using a neonatal murine model of RSV infection has demonstrated that RSV infection can alter the early life gut microbiome. We have also shown that RSV infection predisposes neonates for enhanced allergic disease in adulthood. However, the interplay between early life infections and alterations in the microbiome is not well understood. We hypothesize that a concurrent change in the microbiome with infection in early life leads to enhanced allergic responses later in life through trained innate immunity of immune cell precursors. We will test this hypothesis by assessing the respective factors in gnotobiotic experiments using both naïve and RSV-induced altered microbiomes followed by allergic modeling with cockroach allergen (CRA) to establish the differential and synergistic roles of the altered microbiome and RSV infection. Additional data collected since the initial submission further supports our hypothesis showing that conventional murine microbiome transfer into germ- free neonates reduces the airway hyperreactivity after allergen challenge when compared to germ-free neonates. This does not occur when microbiome is transferred into germ-free adults suggesting that early life is a critical window for protection possibly through epigenetic regulation of the immune system. Additional preliminary data show that immune cell precursors such as bone marrow monocytes are epigenetically altered following early life RSV infection with concurrent gut microbiome alteration further indicating trained immunity. Monocytes seed the lung environment upon inflammation and can differentiate into various other cells that reinforce inflammation within the lung during an allergic response. We plan to obtain a comprehensive understanding of the trained innate immunity after RSV infection by performing ChIP-seq experiments for activating and repressive histone modifications in bone marrow monocytes. This application has also been revised since initial submission based on reviewer’s comments to better investigate the role of microbiome alterations upon immune cell precursors by directly testing the impact of epigenetic alteration of monocytes during allergic inflammation. The results from these studies will further our understanding of how early life pulmonary infections and alterations of the early life microbiome impacts trained innate immunity. This project will also serve as excellent training for the applicant, Alexander Ethridge, to gain the research and critical thinking skills that will help him become a successful, independent scientist.