Project Summary Hematopoietic cell transplantation (HCT) is a potentially curative therapy for a variety of neoplastic disorders. However, the composition of the microbiota is often disturbed during the process of HCT. Alterations or dysbiosis of the lung microbiome post-HCT are associated with poor clinical outcomes, including lung injury. Pulmonary complications commonly occur among HCT recipients and are a leading cause of post-HCT morbidity and mortality. These pulmonary complications include both pathologies generated by infectious agents and also the so called “non-infectious” disorders. Non-infectious pulmonary complications are associated with irreversible pulmonary dysfunction and considerable mortality. No cure exists for these progressive disorders such as idiopathic pneumonia syndrome (IPS) which is characterized by pneumonitis, lung injury and often fibrosis. The etiology and pathogenesis of non-infectious post-HCT pulmonary disorders is poorly understood and research in this area is a critical need within the NIH mission. Our long-term goal is to improve outcomes for HCT recipients by developing microbiome-informed therapeutic strategies to manage post-HCT pulmonary complications. We have shown that primary infection or reactivation of latent herpesviruses increases the risk of post-HCT lung injury such as IPS and that these lung injuries are associated with dysbiosis of lung microbiota in human HCT recipients. We have developed novel animal models that recapitulate the pathologic features of IPS to allow for mechanistic studies. We have shown that a loss in abundance of Lactobacillus species and the Lachnospiraceae family in mice is associated with developing IPS-like pneumonitis and fibrosis, and that the development of pneumonitis and fibrosis post-HCT and herpesviral infection is IL-17-dependent. Importantly, microbiota isolated from the lungs of HCT mice stimulate pro-IL-17 responses by lung dendritic cells (DCs) potentially through impairing the expression of Notch ligand, delta like ligand 4 (DLL4). Thus, we hypothesize that HCT-altered lung microbiota facilitate lung DC modifications/priming so that DCs promote pathogenic IL-17 responses to herpes virus infection leading to lung pathology and the development of pulmonary complications like IPS. We will pursue the following three specific aims in this proposed project. Aim 1. Identify key lung microbiota associated with post-HCT pulmonary complications Aim 2. Determine the mechanism(s) through which lung microbiota regulate lung DC function Aim 3. Determine the role of Lactobacillus species and the Lachnospiraceae family in the development of post-HCT pulmonary complications