Hypoxia and Fungal Pathogenesis: To Air or Not To Air?

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Over the last 3 decades, the frequency of life-threatening human fungal infections has increased as advances in medical therapies, solid-organ and hematopoietic stem cell transplantations, an increasing geriatric population, and HIV infections have resulted in significant rises in susceptible patient populations. Although significant advances have been made in understanding how fungi cause disease, the dynamic microenvironments encountered by fungi during infection and the mechanisms by which they adapt to these microenvironments are not fully understood. As inhibiting and preventing<jats:italic>in vivo</jats:italic>fungal growth are main goals of antifungal therapies, understanding<jats:italic>in vivo</jats:italic>fungal metabolism in these host microenvironments is critical for the improvement of existing therapies or the design of new approaches. In this minireview, we focus on the emerging appreciation that pathogenic fungi like<jats:named-content content-type="genus-species">Candida albicans</jats:named-content>,<jats:named-content content-type="genus-species">Cryptococcus neoformans</jats:named-content>, and<jats:named-content content-type="genus-species">Aspergillus fumigatus</jats:named-content>are exposed to oxygen-limited or hypoxic microenvironments during fungal pathogenesis. The implications of these<jats:italic>in vivo</jats:italic>hypoxic microenvironments for fungal metabolism and pathogenesis are discussed with an aim toward understanding the potential impact of hypoxia on invasive fungal infection outcomes.</jats:p>

Identification of Hypoxia-Inducible Target Genes of Aspergillus fumigatus by Transcriptome Analysis Reveals Cellular Respiration as an Important Contributor to Hypoxic Survival

“…In the surrounding tissue, oxygen availability is further reduced to 2 to 4% and in inflammatory tissue to even less than 1% (7). Such growth conditions were proposed to shape the pathobiology of A. fumigatus, and their in vivo relevance was further supported by a hypoxia-sensitive mutant (⌬srbA) strain, which was avirulent in a mouse model of invasive aspergillosis (8,9). However, the metabolic response of A. fumigatus to hypoxia is less well understood (10).…”

Dsc Orthologs Are Required for Hypoxia Adaptation, Triazole Drug Responses, and Fungal Virulence in Aspergillus fumigatus

“…Recently, there has been an increased interest in how levels of oxygen at the site of infection impact the outcome of IFIs (18,22). A major reason for this interest is that fungal strains with a deficient ability to adapt to hypoxia fail to cause lethal disease in murine models.…”

Riboflavin and pantothenic acid biosynthesis are crucial for iron homeostasis and virulence in the pathogenic mold Aspergillus fumigatus

“…The most remarkable phenotype was observed during iron starvation and iron sufficiency, where the Δ panA strain under hypoxic conditions reached radial wt-like growth but completely lacked sporulation. The role of pantothenic acid during hypoxic conditions could be explained by reduced pantothenic acid requirement or by increased pantothenic uptake under these conditions [32]. In contrast, the riboB, pyroA and thiB null strains under limiting vitamin supplementation and normoxic or hypoxic iron-sufficient conditions grew like the wt (data not shown).…”