Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi?

Abstract

Over the past two decades, the incidence of fungal infections has dramatically increased. This is primarily due to increases in the population of immunocompromised individuals attributed to the HIV/AIDS pandemic and immunosuppression therapies associated with organ transplantation, cancer, and other diseases where new immunomodulatory therapies are utilized. Significant advances have been made in understanding how fungi cause disease, but clearly much remains to be learned about the pathophysiology of these often lethal infections. Fungal pathogens face numerous environmental challenges as they colonize and infect mammalian hosts. Regardless of a pathogen's complexity, its ability to adapt to environmental changes is critical for its survival and ability to cause disease. For example, at sites of fungal infections, the significant influx of immune effector cells and the necrosis of tissue by the invading pathogen generate hypoxic microenvironments to which both the pathogen and host cells must adapt in order to survive. However, our current knowledge of how pathogenic fungi adapt to and survive in hypoxic conditions during fungal pathogenesis is limited. Recent studies have begun to observe that the ability to adapt to various levels of hypoxia is an important component of the virulence arsenal of pathogenic fungi. In this review, we focus on known oxygen sensing mechanisms that non-pathogenic and pathogenic fungi utilize to adapt to hypoxic microenvironments and their possible relation to fungal virulence.