Pulmonary infection induces persistent, pathogen-specific lipidomic changes influencing trained immunity

Resolution of infection results in development of trained innate immunity which is typically beneficial for defense against unrelated secondary infection. Epigenetic changes including modification of histones via binding of various polar metabolites underlie the establishment of trained innate immunity. Therefore, host metabolism and this response are intimately linked. However, little is known regarding the influence of lipids on the development and function of trained immunity. Utilizing two models of pulmonary bacterial infection combined with multi-omic approaches, we identified persistent, pathogen-specific changes to the lung lipidome that correlated with differences in the trained immune response against a third unrelated pathogen. Further, we establish the specific cellular populations in the lung that contribute to this altered lipidome. Together these results expand our understanding of the pulmonary trained innate immune response and the contributions of host lipids in informing that response. [Display omitted] •Pathogens exert differential effects on pulmonary efferocytosis post-infection•Differences in efferocytosis are mediated by macrophage subsets•Unique immune lipid mediator milieus are linked to these macrophage subsets•Changes in the lipid landscape impact trained immunity to an unrelated infection Biological sciences; Immunity; Genomics; Lipidomics