Role of Hypoxia Inducible Factor-1 in Leishmania-Macrophage Interaction: A New Therapeutic Paradigm
Amit Kumar Singh, Vivek G. Vishnu, Shalini Saini, Sandhya Sandhya and Chinmay K. Mukhopadhyay
from: Molecular Biology of Kinetoplastid Parasites (Edited by: Hemanta K. Majumder). Caister Academic Press, U.K. (2018) Pages: 27-38.
Intracellular parasites use host components for their survival and growth after invasion within host, while hosts spread out their innate immune defences to deny any advantage to the invading parasite. The research in the last decade provided evidences of oxygen sensing mammalian transcription factor hypoxia-inducible factor-1 (HIF-1) as a master controller of innate immune response of phagocytes against various intracellular and extracellular pathogens. In response to most of these pathogens host phagocytes increase transcription of HIF-1α, the regulatory component of HIF-1, to express various effector molecules against invaders. The involvement of NFkB in regulating HIF-1α transcription further strengthened the paradigm. However, more recent evidences revealed that protozoan parasite Leishmania donovani (LD), the causative agent of fatal visceral leishmaniasis, in contrary could promote and exploit HIF-1 activation for its survival advantage within host macrophages. HIF-1 is a heterodimer of regulatory subunit HIF-1α and constitutive HIF-1β. In oxygen deficiency or cellular iron depletion, expression of HIF-1α is regulated by a post-translational protein stability mechanism mediated by a family of prolyl hydroxylases (PHDs), while during phagocytic invasion by pathogens HIF-1α is regulated mainly by a transcriptional mechanism. Interestingly, LD activates HIF-1 by both transcriptional and post translational protein stability mechanism. The current chapter will summarize the detail mechanism of HIF-1 activation and its potential role in survival advantage of intracellular LD within host macrophages. Due to its pivotal role in angiogenesis and cancer, HIF-1 is a crucial drug target and matter of intense research. The recent finding of role of host HIF-1 in survival and growth of LD thus presents an opportunity to repurpose the HIF-1 inhibitors as potential drugs against visceral leishmaniasis read more ...