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).