Virulence of catalase-deficient aspergillus nidulans in p47(phox)-/- mice. Implications for fungal pathogenicity and host defense in chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a rare genetic disorder in which phagocytes fail to produce superoxide because of defects in one of several components of the NADPH oxidase complex. As a result, patients develop recurrent life-threatening bacterial and fungal infections. The organisms to which CGD patients are most susceptible produce catalase, regarded as an important factor for microbial pathogenicity in CGD. To test the role of pathogen-derived catalase in CGD directly, we have generated isogenic strains of Aspergillus nidulans in which one or both of the catalase genes (catA and catB), have been deleted. We hypothesized that catalase negative mutants would be less virulent than the wild-type strain in experimental animal models. CGD mice were produced by disruption of the p47(phox) gene which encodes the 47-kD subunit of the NADPH oxidase. Wild-type A. nidulans inoculated intranasally caused fatal infection in CGD mice, but did not cause disease in wild-type littermates. Surprisingly, wild-type A. nidulans and the catA, catB, and catA/catB mutants were equally virulent in CGD mice. Histopathological studies of fatally infected CGD mice showed widely distributed lesions in the lungs regardless of the presence or absence of the catA and catB genes. Similar to the CGD model, catalase-deficient A. nidulans was highly virulent in cortisone-treated BALB/c mice. Taken together, these results indicate that catalases do not play a significant role in pathogenicity of A. nidulans in p47(phox)-/- mice, and therefore raise doubt about the central role of catalases as a fungal virulence factor in CGD.
Chang
Y C
YC
Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Segal
B H
BH
Holland
S M
SM
Miller
G F
GF
Kwon-Chung
K J
KJ
D020642:Acatalasia; D000818:Animals; D001228:Aspergillosis / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D001233:Aspergillus nidulans / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity*; D002374:Catalase / Q000235:genetics; D003348:Cortisone / Q000494:pharmacology; D004195:Disease Models, Animal; D005656:Fungal Proteins / Q000235:genetics; D006105:Granulomatous Disease, Chronic / Q000150:complications*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency* / Q000235:genetics; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics
D005656:Fungal Proteins; D007166:Immunosuppressive Agents; D010750:Phosphoproteins; D006861:Hydrogen Peroxide; D002374:Catalase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D003348:Cortisone