High Glucose and Carbonyl Stress Impair HIF-1-Regulated Responses and the Control of Mycobacterium tuberculosis in Macrophages.

Diabetes mellitus (DM) increases the risk of developing tuberculosis (TB), but the mechanisms behind diabetes-TB comorbidity are still undefined. Here, we studied the role of hypoxia-inducible factor-1 (HIF-1), a main regulator of metabolic and inflammatory responses, in the outcome of Mycobacterium tuberculosis infection of bone marrow-derived macrophages (BMM). We observed that M. tuberculosis infection of BMM increased the expression of HIF-1α and HIF-1-regulated genes. Treatment with the hypoxia mimetic deferoxamine (DFO) further increased levels of HIF-1-regulated immune and metabolic molecules and diminished the intracellular bacterial load in BMM and in the lungs of infected mice. The expression of HIF-1-regulated immunometabolic genes was reduced, and the intracellular M. tuberculosis levels were increased in BMM incubated with high-glucose levels or with methylglyoxal (MGO), a reactive carbonyl compound elevated in DM. In line with the in vitro findings, high M. tuberculosis levels and low HIF-1-regulated transcript levels were found in the lungs from hyperglycemic Leprdb/db compared with wild-type mice. The increased intracellular M. tuberculosis growth and the reduced expression of HIF-1-regulated metabolic and inflammatory genes in BMM incubated with MGO or high glucose were reverted by additional treatment with DFO. Hif1a-deficient BMM showed ablated responses of immunometabolic transcripts after mycobacterial infection at normal or high-glucose levels. We propose that HIF-1 may be targeted for the control of M. tuberculosis during DM. IMPORTANCE People living with diabetes who are also infected with M. tuberculosis are more likely to develop tuberculosis disease (TB). Why diabetic patients have an increased risk for developing TB is not well understood. Macrophages, the cell niche for M. tuberculosis, can express microbicidal mechanisms or be permissive to mycobacterial persistence and growth. Here, we showed that high glucose and carbonyl stress, which mediate diabetes pathogenesis, impair the control of intracellular M. tuberculosis in macrophages. Infection with M. tuberculosis stimulated the expression of genes regulated by the transcription factor HIF-1, a major controller of the responses to hypoxia, resulting in macrophage activation. High glucose and carbonyl compounds inhibited HIF-1 responses by macrophages. Mycobacterial control in the presence of glucose or carbonyl stress was restored by DFO, a compound that stabilizes HIF-1. We propose that HIF-1 can be targeted to reduce the risk of developing TB in people with diabetes.

DHODH inhibition modulates glucose metabolism and circulating GDF15, and improves metabolic balance.

Dihydroorotate dehydrogenase (DHODH) is essential for the de novo synthesis of pyrimidine ribonucleotides, and as such, its inhibitors have been long used to treat autoimmune diseases and are in clinical trials for cancer and viral infections. Interestingly, DHODH is located in the inner mitochondrial membrane and contributes to provide ubiquinol to the respiratory chain. Thus, DHODH provides the link between nucleotide metabolism and mitochondrial function. Here we show that pharmacological inhibition of DHODH reduces mitochondrial respiration, promotes glycolysis, and enhances GLUT4 translocation to the cytoplasmic membrane and that by activating tumor suppressor p53, increases the expression of GDF15, a cytokine that reduces appetite and prolongs lifespan. In addition, similar to the antidiabetic drug metformin, we observed that in db/db mice, DHODH inhibitors elevate levels of circulating GDF15 and reduce food intake. Further analysis using this model for obesity-induced diabetes revealed that DHODH inhibitors delay pancreatic ß cell death and improve metabolic balance.

Atrophy of skin-draining lymph nodes predisposes for impaired immune responses to secondary infection in mice with chronic intestinal nematode infection.

Intestinal nematodes suppress immune responses in the context of allergy, gut inflammation, secondary infection and vaccination. Several mechanisms have been proposed for this suppression including alterations in Th2 cell differentiation and increased Treg cell suppressive function. In this study, we show that chronic nematode infection leads to reduced peripheral responses to vaccination because of a generalized reduction in the available responsive lymphocyte pool. We found that superficial skin-draining lymph nodes (LNs) in mice that are chronically infected with the intestinal nematode Heligmosomides polygyrus, do not reach the same cellularity as worm-free mice upon subsequent BCG infection in the skin. B cells and T cells, all declined in skin-draining LN of H. polygyrus-infected mice, resulting in LNs atrophy and altered lymphocyte composition. Importantly, anti-helminthic treatment improved lymphocyte numbers in skin-draining LN, indicating that time after de-worming is critical to regain full-scale LN cellularity. De-worming, and time for the skin LN to recover cellularity, also mended responses to Bacille Calmette-Guerin (BCG) in the LN draining the footpad injection site. Thus, our findings show that chronic nematode infection leads to a paucity of lymphocytes in peripheral lymph nodes, which acts to reduce the efficacy of immune responses at these sites.

Differences in Nutritional and Health Status in School Children from the Highlands and Lowlands of Bolivia.

Children in the Bolivian Andes are exposed to endemic infections and meager nourishment, and live under poor hygienic conditions. The prevention of children malnutrition is a priority in many countries including Bolivia. In this study, the health status of schoolchildren in Taraco, a Puna district, at 4,000 meters above sea level (masl) and in Caranavi, at 650 masl in the wealthier subtropical valleys, was compared. The weight, height, and hematological and biochemical parameters in blood, parasites in stool, and clinical information in 120 children from rural Taraco and in 96 from semi-urban Caranavi, both predominantly of Aymara ethnicity, were registered. Eleven percent of Taraco children were undernourished compared with 3% in Caranavi. Instead, 41% of the children in Caranavi were obese or overweight, compared with 8% in Taraco. Anemia was found in 74% of the children in Taraco compared with 7% in Caranavi. Albumin levels were normal in all samples, albeit lower in Taraco. Similar and normal serum zinc levels were measured in both groups. Approximately 60% of the children in both locations showed insufficient vitamin D levels, with lower levels in Taraco children. Hymenolepis nana and Entamoeba coli, parasites determinant of poor hygienic conditions, were respectively detected in 78% and 21% of fecal samples from Taraco, and in 29% and 8% of samples from Caranavi. We show increased anemia, nutritional deficiencies, and indications of poor hygienic conditions in highlands compared with lowlands. The prevalence of obesity in the lowlands demands addressing diverse nutritional deficiencies in the regions of Bolivia.

CISH controls bacterial burden early after infection with Mycobacterium tuberculosis in mice.

CISH gene has been associated with increased susceptibility to human tuberculosis. We found that cish-/- mice had higher M. tuberculosis load in spleens and lungs up to 2.5 weeks after infection but not later compared to controls. Cish mRNA levels were increased in lungs at early and late time points after M. tuberculosis infection. In relation, the titers of inos and tnf mRNA in lungs were reduced early after infection of cish-/- mice. The transfer of cish-/- and control T cells conferred rag1-/- mice similar protection to infection with M. tuberculosis. Macrophages showed increased cish mRNA levels after M. tuberculosis infection in vitro. However, mycobacterial uptake and growth in cish-/- and control macrophages was similar. Thus, we here show that CISH mediates control of M. tuberculosis in mice early after infection via regulation of innate immune mechanisms.