The twentieth century saw great improvements in our ability to control infectious diseases through the use of antibiotics and vaccinations. In recent decades, however, some of these improvements have eroded as pathogens evolve antibiotic resistance. Further progress in controlling infectious disease will likely require not just new antibiotics, but also strategies to strengthen and target the host immune response more effectively. To this end, a more nuanced understanding of host immune response regulation is necessary. One key regulatory factor is hypoxia-inducible factor (HIF), which plays a pivotal role in the antimicrobial function of myeloid cells. Here we explore the role of HIF in other aspects of the immune response to infection, and evaluate its potential as a target for new anti-infective therapies. Using a genetic model in which Hif-1[alpha] was ablated specifically in dendritic cells, we studied the role of HIF in initiating the T-cell response. We found that HIF was important for the expression of antigen-presenting and costimulatory surface molecules, the ability to stimulate T cell proliferation, and the overall response to vaccination. Furthermore, pharmacological augmentation of HIF improved both the humoral and cell-mediated response to vaccination, indicating that HIF could be a target for vaccine adjuvants. Previous work by the Nizet lab and others has shown that HIF is crucial for the control of skin infections. Like HIF, the active form of vitamin D increases in the skin upon exposure to molecular signals of infection, leading to increased antimicrobial activity of skin epithelial and immune cells. We used a human skin cell line to elucidate the relationship between HIF and vitamin D in the regulation of skin immunity. We found that vitamin D increases HIF expression and function, and HIF modulates vitamin D-induced expression of the antimicrobial peptide LL-37. These data provide the first suggestion that drugs which augment HIF may help treat infections in vitamin D-deficient patients. It is clear that HIF plays an important and complex role in the immune response to infection. As our understanding of HIF grows, we will be better able to manipulate the host immune response to prevent or control infectious diseases

In the present era of ever-increasing antibiotic resistance and increasingly complex and immunosuppressed patient populations, physicians and scientists are seeking novel approaches to battle difficult infectious disease conditions. Development of a serious infection implies a failure of innate immune capabilities in the patient, and one may consider whether pharmacological strategies exist to correct and enhance innate immune cell function. Hypoxia-inducible factor-1 (HIF-1), the central regulator of the cellular response to hypoxic stress, has recently been recognized to control the activation state and key microbicidal functions of immune cells. HIF-1 boosting drugs are in clinical development for anemia and other indications, and could be repositioned as infectious disease therapeutics. With equal attention to opportunities and complexities, we review our current understanding of HIF-1 regulation of microbial host-pathogen interactions with an eye toward future drug development.