Studies on the role of HIF-1 in the control of infection with Mycobacterium tuberculosis

Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis (TB), is responsible for most deaths caused by a bacterium globally. Two main reasons for this are that (Bacille Calmette–Guérin) BCG, the only available vaccine against TB, cannot provide a full protection against TB in adults and that antibiotic treatment is hampered by the increase of drug resistances to M. tuberculosis. In addition, it is still not completely understood why some people are more prone to developing active TB after infection with M. tuberculosis, while others remain asymptomatic. As the co-infection with the human immunodeficiency virus or the comorbidity with diabetes mellitus (DM) increases the risk of TB reactivation, this indicates that interactions between host immune factors and M. tuberculosis determine the outcome of infection. The interaction would lead to the development of granulomas composed of macrophages, granulocytes, lymphocytes and fibroblasts. M. tuberculosis control is primarily mediated by macrophages, the main host cell of intracellular M. tuberculosis, that are activated by mycobacteria-specific CD4 TH1 cells. The studies presented in this thesis analyze molecular factors that may control the response of macrophages and T cells to M. tuberculosis infection. For increased understanding of generated T cell responses upon vaccination, we studied the phenotype of T cells and their localization after mucosal and distal BCG immunization. Studies were evaluated by using M. tuberculosis-infected mice and were further complemented with mechanistical in vitro studies. Studied molecules in paper I are the hypoxia-inducible factors (HIFs), transcription factors regulating the adaptation to hypoxia of different cell populations, which are negatively regulated by von Hippel-Lindau factor (VHL). One of the transcription factors, HIF-1, has been broadly studied in immune cells. It can mediate metabolic and immunoregulatory responses of immune cells. Therefore, we investigated the role of HIF-1 ...