Abstract:

Intravenous BCG vaccination contributes to protection against Mtb via long-term remodeling of the pulmonary myeloid compartment

Alveolar macrophages are a major replicative niche for Mycobacterium tuberculosis (Mtb) and facilitate the entry of mycobacteria into the lung parenchyma. As such, alveolar macrophages are an attractive target for interventions aimed at preventing Mtb infection. Recent reports have described heightened anti-bacterial responses by myeloid cells in the bone marrow and blood of mice and humans vaccinated with BCG. However, it is unclear how BCG immunization affects tissue-resident myeloid populations. In the present study, we evaluated the long-term effects of BCG vaccination on alveolar macrophages in vivo. We used a BCG vaccination model in which mice were immunized via the intravenous (iv) route, previously shown to stimulate systemic inflammation and enhanced myelopoiesis in the bone marrow. In contrast to conventional subcutaneous (sc) BCG immunization, iv inoculation dramatically altered the composition of the myeloid cell compartment in the lung, triggering a striking, yet transient, depletion in alveolar macrophages that was dependent on IFNγ-producing T cells. The empty alveolar niche was subsequently re-populated by interferon-primed macrophages, likely derived from blood monocytes, that displayed heightened resistance to Mtb upon challenge 5 months after vaccination. Our results indicate that in promoting a robust Th1 response, systemic BCG immunization has a profound and long-term impact on lung-resident macrophages, affecting both their subset composition and responsiveness to microbial stimuli. This remodeling of the lung myeloid compartment may contribute to the enhanced protection against Mtb reported in experimental animals immunized with BCG via the iv route.

This research was supported by the Intramural Research Program of the NIAID, NIH.