The balance between Th1- and Th2-related immune responses is a critical determinant of the outcome of Leishmania infection and the pattern of the disease [1], [2]. While IL-4 and IL-10 counteract Th1 cells, IFN-γ opposes the Th2 cells enhancing susceptibility and resistance, respectively, to infection with L. major and L. donovani [3], [4], [5]. IFN-γ activates M1 macrophages to trigger ROS-mediated Leishmania killing within the macrophages, conversely, IL-4 and IL-10 activate M2 macrophages [6], [7]. Th1 cell–derived IFN-γ induces macrophages to produce IL-12, which supports Th1 cells to secrete IFN-γ suggesting a positive feedback loop in Th subset differentiation [8]. By contrast, IL-10 and TGF-β negatively impact the Th1 cell differentiation and parasite killing but limit collateral tissue injury [9], [10], [11] suggesting a negative feedback component in the anti-leishmanial cellular immunoregulatory framework.

Molecularly, cytokines as coordinators of immune cells utilize the JAK-STAT pathway to transmit their signals from the cell surface into the nucleus of target cells. The binding of STAT proteins to the receptor, facilitated by the Src homology 2 (SH2) domain of the STAT protein, is followed by their phosphorylation by Janus kinases (JAKs). This phosphorylated STATs form homo- or hetero-dimers and translocate into the nucleus, bind to specific sites on DNA, and induce gene expression [12]. The SOCS proteins interfere with STAT activation and are implicated in the molecular pathogenesis of many infectious diseases [13]. For example, Toxoplasma gondii represses the IFN-γ-induced activation of mouse macrophages by upregulating the SOCS1 expression [14]. Similarly, both Mycobacterium bovis and M. tuberculosis upregulate SOCS1 to interfere with immune responses. M. bovis specifically upregulates SOCS1 and SOCS3 to inhibit IFN-γ-induced STAT1 activation impairing the antimicrobial response whereas M. tuberculosis overexpresses SOCS1 effectively suppresses T cell-mediated immune responses [15], [16]. Likewise, Listeria monocytogenes induces SOCS3 [13], whereas Brucella abortus induces both SOCS1 and SOCS3, in human monocytes to intercept IFN-γ-mediated signaling [17]. Additionally, Chlamydia pneumoniae upregulates SOCS1 expression controlling the infection-induced lethal inflammation and bacterial growth [18]. The dysregulated expression of SOCS1 and SOCS3, therefore, significantly impacts the susceptibility to infectious diseases.