The hypoxia-induced reduction in T-cell activity and increase in the development of Tregs may aid in preventing an uncontrolled immune response that provokes autoimmunity or pathological tissue

damage. Manipulation of HIF by Pathogens Hypoxia-inducible factor induction is a general part of the host response to infection. HIF is induced in response to both Gram-positive and Gram-negative bacteria [11, 41], as well as by viruses [89, 90], protozoa [27], and fungi [27]. Given the centrality of HIF in the immune response, it should come as no surprise that some pathogens have developed immune evasion strategies to counteract HIF. For example, oncolytic reovirus can prevent accumulation of HIF-1α in a proteasome-dependent manner, without affecting Hif1a transcription [91]. Moloney murine leukemia virus is able to prevent HIF-1α protein accumulation in infected mice without affecting buy PF-01367338 Hif1a gene transcription by reducing the levels of the HIF-stabilizing host protein Jab1 [92]. Chlamydia www.selleckchem.com/products/MK-1775.html pneumoniae degrades HIF by secreting the chlamydial protease-like activity factor into the cytoplasm of infected cells [93]. Pseudomonas aeruginosa expresses alkyl quinolones that target the HIF-1α protein for proteasomal degradation [94]. Infections by certain other viral pathogens may increase HIF levels or activity, perhaps exerting an anti-apoptotic effect that promotes survival of the host cell they are infecting.

The carboxy terminus of HBx from hepatitis B virus was shown to enhance the transactivation of HIF-1α by enhancing its association with CREB-BP [95]. The Kaposi’s sarcoma-associated herpesvirus (KSHV)

expresses a protein known as latency-associated nuclear antigen (LANA), which targets vHL for degradation via ubiquitination, thereby increasing HIF protein levels [96], and another part of LANA promotes HIF nuclear accumulation [96]. Epstein–Barr virus (EBV) oncoprotein latent membrane protein 1 (LMP1) activates HIF-1α by upregulating Siah1 E3 ubiquitin ligase by enhancing its stability, which allows it to increase the proteasomal degradation of prolyl hydroxylases 1 and 3 that normally mark HIF-1α for degradation [97]. As a result, LMP1 prevents formation of the vHL/HIF complex, and HIF is not degraded. Other viral and parasitic N-acetylglucosamine-1-phosphate transferase Compound C molecular weight organisms are able to subvert HIF activity to their own benefit. HIF-1α stimulates the transcription of HIV-1 genes by associating with HIV-1 long terminal repeat [98], and the JCV polyomavirus genes by binding to the early promoter of the virus [99]. Other viruses may be sensing HIF as a marker of cellular stress to indicate when it is appropriate to exit the cell. Murid herpesvirus 4 [100] and EBV [101] switch from lysogenic to lytic when HIF levels are high. High levels of HIF lead to the expression of platelet-activating factor, which some pathogens then use to increase translocation across the intestinal epithelium [102]. Toxoplasma gondii survives better when HIF is elevated [103].