Exposure tomycobacteriumremodels alveolar macrophages and the early innate response toMycobacterium tuberculosisinfection

Abstract

As innate sentinels in the lung, alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells to encounter bacteria. We previously showed that AMs initially respond to Mtb infection in vivo by mounting a cell-protective, rather than pro-inflammatory response, yet whether the AM response could be modified by environmental factors was unknown. Here, we characterize how previous exposure to mycobacteria, either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb), impacts the initial response by AMs and early innate response in the lung. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory AM response to Mtb in vivo. AMs from scBCG vaccinated mice mount a robust interferon response, while AMs from coMtb mice produce a broader and more diverse inflammatory response. Using single-cell RNA-sequencing, we identify exposure-induced changes to airway-resident cells, with scBCG and coMtb enriching for different AM subpopulations. Ex vivo stimulation assays reveal that AMs from scBCG and coMtb mice switch on an interferon-dependent response, which is absent in AMs from unexposed mice. Overall, our studies reveal significant, durable, and cell-intrinsic modifications to AMs following exposure to mycobacterium, and comparison of scBCG and coMtb models reveals that AMs can be reprogrammed into more than one state. These findings highlight the plasticity of innate responses in the airway and underscore the unexplored potential of targeting AMs through vaccination or host-directed therapy to augment host responses.

CD4-mediated immunity shapes neutrophil-driven tuberculous pathology

“…Even prior to aerosol infection, there were differences in pathways associated with cell cycle and mitochondrial respiration in ILC2s in the setting of CoMtb, but not primary infection, potentially indicating innate training, which is consistent with previous reports (Fig 3A). 27 In agreement with our cellular abundance analysis, a stronger cell cycle/division response was seen in CD4 T cells following CoMtb at d17, indicating ongoing cellular activation and proliferation of T cells within the lung parenchyma. Starting d17 p.i., we also observed striking response differences in interferon response pathways which were upregulated over time across most cell populations (Fig 3A ).…”

Subcutaneous BCG vaccination protects against streptococcal pneumonia via regulating innate immune responses in the lung

“…However, our findings that resident alveolar macrophages in BCG vaccinated hosts display heightened phagocytic and killing capacities indicate that cutaneous BCG vaccination can also remotely impact the functionality of resident AMs. This observation is further supported by a recent study that showed cutaneous BCG vaccination in mice modifies the phenotype of alveolar macrophages in the airways and alters the in vivo alveolar macrophage responses to M. tb infection (28). An ongoing study in our laboratory also demonstrated that s.c BCG vaccination induces memory AMs with the characteristics of TII which goes on to provide enhanced early protection against M. tb infection (unpublished).…”

“…The current study provides further evidence that such TII in the lung following cutaneous BCG vaccination can also mediate heterologous protection against pulmonary S. pneumoniae infection. Interestingly, despite phenotypic and functional alterations in alveolar macrophages, gross cellularity in the airways is unaffected following cutaneous BCG vaccination, indicating that induction of TII in alveolar macrophages is independent of centrally trained monocytes (28, 29). Of note, although pulmonary S. pneumoniae infection led to the recruitment of centrally trained monocytes to the lung in BCG vaccinated hosts, they did not contribute to the enhanced protection as indicated by comparable clinical outcomes and bacterial control in BCG vaccinated CCR2 -/- and WT mice.…”

“…Interestingly, despite phenotypic and functional alterations in alveolar macrophages, gross cellularity in the airways is unaffected following cutaneous BCG vaccination, indicating that induction of TII in alveolar macrophages is independent of centrally trained monocytes (28,29).…”

Subcutaneous BCG vaccination protects against streptococcal pneumonia via regulating innate immune responses in the lung

“…However, our findings that lung-resident AMs in s.c. BCG-vaccinated hosts display heightened phagocytic and killing capacities and protect against S. pneumoniae independent of circulating monocytes indicates that cutaneous BCG vaccination can also remotely impact tissue-resident AMs. This observation is further supported by a recent study that showed cutaneous BCG vaccination in mice remodels AMs in the airways and alters AM responses to M. tb infection via mediating a robust and dominant interferon response (preprint: Mai et al, 2022). Such altered functionality of AMs was long-lasting as indicated by comparable or even elevated enhanced responses to secondary ex vivo stimulation at 23 weeks compared to 8 weeks post-s.c. BCG vaccination.…”