Abstract
Fungal pathogens of humans require molecular oxygen for several essential biochemical reactions, yet virtually nothing is known about how they adapt to the relatively hypoxic environment of infected tissues. We isolated mutants defective in growth under hypoxic conditions, but normal for growth in normoxic conditions, in Cryptococcus neoformans, the most common cause of fungal meningitis. Two regulatory pathways were identified: one homologous to the mammalian sterol-response element binding protein (SREBP) cholesterol biosynthesis regulatory pathway, and the other a two-component-like pathway involving a fungal-specific hybrid histidine kinase family member, Tco1. We show that cleavage of the SREBP precursor homolog Sre1—which is predicted to release its DNA-binding domain from the membrane—occurs in response to hypoxia, and that Sre1 is required for hypoxic induction of genes encoding for oxygen-dependent enzymes involved in ergosterol synthesis. Importantly, mutants in either the SREBP pathway or the Tco1 pathway display defects in their ability to proliferate in host tissues and to cause disease in infected mice, linking for the first time to our knowledge hypoxic adaptation and pathogenesis by a eukaryotic aerobe. SREBP pathway mutants were found to be a hundred times more sensitive than wild-type to fluconazole, a widely used antifungal agent that inhibits ergosterol synthesis, suggesting that inhibitors of SREBP processing could substantially enhance the potency of current therapies.
Highlights
Microbial pathogens must overcome numerous obstacles to infection to successfully colonize a host
Some pathogens, such as Candida albicans, are capable of anaerobic fermentation in rich medium, but even in these species, molecular oxygen is thought to be essential for synthesis of ergosterol, NAD, and heme, molecules likely to be scarce in the host milleu and difficult to obtain
We describe two pathways in the pathogenic fungus Cryptococcus neoformans that are both necessary for adaptation to hypoxia and required for its virulence
Summary
Microbial pathogens must overcome numerous obstacles to infection to successfully colonize a host. While many pathogenic microbes are facultative or obligate anaerobes, a number of major bacterial and fungal pathogens are classified as obligate aerobes. Among these are the bacterial species Neisseria meningiditis, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Bordetella pertussis. In N. meningitidis and B. pertussis, mutants in homologs of the Escherichia coli hypoxiaresponsive regulator Fnr are attenuated in experimental animals, consistent with a role for hypoxic adaptation in virulence [6,7]. Some pathogens, such as Candida albicans, are capable of anaerobic fermentation in rich medium, but even in these species, molecular oxygen is thought to be essential for synthesis of ergosterol, NAD, and heme, molecules likely to be scarce in the host milleu and difficult to obtain.
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