Functional aspects, phenotypic heterogeneity, and tissue immune response of macrophages in infectious diseases

de Sousa, Jorge Rodrigues; Da Costa Vasconcelos, Pedro Fernando; Quaresma, Juarez Antonio Simões

Just as the cell death process directly impacts the immune evasion strategies triggered by microorganisms, autophagy is used to mediate pathogen replication at various stages of development. [204] [205] [206] Interestingly, the apoptotic-like Leishmania uses autophagy to reduce the elimination of the promastigote forms in macrophages and diminish the response of T cells. It is worth noting that Annexin V, light chain 3 (LC3), beclin 1, and mechanistic target of rapamycin (mTOR) participate actively in this mechanism. 207 On the other hand, T. cruzi uses autophagy to subvert the lysosomal exocytic process and invade host cells under basal conditions. This occurs frequently because of recruitment of the LC3 protein. 208 Interestingly, when the process Figure 3 Immune evasion and strategies adopted by Mycobacterium tuberculosis, Leishmania, and Trypanosomiasis cruzi to evade microbicidal response of macrophages. Because it is a sequence of events that trigger destruction of microorganisms, immune escape strategies that inhibit microbicidal responses are as varied as possible. However, we seek to centralize an understanding of the crucial points that facilitate a pathogen's survival in the environment. For M. tuberculosis, it is noteworthy that TLR2 is the main receptor by which the immune escape correlates with ESAT-6 and CFP-10 response, whereas inhibitory modulation mainly affects the inflammatory cascade associated with NF-κB and to iNOS. Since sufoglycolipids inhibit activation of TLR2 and NF-κB, this not only compromises the microbicidal response but also facilitates the survival and proliferation of the bacillus. Through evolution of mycobacterial destruction mechanisms, adaptation of pathogens to evade the immune system has generated certain strains such as H37Rv that modulate phagosome maturation and facilitate translocation of bacillus to the cytosol. In addition, a recombinant lipoprotein derived from M. tuberculosis, such as RV1016c, regulates the mechanism of apoptosis through the annexins. This is crucial to facilitating proliferation of the bacillus in the tissue environment because RV1016c inhibits MHC II expression, compromising the CD4 T cell response and immune surveillance. Considering that the cytokine response is fundamental to induce the activation of macrophages, as well as the microbicidal response, M. tuberculosis inhibits the action of IFN-γ by inhibiting autophagy through responses of IL-6 and IL-27. Expansion of this scenario negatively regulates Atg12-atg5 and positive intracellular cascade involving JAK/PIK3/AKt/mTOR/Mcl1. Implications of such events are inhibitive of phagolysosome maturation and, consequently, the microbicidal response of the cell, which favors pathogen survival in phagocytes. With regard to protozoa, we highlight Leishmania, which, in addition to using the cells of the phagocytic system as a reservoir, also uses innumerable strategies of immune evasion to survive. Therefore, Leishmania major modulates TLR2 responses to induce SOCS1 and 3 to inhibit not only intracellular cascades of NF-κB but also the response of IFN-γ and TNF-α. For Leishmania donovani, by ubiquitination of TRAF 6 through A20, the response of NK-κB is compromised as well as the production of IL-6 and IL-12. Interestingly, L. major modulates immunosuppressive responses to facilitate its survival, and L. donovani follows the same path by mainly regulating expression of SOCS1 and 3 to avoid oxidative stress and catastrophic ef