**5. Conclusions**

Macrophages are the first line of innate defense against *Mtb* infection, and the subversion of macrophage apoptosis is considered a hallmark of *Mtb* pathogenesis. *Mtb* is a mystery pathogen that utilizes multiple strategies to abolish apoptotic signaling pathways in order to establish persistent infection. The impairment of macrophage apoptosis leads to the enhanced intracellular survival of bacilli and compromises the cell-mediated immune response. *Mtb* has a broad spectrum of anti-apoptotic e ffector molecules that direct targeting cellular pro-apoptotic factors or block the signaling that regulates their expression. Some *Mtb* anti-apoptotic e ffectors, including PE\_PGRS18 and IcI, impaired macrophage apoptosis by unrecognized mechanisms. Moreover, the role of *Mycobacterium* lipoprotein (LpqT) in modulating macrophage apoptosis needed to be clarified. Future studies are

needed to identify unrevealed mechanisms of *Mtb* anti-apoptotic e ffectors and to develop methods able to hamper *Mtb* effectors' capability to abrogate macrophage apoptosis.

*Mtb* can also manipulate macrophage apoptosis by selectively regulating cytokines and miRs expression. It is also important to understand how *Mtb* selectively regulates anti-apoptotic cytokines and miRs expression. The mechanisms by which cytokines and miRs enhance the viability of macrophages are dependent on the aberrant activity of key pro-apoptotic regulators, including P53, TNFα, Fas, FOXO, and Bad. They promote the activity of anti-apoptotic regulators such as SHIP, Bcl-2, and Mcl-1. Taken together, these insights into the intelligent subversion mechanisms of macrophage apoptosis by *Mtb* elucidate promising and novel therapeutic targets to eliminate the intracellular survival of bacilli and promote an adaptive immune response.

**Author Contributions:** A.E.A. conceived the idea and drafted the manuscript. M.O.M., A.A.M.A., K.O.A.A., M.Y.M.E., and M.A.M. reviewed the literature and helped in the drafting and analysis of the manuscript. H.E. contributed in drafting and critical revision of the manuscript. All authors have read and agree to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
