Introduction
One third of the people suffering with type 2 diabetes mellitus (DM) reside in developing countries many of which are endemic for Tuberculosis (TB). In Pakistan, the prevalence of diabetes is reported to be 9.8% and 3% of all national deaths are thought to be associated with DM and DM-related conditions (1). As Pakistan also ranks 5th amongst high TB burden countries, it is an additional challenge to manage patients with TB and DM comorbidity (2). Different risk factors may account for an important proportion of TB cases in the population. Diabetes (DM) occurs as the individual becomes resistant to insulin, resulting in poor metabolism of glucose. Individuals with DM have a threefold increased risk of developing TB (3, 4). DM has also a negative impact on treatment outcomes in patients with tuberculosis (TB) (5). Latent, asymptomatic infection or immune reactivity with M. tuberculosis (LTBi) occurs in around one fourth of the world population (6), and the association between LTBi and DM-2 has been suggested (7).
Studies on host immunity of individuals with LTBi indicate that CD4 T cell responses specific to MTB antigens are raised in this group (8). Which is the premise of the MTB-specific T cell -derived IFNγ assay testing for LTBi diagnosis (9). Additional cytokines and chemokines such as IL-10, TNFα, CXCL10, CXCL9 are also found to be raised in LTBi as compared with healthy endemic controls (EC) (10). Gene expression studies have identified particular biomarker expression patterns within LTBi individuals that discriminate them from those who are healthy and those who have active TB (11) (12). Heterogeneity of LTBI was further recognised by epidemiological differences in the risk of TB between those with recent and remote infection (13). It is well understood that immune regulatory factors such as, IL-12, IFN-γ and TNF-α confer protective immunity against MTB infection, the understanding of factors which lead to disease progression from LTBi to TB is very limited (14).
DM is associated with altered cellular and humoral immune responses with modulation of macrophage and lymphocyte function (15). Delayed management of DM can lead to diverse complications including susceptibility to infections (16). Inflammatory mediators including, proinflammatory cytokines such as IFNγ, TNFα, IL-6, and downregulatory cytokines IL-10, TGFβ together with adipokines, which affect leptin regulation and impact metabolism in glycogen stores, are all raised in DM cases (17). Individuals with LTBi and DM have been shown to sub-optimal CD4 T cell responses to MTB-specific antigens and increased production of the Th 2 cytokines IL-10 and TGF-beta (18).
Host innate and adaptive responses are both crucial in protection against TB. Suppressor of cytokines signaling (SOCS) molecules regulate key cytokine drivers of activation of both innate and adaptive immunity. SOCS has eight member molecules including cytokine-inducible regulator of signaling (CIS), SOCS1-7 (19). SOCS1 and 3 are found to play a role in the pathogenesis of TB and diabetes (20). SOCS1 suppresses STAT1, the transcription factor involved in IFN-γ and IFN-α/β signaling, while SOSC3 has different targets, including STAT3 activation via certain receptors as the IL6-receptor family (21). SOCS1 and 3 molecules are modulated by MTB for its own survival, play a pivotal role in controlling infection outcomes (19, 22, 23).
Separately, SOCS1 and SOCS3 inhibit the insulin receptor substrates 1 and -2 (IRS-1 and IRS-2) protein, hindering insulin responses and insulin growth factor (IGF)-1 signaling, thereby affecting glucose metabolism (24). Here we investigated the impact of diabetes on progression of MTB infection to active disease through the study of mycobacterial antigen-induced cytokine activation and their association of regulatory SOCS1 and SOCS3.