Mycobacterium tuberculosis Infection and Innate Responses in a New Model of Lung Alveolar Macrophages

Minjeong Woo, Connor Wood, Doyoon Kwon, Kyu-Ho Paul Park, György Fejer, Vincent Delorme

Lung alveolar macrophages (AMs) are in the first line of immune defense against respiratory pathogens and play key roles in the pathogenesis ofMycobacterium tuberculosis(Mtb) in humans. Nevertheless, AMs are available only in limited amounts forin vitrostudies, which hamper the detailed molecular understanding of host-Mtbinteractions in these macrophages. The recent establishment of the self-renewing and primary Max Planck Institute (MPI) cells, functionally very close to lung AMs, opens unique opportunities forin vitrostudies of host-pathogen interactions in respiratory diseases. Here, we investigated the suitability of MPI cells as a host cell system forMtbinfection. Bacterial, cellular, and innate immune features of MPI cells infected withMtbwere characterized. Live bacteria were readily internalized and efficiently replicated in MPI cells, similarly to primary murine macrophages and other cell lines. MPI cells were also suitable for the determination of anti-tuberculosis (TB) drug activity. The primary innate immune response of MPI cells to liveMtbshowed significantly higher and earlier induction of the pro-inflammatory cytokines TNFα, interleukin 6 (IL-6), IL-1α, and IL-1β, as compared to stimulation with heat-killed (HK) bacteria. MPI cells previously showed a lack of induction of the anti-inflammatory cytokine IL-10 to a wide range of stimuli, including HKMtb. By contrast, we show here that liveMtbis able to induce significant amounts of IL-10 in MPI cells. Autophagy experiments using light chain 3B immunostaining, as well as LysoTracker labeling of acidic vacuoles, demonstrated that MPI cells efficiently control killedMtbby elimination through phagolysosomes. MPI cells were also able to accumulate lipid droplets in their cytoplasm following exposure to lipoproteins. Collectively, this study establishes the MPI cells as a relevant, versatile host cell model for TB research, allowing a deeper understanding of AMs functions in this pathology.