Notch regulates Histoplasma capsulatum clearance in mouse lungs during innate and adaptive immune response phases in primary infection

The clearance of the pathogenic fungus, Histoplasma capsulatum, requires cooperation between innate and adaptive immunity. Since this organism is inhaled, lung macrophages and dendritic cells (DCs) are the first lines of defense. Moreover, DCs act as APCs to drive the education of type 1 Th cells to produce IFNγ, which contributes to the final elimination of H. capsulatum. In this study, we explored the importance of Notch signaling in host defenses using a mouse model of pulmonary histoplasmosis. We found up-regulation of Notch ligands (NLs) and Notch receptors (NRs) on phagocytes and IFNγ⁺ CD4⁺ T cells upon infection in lungs and lymph nodes. To ascertain the influence of Notch on the course of infection, we used a gamma-secretase inhibitor (GSI), LY-411,575, which inhibits NR downstream signaling. This compound impaired fungal clearance when given at the time of infection or 7 days after infection. However, GSI did not impact fungal clearance in mice with preexisting immunity. The dampened host defenses were associated with reduced differentiation and maturation of monocyte-derived DCs and elevatmonocyte-derived macrophage and alveolar macrophage polarization to M2. Our study reveals the critical nature of Notch signaling in maintaining control of this infectious agent.