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

Abstract

<i>Mycobacterium tuberculosis</i>, 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 <i>M. tuberculosis</i> 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 against <i>M. tuberculosis</i> 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 <i>M. tuberculosis</i> exposure and whether such AwM play a critical role in host defense against <i>M. tuberculosis</i> infection. Our study reveals an important role of AwM in innate immune protection in early stages of <i>M. tuberculosis</i> infection in the lung.