Mycobacterial DNA-binding protein 1 is critical for BCG survival in stressful environments and simultaneously regulates gene expression

Abstract Survival of the live attenuated Bacillus Calmette-Guérin (BCG) vaccine amidst harsh host environments is key for BCG effectiveness as it allows continuous immune response induction and protection against tuberculosis. Mycobacterial DNA binding protein 1 (MDP1), a nucleoid associated protein, is essential in BCG. However, there is limited knowledge on the extent of MDP1 gene regulation and how this influences BCG survival. Here, we demonstrate that MDP1 conditional knockdown (cKD) BCG grows slower than vector control in vitro, and dies faster upon exposure to antibiotics (bedaquiline) and oxidative stress (H2O2 and menadione). MDP1-cKD BCG also exhibited low infectivity and survival in THP-1 macrophages and mice indicating possible susceptibility to host mediated stress. Consequently, low in vivo survival resulted in reduced cytokine (IFN-gamma and TNF-alpha) production by splenocytes. Temporal transcriptome profiling showed more upregulated (81–240) than downregulated (5–175) genes in response to MDP1 suppression. Pathway analysis showed suppression of biosynthetic pathways that coincide with low in vitro growth. Notable was the deferential expression of genes involved in stress response (sigI), maintenance of DNA integrity (mutT1), REDOX balance (WhiB3), and host interactions (PE/PE_PGRS). Thus, this study shows MDP1’s importance in BCG survival and highlights MDP1-dependent gene regulation suggesting its role in growth and stress adaptation

Rice Endosperm Protein Administration to Juvenile Mice Regulates Gut Microbiota and Suppresses the Development of High-Fat Diet-Induced Obesity and Related Disorders in Adulthood

Obesity and related disorders, which are increasing in adults worldwide, are closely linked to childhood diet and are associated with chronic inflammation. Rice endosperm protein (REP) intake during adulthood has been reported to improve lipid metabolism and suppress the progression of diabetic kidney disease in animal models. However, the effects of REP intake during childhood on adulthood health are unclear. Therefore, we used a mouse model to experimentally investigate the preconditioning effects of REP intake during childhood on the development of obesity and related disorders in adulthood. Male C57BL/6J mice were pair-fed a normal-fat diet containing casein or REP during the juvenile period and then a high-fat diet (HFD) containing casein or REP during adulthood. Mice fed REP during the juvenile period showed better body weight, blood pressure, serum lipid profiles, lipopolysaccharide (LPS)-binding protein levels, and glucose tolerance in adulthood than those fed casein during the juvenile period. HFD-induced renal tubulo-glomerular alterations and hepatic microvesicular steatosis were less evident in REP-fed mice than in casein-fed ones. REP intake during the juvenile period improved HFD-induced dysbiosis (i.e., Escherichia genus proliferation and reduced gut microbiota diversity), thereby suppressing endotoxin-related chronic inflammation. Indeed, REP-derived peptides showed antibacterial activity against Escherichia coli, a major producer of LPS. In conclusion, REP supplementation during the juvenile period may regulate the gut microbiota and thus suppress the development of obesity and related disorders in adulthood in mice