Leishmania, too, survives better when HIF is elevated, and HIF inhibition reduces survival of the parasite [105, 106]. HIF for Prevention and Treatment of Infectious Disease As a master regulator of innate immunity, HIF stands as a promising target for fine-tuning the immune

response. In most infections, Duvelisib clinical trial increasing HIF levels could be expected to boost diverse myeloid cell antimicrobial activities and promote clearance of infection. Under certain conditions, particularly CH5183284 among viral pathogens, HIF stabilization may promote the extended survival of infected cells, therefore care must be taken in determining when HIF augmentation can be a beneficial strategy. Along with in vitro work showing that HIF increases the bactericidal capacity of immune cells, it has also been found that treating mice with the HIF stabilizers mimosine [43] or AKB-4924 [44] improves their ability to fight skin infections. While HIF-boosting agents (prolyl hydroxylase inhibitors) are in advance clinical trials for anemia due to their ability to

boost erythropoietin production [107], no trials in humans have been initiated to date in which drugs that upregulate HIF are used to treat acute bacterial infection. Nonetheless, such a strategy could be effective for difficult clinical scenarios such as opportunistic bacterial infections in patients with weakened immune systems or ubiquitin-Proteasome system with pathogens exhibiting multidrug resistance to conventional antibiotics. Theoretically, HIF boosting may also have an advantage in reducing the likelihood of drug resistance; it would be prohibitively difficult for bacteria to evolve resistance to the whole arsenal of antimicrobial factors that are increased when HIF activity increases [3]. For those scenarios in which bacteriologic control is easily achievable by conventional

antibiotics and in which pathology is being driven by an overactive immune response to bacterial components, HIF induction would have unclear utility. In noninfectious experimental LPS-induced sepsis, for example, which provokes an immunopathological cytokine storm, knocking crotamiton out HIF in either myeloid cells [108] or T cells [109] reduces the severity of disease. This is in agreement with clinical research showing that septic patients exhibit reduced levels of HIF-1α mRNA with an inverse relationship between mRNA level and disease severity [110]. Ιnflammatory bowel disease, which involves a complex interaction between epithelial barrier function, mucosal immune response and the normal colonic flora, has emerged as a promising therapeutic target for HIF-1 boosting. Treatment of mice with HIF-boosting agent AKB-4924 provided protection from chemical-induced colitis [111].