Strain-Specific Behavior of Mycobacterium tuberculosis in Interruption of Autophagy Pathway in Human Alveolar Type II Epithelial A۵۴۹ Cells

Background: Autophagy induction has been shown to differ in magnitude depending on the mycobacterial species. However, few studies have investigated the specific autophagic capacity of different Mtb strains in ATs. This study aimed to elucidate the host autophagic response to different Mtb strains in ATs responsible for TB in the capital of Iran, Tehran. Methods: A۵۴۹ cells were infected with three different Mtb clinical isolates (Beijing, NEW۱, and CAS۱/Delhi) and the reference strain H۳۷Rv. Following RNA extraction, the expression of eight ATG genes, four mycobacterial genes, and three miRNAs was evaluated using quantitative RT-PCR. Results: The results revealed that all four strains influenced the autophagy pathway in various ways at different magnitudes. The Beijing and H۳۷Rv strains could inhibit autophagosome formation, whereas the CAS and NEW۱ strains induced autophagosome formation. The expression of genes involved in the fusion of autophagosomes to lysosomes (LAMP۱) indicated that all the studied strains impaired the autophagolysosomal fusion; this result is not unexpected as Mtb can block the autophagolysomal fusion. In addition, the Beijing and H۳۷RV strains prevented the formation of autophagic vacuoles, besides mycobacterial targeting of lysosomes and protease activity. Conclusion: This preliminary study improved our understanding of how Mtb manages to overcome the host immune system, such as autophagy, and evaluated the genes used by specific strains during this process. This study provides valuable insights into the strain-specific mechanisms of Mycobacterium tuberculosis in modulating host autophagy. By identifying how prevalent clinical isolates in Tehran differently regulate autophagosome formation and autophagolysosomal fusion, the findings offer a foundation for developing adjunct therapies that enhance autophagy and overcome bacterial immune evasion. Moreover, understanding these differences supports precision medicine approaches in tuberculosis treatment and guides future research on host- pathogen interactions across diverse Mtb lineages. Further studies with a large number of Mtb strains, encompassing the other main Mtb lineages, are inevitable.