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

fects that may occur with apoptosis. Despite this dynamic, Leishmania amazonensis can induce macrophages to produce IFN-β to generate SOD in order to create an environment conducive for the parasite to evade the immune system, survive, and multiply. Considering that vesicular traffic is fundamental for phagosome maturation, either protozoa or M. tuberculosis manipulates macrophages to maintain Rab5 expression increased to establish early phagosome fusion with lysosome, as well as formation of the calcium-calcineurin complex to inhibit the production of cathepsin D and Rab7 and to facilitate the survival of the pathogens. The effect of evasion of Leishmania with T. cruzi is very peculiar in the case of leishmaniasis, autophagy is explored to eliminate promastigotes forms and reduce responses of T cells. In contrast, T. cruzi uses autophagy as a central point to invade phagocytic cells and multiplies whether at basal levels or not. Interestingly, LC3 protein serves as the gateway to mediate this process. is induced by starvation or rapamycin, autophagolysosome formation and LC3 expression is increased. This also results in large-scale formation of the parasitoid vacuole. As a form of escape, the trypomastigote form resides in the autophagolysosome and escapes into the cytosol, increasing the autophagic cell response (Figure 3 ). 209 For M. tuberculosis, the suppression of autophagy to increase the survival of mycobacteria serves as a potential regulatory effect. In this context, cytokines such as IL-6 and IL-27 inhibit IFN-γ-induced autophagy. In this process, expression of IL-6 or IL-27 considerably reduces the maturation of the autophagolysosome from the negative regulation of Atg12-Atg5 and positive effects of complex JAK/PI3K/Akt/mTOR and Mcl-1 ( Figure 3) . 210, 211 Concerning the modulation of the autophagic cascade for flavivirus, autophagy seems to be a crucial factor in mediating the biogenesis of viral replication. [212] [213] [214] This relationship overlaps in a dynamic where the internalization of viruses at endocytosis facilitates the change in pH and, consequently, the release of viral RNA (vRNA) into the cytoplasm. The events of autophagy manipulation are mainly modulated by non-structural proteins, such as Among the receptors, we highlight RIG-I and MDA5 that recognize PAMPs either HCV or flaviviruses to activate MAVS and STING, which in turn, provoke the formation of TBK1/IKKε and NEMO/IKK-α/β complex. This mechanism has the final product for both phosphorylation of IRF7 and IRF3 and the release of KF-κB p50/p65 subunit that migrates to the nucleus to activate genes responsible for production of inflammatory cytokines and IFN-type 1. In the case of IFN-α and β, IFNR activation recruits JAK1 and TYR2, which when phosphorylated, trigger formation of an intracellular cascade that culminates in formation of the STAT1/STAT2/IRF9 complex, which migrates to the nucleus, activating genes associated with the antiviral response such as Mx, OAS, PKR, and ISGs. To evade the immune response, HCV or flaviviruses induce the production of non-structural proteins that inhibit response of several markers at points considered essential for the development of the intracellular cascade, facilitating the viral replication process. A priori WNV can establish primordial control of antiviral responses at the level of inhibition of RIG-I and MDA5. In another follow-up, ZIKV, DENV, WNW, or HCV through NS1, NS2A, NS2B, NS3, NS4A, NS4B, or NS5 inhib