Adaptive-like Natural Killer cells in pulmonary cytomegalovirus reactivation

About This Grant

PROJECT SUMMARY AND ABSTRACT Cytomegalovirus (CMV) is a common herpesvirus that establishes latency for the lifetime of the host and drives immune dysregulation. The lung is an important reservoir for CMV in both humans and mice. CMV infection can reactivate during episodes of immunosuppression, with age, and from direct tissue injury. Importantly, CMV reactivation is associated with increased risk for death following lung transplantation, acute respiratory distress syndrome (ARDS) and SARS-CoV-2 pulmonary disease. Natural killer (NK) cells are effector innate immune cells that can recognize damaged or missing-self. They play a central role in mitigating CMV infection with long- lived tissue-resident, CMV-specific and adaptive abilities. Our prior publications have established novel roles for NK cells in mediating acute lung injury and found increased prevalence of CMV-specific NK cells in human lungs preceding injury. Our preliminary data identify tissue-resident NK cell populations as key effectors of airway- centric acute lung injury. Moreover, we found that adaptive-like NK cells are increased in tissue surrounding chronically-injured lung transplant airways. Identifying whether adaptive NK cell differentiation occurs locally in the lung in response to CMV reactivation and drives lung damage represents a fundamental gap in knowledge. Based on our observations, we hypothesize that local CMV-specific NK cell immune responses potentiate lung damage after transplant. Across 2 independent Aims we will use mouse models of CMV reactivation and observations in 2 established human lung transplant cohorts to investigate mechanisms of adaptive NK cell lung injury. Aim 1 will determine the impact of CMV reactivation on the adaptive NK cell response in the mouse and human lung. We will use 2 lung transplant mouse models and a previously recruited cohort of 56 lung transplant recipients’ bronchoalveolar lavage and tissue samples to measure NK cell phenotypes and spatial distributions relative to CMV activity and to probe the mechanism whereby lung adaptive NK cells develop in the allograft. In a non-interdependent fashion, Aim 2 will determine the mechanisms through which adaptive NK cells potentiate acute injury and their role in establishing allograft tolerance using established orthotopic allogeneic mouse lung transplant models. These proposed innovative approaches will examine the novel concept that tissue injury potentiates geographic residency of CMV-specific adaptive NK cell populations, raising the allograft immune tone and the risk for lung allograft damage. Work resulting from this proposal will be broadly applicable to other solid organ transplant recipients and patients suffering from acute respiratory distress syndrome and acute exacerbations of chronic lung disease. Importantly, we will identify: mechanisms of novel biology, cell populations that may risk stratify clinical outcomes, and new rational targets for future prevention and treatment of lung allograft syndromes.