Relation between nutritional status, the outcome of infection and immune responses

Sammanfattning: A causal interaction between nutrition and the outcome of different infections has been known since long time ago. Moreover, responses of human beings to infection are diverse and demarcated by immunity. A deficient and unappropriated nutrition allows to a deficient immune response. The dynamic interconnection between nutrition, immunity and the outcome of infection creates a cycle. If one of these states is altered, the proper balance of a healthy system will varnish. The purpose of this thesis is to introduce studies that reflect this interaction by exploring both, epidemiological and experimental settings. The first cross-sectional, epidemiological study showed a considerable prevalence of overweight and obesity in school children from Caranavi, a community that represented the Bolivian Lowlands. As for the Highlands, Taraco community remained opposite, with higher prevalence of undernourishment and even stunting, while overweight and obesity were not that prevalent. Remarkably, anemia was found highly prevalent in children from Taraco, compared to lower numbers in Caranavi. More than half of both populations showed vitamin D insufficiency. This study showed increased anaemia, nutritional deficiencies, and indications of poor hygienic conditions in highlands compared with lowlands. Intestinal nematodes modulate immune responses in the context of secondary infection and vaccination. Several mechanisms have been proposed for a possible suppressive effect. In the second study, it was shown that chronic nematode infection leads to reduced peripheral responses to vaccination because of a generalized reduction in the available responsive lymphocyte pool. In detail, it was shown that superficial skin-draining lymph nodes (LNs) in infected mice with the intestinal nematode Heligmosomoides polygyrus, have an altered lymphocyte composition and less cellularity than uninfected mice upon subsequent BCG infection in the skin. Moreover, B cells and T cells were also lower in skin draining LN. Notably, de-worming and time improved lymphocyte cellularity in LNs and restored Bacillus Calmette-Guerin (BCG) responses in the draining LN of the footpad injection site, concluding that chronic nematode infection leads to a paucity of lymphocytes in distal lymph nodes that reduces the efficacy of peripheral immune responses. Obesity can lead to diabetes. Moreover, diabetes increases the risk of developing tuberculosis (TB), but the underlying mechanisms in the tuberculosis-diabetes (TB-DM) co-morbidity are not well defined. This study analyzed the susceptibility to Mycobaterium tuberculosis (Mtb) in a diabetic mice model and focused in the role of HIF-1α, a main regulator of metabolic and inflammatory responses, in the outcome of Mtb infection under hyperglycemia and diabetic models. It was observed that mycobacterial infection of macrophages (BMM) or mice increased the expression of HIF-1α-regulated glut1 and vegfa genes. Interestingly, incubation of BMM with deferoxamine (DFO), a HIF-1α stabilizer, increased levels of HIF-1α-regulated immune and metabolic transcripts in both mycobacteria-infected and uninfected BMM. Moreover, M. tuberculosis load was reduced in DFO-incubated BMM. Hyperglycemic conditions reduced the expression of glut1, vegfa, inos and il1b mRNA in mycobacteria infected BMM and DFO treatment reversed this effect. In line with this, M. tuberculosis levels were higher, and HIF-1α - responses reduced in lungs from db/db mice. DFO-treated mice had increased levels of HIF-1α-regulated transcripts in infected organs, and reduced M. tuberculosis load in lungs. These findings suggest that an increase of HIF-1α function can improve the control of infection with M. tuberculosis during DM. Altogether, these studies, although diverse, support the importance of the link between nutrition, immune responses and the outcome of two different infections.