Endoplasmic Reticulum Stress in Tuberculosis: Molecular Bases and Pathophysiological Implications in the Immunopathogenesis of the Disease

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a severe pulmonary disease with high mortality, particularly in low-income countries. Early diagnosis and timely treatment, including both intensive and maintenance phases, are critical for controlling the disease and preventing its transmission. In Brazil, where TB incidence remains high, thousands of new cases are reported annually. Transmission occurs primarily through airborne droplets expelled by infected individuals. The immune response involves various cell types, such as lymphocytes and macrophages, which form granulomas to limit the spread of the bacillus. Upon entering the lungs, Mtb is phagocytosed by immune cells, where it evades destruction by blocking phagolysosome formation and inhibiting phagosome acidification. In response, the immune system forms granulomas that contain the infection, although these can become reactivated if immune function deteriorates. Mtb also interferes with host cellular organelles, particularly the endoplasmic reticulum (ER) and mitochondria, inducing cellular stress and apoptosis, which aids in its survival. Key Mtb-secreted proteins, such as BAG2 and CdhM, modulate autophagy and apoptosis pathways, influencing pathogen survival within immune cells. A deeper understanding of these molecular mechanisms, particularly the role of ER stress and its impact on immune responses, is essential for developing novel therapeutic strategies for TB prevention and treatment.