Turning on virulence: Mechanisms that underpin the morphologic transition and pathogenicity of Blastomyces

Figures & data

Table 1. Established and putative virulence factors in Blastomyces.

Gene	Function	Impact on virulence
BAD1 (Blastomyces adhesin-1; formerly WI-1)	Promotes adhesion of yeast to host cells and immune evasion through inhibition of cytokines (TNF-α, IL-17 and INF-γ) and CD4^+ T lymphocyte activation. BAD1 is the most upregulated gene in B. dermatitidis during pulmonary infection.	bad1∆ yeast are attenuated during murine pulmonary infection. When injected subcutaneously in mice, bad1∆ yeast induce sterilizing immunity against lethal pulmonary infection.
DPPIVA (dipeptidyl-peptidase)	Serine protease that degrades GM-CSF and impedes recruitment of innate immune cells	DPPIVA knockdown strains have reduced survival in the presence of activated innate immune cells and attenuated virulence in murine pulmonary infection
Cysteine synthase	Involved in the biosynthesis of L-cysteine.	Important for transition to yeast and maintenance of the yeast-phase growth.
CDG (cysteine dioxygenase)	Catabolic enzyme that catabolizes L-cysteine to L-cysteine sulfonic acid, which can further be broken down to sulfite.	In C. albicans deletion of CDG1 attenuates virulence during murine infection. Arthroderma benhamiae cdg∆ mutants have reduced growth on hair and nails. Potential to contribute to growth of Blastomyces on keratinized structures.
SSU1	Transmembrane sulfite efflux pump. Sulfite is toxic to cells and is secreted via the SSU1 efflux pump.	Arthroderma benhamiae ssu1∆ mutants have impaired growth on hair and nails. Potential to contribute to growth of Blastomyces on keratinized structures.
PRA1, ZRT1, ZRT2	PRA1 encodes a zincophore. ZRT1 and ZRT2 encode high and low affinity zinc transporters, respectively. These genes are upregulated in yeast during pulmonary infection.	C. albicans pra1∆ mutants have decreased ability to lyse endothelial cells under zinc-poor conditions. Blastomyces pra1∆ and zrt1∆ mutants are impaired in establishing infection in mice.
NIC1	Transports nickel which is used as a cofactor for urease (Urea → Ammonia + CO2).	In C. neoformans, deletion of NIC1 results in decreased ability of yeast cells to enter CNS. Potential to contribute to Blastomyces virulence or dissemination.
DRK1	Essential for the temperature-dependent conversion to yeast at 37^oC.	DRK1 silenced strains of B. dermatitidis and H. capsulatum are avirulent in a murine model of pulmonary infection. These strains also exhibit defects in cell wall integrity and fail to upregulate yeast-phase specific virulence factors (BAD1, CBP1). T. marneffei drkA∆ mutants have impaired conidial germination in macrophages.
RYP1-4 (Required for yeast phase 1-4)	Conserved transcription factors in the dimorphic fungi that are essential for the morphologic switch to yeast at 37^oC	RNAi-silenced RYP1-4 H. capsulatum strains fail to convert to yeast at 37^oC and are unable to upregulate yeast-phase specific virulence genes (CBP1, YPS3).