Airway Macrophages Mediate Mucosal Vaccine–Induced Trained Innate Immunity against Mycobacterium tuberculosis in Early Stages of Infection

Mycobacterium tuberculosis , the causative agent of pulmonary tuberculosis (TB), is responsible for millions of infections and deaths annually. Decades of TB vaccine development have focused on adaptive T cell immunity, whereas the importance of innate immune contributions toward vaccine efficacy has only recently been recognized. Airway macrophages (AwM) are the predominant host cell during early pulmonary M. tuberculosis infection and, therefore, represent attractive targets for vaccine-mediated immunity. We have demonstrated that respiratory mucosal immunization with a viral-vectored vaccine imprints AwM, conferring enhanced protection against heterologous bacterial challenge. However, it is unknown if innate immune memory also protects agains M. tuberculosis In this study, by using a murine model, we detail whether respiratory mucosal TB vaccination profoundly alters the airway innate immune landscape associated with AwM prior to M. tuberculosis exposure and whether such AwM play a critical role in host defense agains M. tuberculosis infection. Our study reveals an important role of AwM in innate immune protection in early stages of M. tuberculosis infection in the lung.