(453) Endoplasmic reticulum stress as a determinant of Mycobacterium tuberculosis survival in alveolar macrophages

Introduction/Rationale: Alveolar macrophages (AMs) are the first innate immune cells to encounter Mycobacterium tuberculosis (M.tb) following natural infection. AMs are potent phagocytes, and they are permissive to M.tb survival, replication, and dissemination. Endoplasmic reticulum stress (ERS) is triggered by the accumulation of misfolded/unfolded proteins during cellular stress, and ERS-mediated apoptosis plays a critical role in eliminating intracellular pathogens. While ERS-induced apoptosis in M1 macrophages can effectively clear M.tb, in M2 macrophages it can favor bacterial persistence. AMs exhibit unique molecular and metabolic features, expressing a hybrid M1/M2 phenotype. However, the role of ERS in M.tb infected AMs and its impact on bacterial survival remain poorly understood.

Methods: In this study, alveolar macrophage-like (AML) cells derived from peripheral blood mononuclear cells were infected with M.tb to characterize the ERS response over time. We analyzed the expression of key ERS-related genes and proteins following infection with either live M.tb or its virulence factors, HBHA and ESAT-6. Additionally, ERS was induced in AML cells to assess its influence on bacterial survival.

Results: AML cells displayed distinct ERS signatures upon infection, with significant differences in gene and protein expression compared to ERS-induced and virulence factor only controls. Notably, cells without ERS harbored higher viable bacterial counts.

Conclusion: The permissive nature of AMs to M.tb could be in part due to the down-regulation of ERS and related apoptosis. The results of our study highlight a potential protective role of ERS in restricting M.tb survival.