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.

Fig. 1. Schematic of the oxygen sensing pathways in Saccharomyces cerevisiae and Candida albicans

The proteins are defined in the text.

Fig. 2. Mutants in SREBP Pathway and Tco1 are sensitive to hypoxia

Growth in normoxic and hypoxic conditions. A) Candida albicans: A heterozygous UPC2/upc2Δ and a homozygous upc2Δ/upc2Δ C. albicans strain were serially diluted and spotted on CSM plates and grown at 30°C. The top panel shows growth in aerobic conditions after 48h. The bottom panel shows growth in hypoxic conditions after 96h. Under hypoxic conditions the wild-type (WT) and the heterozygous strain showed comparable growth but the homozygous deletion strain did not demonstrate any detectable growth (Courtesy Chelsea Samaniego and Dr. Theodore C. White); B) Aspergillus fumigatus: 1×10⁶ conidia were plated on GMM plates and incubated at 37°C under normoxic and hypoxic conditions for 48h. The wild-type and the reconstituted strain grew comparably under hypoxic conditions while no growth was detectable for the mutant strain (modified from Willger et al. (124)); C) Cryptococcus neoformans: C. neoformans cultures diluted to OD_600nm = 0.6 were diluted serially in 10-fold increments prior to being spotted onto YPD plates. The plates were incubated in normoxic or hypoxic conditions in the dark at 37°C. Under hypoxic conditions all mutants in the SREBP pathway and the tco1Δ mutants showed reduced growth compared to the wild-type (modified from Chun et al. (100)).

Fig. 3. Schematic of the oxygen sensing pathways in Schizosaccharomyces pombe, Cryptococcus neoformans and Aspergillus fumigatus

The proteins are defined in the text.