Ag85a/b DNA vaccine therapy reduces the catabolism of tuberculosis.
TB is a consumptive disease(47). The results of DE gene analysis, GO biological process, and KEGG pathway analyses in this study all proved that the metabolic function of the mouse TB model group had changed greatly and their catabolism had increased. Some DE genes related to pancreatic islet dysfunction (Iapp, Scg2, Chga, Chgb, Slc30a8), carbohydrate and glycogen metabolism (Amy2a5, Gcg, Ins1, Amy1), protein hydrolysis (Try5, Cpa1, Gm13011, Try4, Cpb1), lipid metabolism (Ins1, Pnlip), neuroendocrine (Vstm2l, Resp18) were significantly up-regulated, which undoubtedly increased the basic metabolic rate of the mice with MTB infection. However, the state of chronic high consumption will lead to malnutrition of the body and tuberculosis will worsen. We further characterized five highly enriched genes relevant to islet dysfunction in the TB model group. Among them, the most up-regulated islet amyloid peptide (IAPP) is a peptide hormone that regulates glucose metabolism synthesized and secreted by islet B cells. At present, studies have found that IAPP aggregation not only had direct toxicity to insulin-producing B cells but also lead to inflammation and dysfunction of pancreatic B cells by activating NLRP3 inflammasome in infiltrating macrophages(48, 49). Therefore, IAPP is an important pathological factor that causes type 2 diabetes mellitus (T2DM). Vogt AS et al. used monoclonal antibody (mAb) m81 to prevent IAPP accumulation, which could block islet inflammation and delay the onset of T2DM(50). Slc30a8 encodes zinc transporter 8 (ZnT8) playing an essential role in zinc homeostasis inside pancreatic B cells and ZnT8 is vital for the biosynthesis and secretion of insulin(51). ZnT8 is a minor diabetogenic antigen that can participate in type 1 diabetes mellitus (T1DM) in conditions in which the islet is first made receptive to immunological insults(52).In addition, Slc30a8 was identified as a novel T2DM susceptibility gene(53). Both our study and the GSE89403 confirm that Slc30a8 expression levels would decrease after anti-TB treatment, which is beneficial to improve pancreatic dysfunction. Other three genes Scg2 (secretogranin II), Chga, and Chgb (chromogranins A and B), belonging to the chromogranin/secretogranin family(54), are considered to have anti-inflammatory properties, participate in inflammatory reactions, and contribute to host defense(55, 56). The increase in CHGA has been used as a new biomarker to evaluate the death risk of patients with severe sepsis or coronavirus disease(56, 57). In addition, CHGA, CHGB, SCG2, and some CHGA cleavage products affect glucose homeostasis and different types of diabetes(58). This study found for the first time that the significant increases of these three genes may be related to the inflammatory reaction after MTB infection, and also play important roles in the pathogenesis of various types of diabetes(58, 59). The current research showed that the risk of pulmonary TB in T2DM patients was about 2-3 times that of the general population(60), and the results of this study suggest that TB may also increase the incidence rate of diabetes. Amy2a5 is an amylase alpha 2 that catalyzes the hydrolysis of starch into sugar, providing energy for the body(61). It was reported that Amy2a5 increased in some infectious diseases(62). This study is the first report that the expression of Amy2a5 was significantly increased in the mouse TB model, but only showed an increasing trend in the newly-treated TB patients, which may be caused by the fact that the catabolism of newly-treated TB patients was not very severe. After the immunotherapy with the ag85a/b DNA vaccine IM or EP, the metabolism of sugar, protein, and lipid in mice was reduced, and the state of high metabolism was corrected. The expressions of genes IAPP, Slc30a8, Scg2, Chga, and Chgb were significantly reduced, which can protect islet B cells from apoptosis and can also change the insulin secretion defect caused by the inflammatory environment of pancreatic islets, thus improving the function of islet B cells and reducing the risk of TB patients complicated with T2DM(48, 59).