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Susceptibility of Blastomyces dermatitidis strains to products of oxidative metabolism
Abstract:
Three strains of Blastomyces dermatitidis which differ in their virulence for mice were exposed in their yeast form to various components of the peroxidase-hydrogen peroxide-halide system. Susceptibility to H2O2 alone correlated with virulence, with the most virulent strain (ATCC 26199) least susceptible (50% lethal dose, greater than 50 mM) and an avirulent strain (ATCC 26197) most susceptible (50% lethal dose less than 3.3 mM). A strain of intermediate virulence (ATCC 26198) was of intermediate susceptibility (50% lethal dose, 11.5 mM). The addition of a nontoxic concentration of KI (5 X 10(-4) M) did not increase H2O2 toxicity. However, the addition of either myeloperoxidase or horseradish peroxidase and KI markedly decreased the amount of H2O2 required to kill the organisms, with 100 +/- 0% of all strains killed at 5 X 10(-5) M H2O2 and 97 +/- 4, 100 +/- 0, and 94 +/- 8% of ATCC 26199, ATCC 26198, and ATCC 26197 killed, respectively, at 5 X 10(-6) M H2O2. Kinetic studies with H2O2 alone revealed a delayed onset of killing, but virtually 100% of organisms were killed by 120 min of exposure in all strains. By comparison, the peroxidase-hydrogen peroxide-halide system was 100% lethal for all strains at 1 min. The relatively high concentrations of H2O2 required to kill the yeast phase of B. dermatitidis suggest that H2O2 alone does not account for host resistance to the organism. However, the rapidly lethal effect of the peroxidase-hydrogen peroxide-halide system at physiologically relevant concentrations suggests that this may be one mechanism of host defense to B. dermatitidis.
Insights
Blastomyces dermatitidis virulence correlates with susceptibility to hydrogen peroxide (H2O2). The peroxidase-hydrogen peroxide-halide system, not H2O2 alone, rapidly kills B. dermatitidis, suggesting a host defense mechanism.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Host-Pathogen Interactions
Background:
- Blastomyces dermatitidis is a fungus causing serious lung infections.
- Host defense mechanisms against B. dermatitidis are not fully understood.
- The role of oxidative stress in fungal resistance is an area of active research.
Purpose of the Study:
- To investigate the susceptibility of B. dermatitidis yeast forms to the peroxidase-hydrogen peroxide-halide system.
- To compare the killing efficacy of hydrogen peroxide (H2O2) alone versus the complete system.
- To correlate fungal susceptibility with known virulence factors.
Main Methods:
- Exposure of three B. dermatitidis strains (varying virulence) to H2O2 alone.
- Testing the effect of myeloperoxidase or horseradish peroxidase with potassium iodide (KI) and H2O2.
- Kinetic analysis of fungal killing over time.
- Determination of 50% lethal dose (LD50) values.
Main Results:
- Susceptibility to H2O2 alone inversely correlated with B. dermatitidis virulence (LD50 >50 mM for virulent strain, <3.3 mM for avirulent strain).
- Potassium iodide (KI) alone did not enhance H2O2 toxicity.
- The complete peroxidase-hydrogen peroxide-halide system rapidly killed all strains at physiologically relevant H2O2 concentrations (within 1 minute).
Conclusions:
- H2O2 alone at high concentrations is not sufficient to explain host resistance to B. dermatitidis.
- The peroxidase-hydrogen peroxide-halide system represents a potent, rapid mechanism of host defense against B. dermatitidis infections.