The SOCS protein structure consists of an N-terminal domain, a central SH2 domain and a C-terminal SOCS box (Bullock et al., 2007; Hao and Sun, 2016). They all share sequence homology, but especially these pairs, CIS/SOCS1/SOCS2, SOCS3/SOCS4/SOCS5, and SOCS6/SOCS7 have unquestionable marked pair-wise homology. Specifically, the SOCS box is a small, 40- to 60-amino acid (aa) residue domain structurally similar to the domain of the von Hippel–Lindau protein and lesser to the F-box from Skp2 (Kile et al., 2002). The SOCS box interacts with Elongins (B and C) to recruit E2 ubiquitin–transferase, necessary for negative regulation of cytokine signaling (Kamizono et al., 2001). The interaction between SOCS and Elongin BC complex and Cullin 2, facilitates the ubiquitination of JAKs and their cytokine receptors, which targets them for proteasomal degradation (Rawlings et al., 2004; Kershaw et al., 2013).

Structurally, SOCS family of proteins can be subdivided based on aa residues, with the shortest N-terminal region being CIS, SOCS1-3, or longest being SOCS4-7. CIS and SOCS1-3 act in a negative feedback loop through the JAK/STAT pathway in response to cytokine signaling; whereas, SOCS4-7 mainly regulate growth factor receptor signaling (Krebs et al., 2002; Kario et al., 2005; Trengove and Ward, 2013) (Table 1). Notably, SOCS1 and SOCS3 share a similar kinase inhibitory region (KIR) at the N-terminus that is essential for JAK inhibition (Sasaki et al., 1999; Yasukawa et al., 1999; Alexander, 2002; Ushiki et al., 2016). The SH2 domain/KIR ability to inhibit the signaling cascades independently by either blocking STAT docking or directly inhibiting JAK kinase activity confers substrate specificity. Depending on the size and structure of the SOCS protein, each domain interacts directly or indirectly with JAKs or their specific cytokine receptors to inhibit signaling proteins (Hilton, 1999; Nicholson et al., 1999; Sasaki et al., 1999, 2000; Yasukawa et al., 1999; Lehmann et al., 2003). Supposedly, the SOCS box mediates signaling suppression differently by promoting the degradation of bound signaling intermediates via an interaction with the cellular ubiquitination machinery (Zhang et al., 1999, 2001; Kamizono et al., 2001; Kile et al., 2002; Rui et al., 2002; van de Geijn et al., 2004). Revealing how SOCS proteins associate and interact with other proteins or external factors may offer much-needed premise in biomedical therapy approaches.

The SOCS proteins were first identified based on their ability to suppress cytokine signaling through the JAK/STAT pathway (Dalpke et al., 2003, 2008). The mechanism of cytokines binding to their putative cell surface receptors induces receptor dimerization, which allows trans-phosphorylation of JAKs (Dalpke et al., 2008) and tyrosine phosphorylation of the intracellular receptor subunits, to be bound by STATs. Following STAT phosphorylation, there is dimerization and then translocation into the nucleus (Dalpke et al., 2001). All SOCS proteins inhibit the JAK/STAT pathway similarly, (Dalpke et al., 2001; Caballero et al., 2016) upon cytokine stimulation, which blocks further signaling in a classic feedback loop by targeting signaling intermediates for degradation (Elliott and Johnston, 2004). Moreover, SOCS proteins have been implicated in regulating inflammation and determining cell fate because their obstruction or imbalance causes a broad range of diseases (Elliott and Johnston, 2004).

Upon receiving a signal, a receptor protein changes conformation simultaneously, creating a series of biochemical reactions within the cell that are amplified by intracellular signaling pathways. The JAK/STAT pathway, which coincidentally is involved in SOCS induction, serves as the primary signaling mechanism for most cytokines in mammals (Rawlings et al., 2004). Moreover, the JAK/STAT circuitry includes a negative feedback loop that activates STATs to stimulate the transcription of SOCS genes (Alexander, 2002; Rawlings et al., 2004). JAK is first activated when various ligands, usually cytokines and growth factors bind to cell surface receptors to form a dimer that can phosphorylate each other. This phosphorylation further activates JAK, allowing it to phosphorylate the receptor. When STAT binds to the receptor, it then becomes phosphorylated by JAK. Once phosphorylated, STAT dimerization occurs followed by translocation to the nucleus, where it binds to specific sequences in the DNA. Inactivation of STATs occurs via dephosphorylating proteins along the signaling pathway. Alterations or mutations that perturb the JAK/STAT pathway will affect homeostasis, growth regulation, survival and cell migration; which are all critical functions of this pathway (Rawlings et al., 2004). Furthermore, mutations that activate or fail to regulate JAK signaling properly, cause inflammatory diseases and other etiologies (Rawlings et al., 2004). Because understanding the mechanism of signaling during SOCS-induced responses to bacteria can assist in halting or altering disease pathogenesis, this pathway is of great scientific interest for targeted therapeutics.

Despite this new era of biomedical development, the leading cause of mortality is still significantly influenced by new and pre-existing infectious diseases (O'Connor et al., 2006). Added to this for further exacerbation is the increasing incidence of antimicrobial resistant strains, the emergence of new diseases, and the re-surging of older deadly infectious diseases causing a direct negative impact on the economy and welfare in endemic areas (Peterson, 1996; Morens et al., 2004). It is well-documented that microbial pathogens use common strategies to cause infection and disease. These include adherence, invasion, and enhanced pathogenicity, while also evading host defenses (Peterson, 1996; Wilson et al., 2002; Morens et al., 2004). A common strategy employed by bacterial pathogens is the Type III secretion system (T3SS), which in some cases can be used to invade host cells and/or evade immune detection by injecting bacterial signaling proteins to manipulate host immune response for their intracellular survival. Some bacteria that employ the T3SS machinery, as well as the secreted effector proteins for their virulent functions, are C. trachomatis (Betts-Hampikian and Fields, 2010), Yersinia pestis (Nair et al., 2015), Salmonella serovar Typhi (Johnson et al., 2017), Shigella (Hu et al., 2017), Escherichia coli (Hu et al., 2017; Shaulov et al., 2017), and Pseudomonas aeruginosa (Brannon et al., 2009). Pathogens may also reside within a phagolysosome, a phagosome or within the host cell cytosol to evade host immune responses (Wilson et al., 2002). The production of virulent microbial toxins also plays a vital role in the pathogenesis of some diseases (de Sousa, 2003; Ramachandran, 2014). Highly infectious microbes such as Clostridium tetani (tetanus toxin) (Caballero et al., 2016), Corynebacterium diphtheria (diphtheria toxin) (Bermejo-Martin et al., 2016), Shigella dysenteriae (Shiga toxin) (Zadravec et al., 2016), and Clostridium botulinum (botulinum toxin) (Ozcan and Ismi, 2016) produce some of the most potent and lethal toxins.

The manifestation and severity of a disease are under the influence of the host immune response induced by a bacterial pathogen. Mediation of the host defense mechanisms occurs by its primary and secondary defense responses, respectively innate and adaptive immune responses (Chaplin, 2010). Consequently, the host inflammatory response may be the most important for dealing with microbial infections because it purposely diverts antimicrobial factors such as phagocytes and lymphocytes directly to the infection site. Mediation of inflammation occurs via central effector cells such as mast cells or blood basophils that give rise to localized or systemic responses, respectively (Chaplin, 2010; Ren and Dubner, 2010). Other effectors include phagocytes that engulf microbes, neutralization of microbial pathogens by antibodies or toxins that possess potent antimicrobial properties as well as by lymphocytes and macrophages that initiate immune responses against the pathogen (Tosi, 2005).

When bacteria, such as Neisseria meningitidis, and Salmonella spp. invade their respective hosts; complement proteins are up-regulated and assist in bacteria-killing via complement-mediated lysis (Finlay and McFadden, 2006; Lewis and Ram, 2014). Gram-positive bacteria such as Staphylococcus spp. that are resistant to this type of bacteria-killing mechanism eventually will become opsonized by acute phase proteins and destroyed by phagocytes. However, other pathogens can avoid these above-described killing mechanisms. In these cases, the host relies on cell-mediated immune responses to identify and eliminate such organisms. Macrophages are targets for intracellular bacteria (e.g., Salmonella spp.) that have evaded detection by complement or antibody (do Vale et al., 2016). When infected, these macrophages use MHC class II molecules to present bacterial peptides on their cell surface for recognition by T-helper cells (Goldman and Prabhakar, 1996). T-helper cells recognize the microbial peptides and release IFN-γ that initiates killing mechanisms for clearance of the invading intracellular bacterium (Goldman and Prabhakar, 1996). Notably, many bacteria can benefit from the stimulation of inflammatory reactions as their induced responses usually cause considerable tissue damage to the host making the host more susceptible to an infection (Mogensen, 2009). Moreover, the same cytokines and chemokines present at the inflammatory site are also very critical in regulating the immune system and inflammation (Cekici et al., 2000). Thus, dysregulation or an improper balance of cytokine signaling can cause a variety of diseases not only limited to bacterial but also including allergy, intensified inflammation, and some forms of cancer (26). It is therefore urgent that additional studies be performed with SOCS proteins as inflammatory regulators to encourage novel therapeutic approaches to eradicate bacterial diseases.

Robust innate and adaptive immune responses against microbial pathogens are determined by the detection of the diverse repertoire of their specific PAMPs, by PRRs of the host innate immune cells such as TLRs, and nucleotide oligomerization domain proteins (NOD) (Janeway and Medzhitov, 2002; O'Riordan et al., 2002; Takeuchi and Akira, 2010). Upon bacterial infection and PAMPs recognition, the PRRs initiate highly complex intracellular signaling pathways, which trigger pro-inflammatory and antimicrobial responses allowing the host to respond promptly to the infection (Athman and Philpott, 2004; Philpott and Girardin, 2004; Kumar and Yu, 2006; Gerold et al., 2007; Mogensen, 2009; Takeuchi and Akira, 2010; Stokes et al., 2015). TLRs play a central role in recognition of PAMPs and in driving host inflammatory responses. They activate the cells of innate immunity and promote pathogen-specific adaptive immunity through their action on antigen-presenting cells (Dalpke et al., 2001; Athman and Philpott, 2004; Kumar and Yu, 2006; Tapping, 2009). Triggering of PRRs and cytokine signaling in immune effector cells induces the expression of inflammatory and antimicrobial mediators as well as regulatory factors, which coordinate the elimination of the pathogen and infected cells (Mogensen, 2009; Takeuchi and Akira, 2010; Stokes et al., 2015). This process mainly occurs via the activation of JAK/STAT signaling pathways and results in gene expression and production of a variety of molecules, including an array of cytokines, chemokines, growth factors and immune-receptors (Rawlings et al., 2004; Mogensen, 2009). These proteins, especially cytokines play essential roles as mediators of immune responses and therefore have to be tightly regulated to induce appropriate and safe antimicrobial responses (Baetz et al., 2007; Dalpke et al., 2008).

SOCS proteins, protein inhibitors of activated stats (PIAS) and protein tyrosine phosphatases (PTPs) are negative regulators that activate the JAK/STAT pathway effectors of PRRs (Rawlings et al., 2004; Abbas et al., 2012). SOCS proteins represent one of the fundamental molecular mechanisms, which regulate the level of microbial pathogen-induced signaling of cytokines employing JAK/STAT signaling cascades (Yoshimura et al., 2012; Trengove and Ward, 2013; Kyoko Inagaki-Ohara, 2014), and also they interfere with cell signaling by mediating the degradation of signaling proteins (Grutkoski et al., 2003). These proteins regulate a broad range of pro- and anti-inflammatory cytokines in immune cells and therefore determine the sensitivity of the host to bacterial infections and the outcome of various bacterial infections (Dalpke et al., 2003; Baetz et al., 2004; Takagi et al., 2004; Yoshimura et al., 2004, 2007; Chaves de Souza et al., 2013).

Many gram-negative bacteria of the genera Escherichia, Pseudomonas, Chlamydia, Klebsiella, Neisseria, and Salmonella can cause spectra of manifestations in humans (Kang et al., 2005; Mogensen, 2009). Their cell wall is composed of peptidoglycan surrounded by LPS, phospholipids, and proteins (Mogensen, 2009); LPS is their main immune-stimulatory component and primary PAMP (Freudenberg et al., 2008). LPS interacts with host immune cells via TLR4 in association with several co-receptors: myeloid differentiation protein-2 (MD2), CD14 and LPS-binding protein (LBP) (Dumitru et al., 2000; Kumar and Yu, 2006; Strengell et al., 2006; Freudenberg et al., 2008). Moreover, these bacteria can simultaneously activate other TLRs via alternative PAMPs, including TLR2 (peptidoglycan and bacterial membrane proteins), TLR9 (non-methylated CpG (cytosine-guanosine)-DNA), and TLR5 (flagellin) (Mogensen, 2009). The interaction of LPS with TLR4 leads to activation of NF-κB and MAPK (JNK, p38, ERK) via myeloid differentiation factor 88 (MyD88)-dependent pathway, serine/threonine kinase IL-1R-associated kinase 4 (IRAK-4), and TNFR-associated factor 6 (TRAF-6). Besides, there are MyD88-independent pathways that activate interferon regulatory factor-3 (IRF-3) and IRF-7 resulting in the induction of IFN-dependent genes to activate the JAK/STAT pathway (Qin et al., 2007; Freudenberg et al., 2008; Hu et al., 2009). These various activation machineries culminate in triggering multiple immune response genes, especially pro-inflammatory cytokines and chemokines (Nakagawa et al., 2002; Qin et al., 2007; Freudenberg et al., 2008; Hu et al., 2009) (Figure 1).

Host immune cells have developed negative regulatory mechanisms, such as SOCS proteins, to control the exacerbated inflammatory reactions caused by prolonged exposure to LPS. Studies have shown that SOCS1 protects a host from fatal LPS responses (Kinjyo et al., 2002; Nakagawa et al., 2002; Hu et al., 2012), as underscored in SOCS1-deficient mice that exhibit a high sensitivity to LPS mediated thru MyD88-dependent and—independent pathways in association with IRAK1 (Kinjyo et al., 2002; Baetz et al., 2004; Croker et al., 2008; Manicassamy and Pulendran, 2009; Fujimoto and Naka, 2010). SOCS1 also facilitates blocking the uptake of LPS in mouse hepatocytes potentially to control sepsis (Scott et al., 2009). Experiments using SOCS1- and IFN-γ-deficient mice showed that IFN-signaling was modulated via JNK, p38, and NF-κB activations (Kinjyo et al., 2002; Croker et al., 2008) through direct interactions with NF-κB p65 and TLR/MAL (MyD88-adaptor-like protein) leading to their suppression and degradation (Nakagawa et al., 2002; Abbas et al., 2012). Others have reported that SOCS1 regulates the IFN-β-induced JAK/STAT pathway by directly inhibiting STAT1 phosphorylation and indirectly TLR4 signaling via IRF-3 (Wilson, 2014).

SOCS3 plays a vital role in regulating LPS inflammation by targeting multiple cytokine signaling cascades. Results from Qin et al. (2007) confirm that the transcriptional expression of SOCS3 by LPS in macrophages and microglia was mediated by activation of MAPK (ERK1/2, JNK, p38), STAT3 and endogenously produced IL-10. Macrophages deficient in SOCS3 expressed heightened LPS-induced STAT1, STAT3, and IL-6, but with no ensuing effect on NF-κB and ERK1/2 activation (Qin et al., 2012; Wilson, 2014). Moreover, it appears that depletion of SOCS3 in macrophages results in positively regulating TLR4 responses by, respectively suppressing STAT3- and SMAD3-mediated IL-6R and TGF-β activations, which are both necessary for negatively regulating LPS-induced IL-6 and TNF-α (Frobose et al., 2006). Also, SOCS3 has been implicated in controlling bone-associated inflammation as it inhibited LPS-induced IL-6 in osteoblasts by blocking the transcription factor, CAAT/enhancer-binding protein (C/EBPβ) (Yan et al., 2010). Paradoxically, SOCS3 positively regulated LPS/TLR4 responses by a feedback inhibition of endogenous TGFβ-1/SMAD3 signaling in macrophages (Liu et al., 2008). Others have reported that SOCS3 regulates IL-10 control of LPS-induced TNF, iNOS (inducible nitric oxide synthase) and nitric oxide (NO) in macrophages by targeting specific SOCS3 protein domains (SH2, SOCS box, and KIR) (Qasimi et al., 2006), thus associating SOCS3 with the IL-10 anti-inflammatory effects. SOCS3 inhibited STAT1 and regulated IFN-γ signaling, in response to LPS stimulation by binding to phosphorylated tyrosine sites of the JAK2 receptor domain (Stoiber et al., 1999) to control macrophage anti-bactericidal effects. Likewise, SOCS3 prevented IL-1 signaling, among others, by inactivating the TRAF-6/TAK1 complex (Posselt et al., 2011; Qin et al., 2012) to regulate LPS deleterious inflammatory responses.

Unlike SOCS1 and SOCS3, the control of LPS signaling by SOCS2 is minimal. Moreover, SOCS2 is differentially regulated in human and mouse cells (Frobose et al., 2006; Hu et al., 2009; Posselt et al., 2011), and the reason for this divergence has yet to be delineated. To promote TLR4 signaling, SOCS2 may target and mediate proteasome-dependent degradation of SOCS1 and SOCS3 (Tannahill et al., 2005; Hu et al., 2009). It is noteworthy to mention that some intact gram-negative organisms like E. coli (Qin et al., 2007; Hu et al., 2012; Demirel et al., 2013), P. aeruginosa (Ding et al., 2017), Chlamydia pneumoniae (Yang et al., 2008), Burkholderia pseudomallei (Ekchariyawat et al., 2005), Salmonella enterica (Uchiya and Nikai, 2005, 2008), Rickettsia conorii (Colonne et al., 2013), and Anaplasma phagocytophilum (Bussmeyer et al., 2010) can directly stimulate the expression of SOCS1 and SOCS3 in vitro and in vivo. These organisms exploit multiple signaling pathways including STAT1, STAT3, MAPK and NF-κB to induce the transcription and/or protein expressions of SOCS1 or SOCS3 as a feedback mechanism to control their induced inflammatory responses (Ekchariyawat et al., 2005; Uchiya and Nikai, 2005, 2008; Yang et al., 2008; Bussmeyer et al., 2010; Colonne et al., 2013; Demirel et al., 2013; Ding et al., 2017).

Gram-positive bacteria such as Listeria, Bacillus, Clostridium, Staphylococcus, Streptococcus, and Enterococcus cause numerous severe infections in humans (Navarre and Schneewind, 1999; Plouffe, 2000; Hessle et al., 2005; Moellering, 2009; Woodford and Livermore, 2009; van 't Veer et al., 2011). These bacteria have a high resistance to a variety of antimicrobial therapies (Plouffe, 2000; Hessle et al., 2005; Moellering, 2009; Woodford and Livermore, 2009; van 't Veer et al., 2011; Schneewind and Missiakas, 2012) as their cell wall is composed of a layer of peptidoglycan (PGN) and lipoteichoic acid (LTA), encased in the cytoplasmic membrane by diacylglycerol (Nandi et al., 2004; Hessle et al., 2005; Brown et al., 2015). PGN is their principal PAMP that is recognized through Nod-like receptors [NLRs (Nod1 and Nod2)] and cryopyrin response proteins (Plouffe, 2000; Draing et al., 2008; Brown et al., 2015). Exposure to gram-positive bacteria triggers various patterns of pro-inflammatory cytokines notably, amongst many, IL-1α/β, TNF-α, IL-6, and IL-8 (Plouffe, 2000; Draing et al., 2008; Brown et al., 2015). TLR2 is the primary receptor activated in response to PGN and LTA (Draing et al., 2008). Furthermore, both S. aureus and S. pneumoniae LTA-recognition is attained by TLR2 associated with LBP and CD14 in human monocytes to y contribute in the pathogeneses of their diseases (McDonald et al., 2005). The activation of TLR2 by these bacteria is mediated by MyD88 and Toll/interleukin-1 (IL-1)-receptor (TIR)-domain, which leads to the activation of NF-κB, MAPK (via JNK, ERK-1, and p38) and pro-inflammatory caspase-1 (Schroder et al., 2003; Draing et al., 2008) (Figure 2).

The role of SOCS proteins in regulation of gram-positive bacteria-induced inflammation has not been extensively investigated in comparison to gram-negative bacteria and their LPS. Wu and colleagues (Son et al., 2015) reported that SOCS1 enhancement in macrophages infected with the pathogenic Group A Streptococcus (GAS), led to the blockage of cytokine expression. In addition to IFN-β signaling, which is involved in the GAS-induced SOCS1, the TLR4/MyD88 pathway was observed to play a crucial role in stimulating SOCS1 by forming a complex with JAK1/STAT1 (Son et al., 2015). Both Bifidobacterium (B. breve, B. longum, and B. adolescentis) and E. faecalis stimulated an increase in SOCS1 and SOCS3 mRNA transcripts in mouse macrophages by triggering NF-κB and MAPK signaling pathways to regulate the production of pro-inflammatory cytokines (Wu et al., 2015).

A study by Stoiber et al. (Okada et al., 2009) revealed that prolonged infection of macrophages with L. monocytogenes inhibited the phosphorylation of STAT1 and IFN-γ signaling with an enhancement of SOCS3 transcript and protein via the p38 MAPK pathway. Both live and heat-killed bacteria induced SOCS3; however, live bacteria induction of SOCS3 required de novo protein synthesis (Okada et al., 2009). The non-pathogenic probiotic bacterium Lactobacillus and non-pathogenic/pathogenic Streptococcus spp. induced the expression of SOCS3 mRNA in human primary macrophages by directly stimulating macrophages. Expression of SOCS3 by these bacteria was dependent on endogenously produced IL-10 and mediated through the p38 MAPK signaling pathway (Stoiber et al., 2001). Consequently, their stimulation of SOCS3 is induced directly, through at least p38 MAPK-mediated signaling pathway, and indirectly through IL-10 produced by bacterial-stimulated macrophages.

The Mycobacterium genus includes, but not limited to, M. tuberculosis and M. avium complexes (Imai et al., 2003; Gao et al., 2006; Latvala et al., 2011), that are responsible for several pulmonary diseases in humans, in particular, Tuberculosis (TB) caused by M. tuberculosis (MTB) (Prince et al., 1989; Gao et al., 2006). Mycobacteria cell wall is composed of a thin internal layer of peptidoglycan, phosphatidyl-myo-inositol mannosides (PIMs) and arabinogalactan, and an external layer of hydrophobic mycolic acids (Nandi et al., 2004; Rottenberg and Carow, 2014). Other components include mannose-capped lipoarabinomannan (Man-LAM), a significant virulence factor; the related lipomannan (LM), and mannoglycoproteins (Rottenberg and Carow, 2014). Mycobacteria are facultative intracellular pathogens, and macrophages are their primary host cells (Gao et al., 2006; Kleinnijenhuis et al., 2011).

Several PRRs are implicated in recognition of mycobacteria by host macrophages and DCs, including TLR1, TLR2, TLR4, and TLR9, C-type lectin receptors (CLRs) (i.e., mannose receptor, DC-SIGN, Mincle, and Dectin-1) and NLRs (Rottenberg and Carow, 2014; Zhao et al., 2014; Mortaz et al., 2015). Numerous mycobacterial components activate TLRs, namely lipoproteins (LpqH, LprA, LprG), PhoS1, LAM, LM, and PIMs, which activate TLR2; glycolipoprotein and PIM6, which activate TLR2/TLR4; and mycobacterial DNA, which respond via TLR9/TLR2 (Killick et al., 2013). Mycobacteria interaction with TLRs results in the activation of NF-κB activated protein-1 (AP-1) via MyD88, MAL, and IRAK, leading to the production of chemokines and several pro-inflammatory cytokines (Rajaram et al., 2014; Rottenberg and Carow, 2014; Zhao et al., 2014) (Figure 3). Mycobacterial components also induce IL-10 via caspase recruitment domain-containing protein 9 (CARD9) or p38 MAPK and serine/threonine Akt kinases (Jo, 2008; Redford et al., 2011).

Mycobacterial infections trigger the expressions of SOCS1 and SOCS3 (Gao et al., 2006; Dorhoi et al., 2010; Killick et al., 2013) along with SOCS4 and SOCS5 in mice infected with highly virulent MTB isolates (Vazquez et al., 2006). Overexpression of SOCS1 and SOCS3 results in polarizing effects permitting induction of suppressor responses, but also the survival of mycobacteria through the manipulation of cytokine responses, especially IFN-γ that is required in the resolution of mycobacterial infections (Manca et al., 2005; Dorhoi et al., 2010). Mycobacterial-induced SOCS1 and SOCS3 are dependent TLR2/MyD88 along with NF-κ and p38 MAPK activation (Manca et al., 2005). Specifically, SOCS1 suppressed STAT1 phosphorylation resulting in the inhibition of STAT1-mediated IFN-α/β signaling (Manca et al., 2005; Dorhoi et al., 2010). SOCS1 also promotes mycobacterial growth in macrophages by blocking IFN-γ secretion in response to IL-12 induced by the infection (Srivastava et al., 2009).

Mycobacteria-specific components (i.e., PIM2 and PPE protein, PPE-18) via TLR2/MyD88-activation of macrophages augment SOCS3 expression, and dislocation of the MyD88/TLR2 pathway modulated SOCS3 expression (Prince et al., 1989). Additionally, SOCS3 induced by PPE18 inhibited NF-κB activation by diminishing the phosphorylation of IκBα (Carow et al., 2011). In general, mycobacterial-induced SOCS3 inhibits STAT3 activation through cytokine receptors that activate STAT3 (Prince et al., 1989). As an example, SOCS3 binding to gp130 mediated the control of MTB infection in myeloid cells by inhibiting the IL-6/STAT3 signaling pathway (Nair et al., 2011; Carow et al., 2013).

Both SOCS2 and CIS can also play a role in regulating responses to mycobacterial infections. The expression of SOCS2 increased in macrophages infected with mycobacteria, and SOCS2-deficient mice exhibited a higher sensitivity to the inflammation induced by M. bovis infection (Carow and Rottenberg, 2014). Nonetheless, the activity of SOCS2 seems to be scarce and redundant and still requires a better understanding. CIS, on the other hand, is associated with increased susceptibility to TB (Sun et al., 2014; McCormick and Heller, 2015), likely by negatively regulating SOCS1 and SOCS3 (Trengove and Ward, 2013).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.