Immunopathogenesis of Nocardia infections

In FY24, we developed a novel Nocardia reporter strain that will be useful to the broader research community. Several enhancements and optimizations were made to our previously developed reporter strain from FY23. Compared to our first-generation reporter strain, the strain developed in FY24 demonstrates superior performance and a substantial reduction in the time required for cultivation. These improvements have provided us with the opportunity to perform more complex in vivo experiments. We have utilized this novel reporter strain to track the fate of Nocardia following inoculation in mouse models of human nocardiosis. Using high-dimensional flow cytometry, we have determined the contribution of various immune and stromal cell types to the phagocytosis and killing of Nocardia in in vivo. Furthermore, we have used this system to better understand the pathogenesis of nocardiosis in the immunocompromised host using several mouse models of clinically relevant conditions known to predispose patients to nocardiosis. Examples include inherited disorders (including Chronic Granulomatous disease), acquired immunodeficiencies (anti-GM-CSF autoantibodies), and iatrogenic immunosuppression (corticosteroid treatment). These experiments have uncovered tissue- and cell-type specific defects in phagocytosis and killing in the settings of certain impairments in host defense. Guided by our experimental findings, we have also investigated the ability of various therapeutic interventions (inhaled GM-CSF, for example) to enhance phagocytosis and killing in vivo and improve clinical outcomes in our mouse model of nocardiosis.