Three different aspects of Aspergillus species have been studied: 1) Molecular dissection of the genes involved in A. fumigatus spore color synthesis and their role in virulence; 2) Implication of Aspergillus catalases in pathogenicity and host defense in Chronic Granulomatous Disease (CGD) and 3) Pathogenicity of A. fumigatus in mice lacking the CC chemokine receptor 1. 1). Aspergillus is one of the most common fungal pathogens affecting neutropenic patients and other types of immunocompromised individuals such as those with Chronic granulomatous Disease of Childhood. All Aspergillus species propagate by conidia (spores), which humans encounter daily through inhalation. We have focused our attention on the molecular genetic aspects of conidial pigment biosynthesis since pigment is one of the visible components of the wall that protect conidia. In the previous years we have identified and characterized the ARP1 and ARP2 genes and their products which are involved in 1,8-dihydroxynaphthalene (DHN) melanin synthesis. This year we have identified the ALB1 gene which is at the upstream of the ARP1 and ARP2 in DHN-melanin pathway. Disruption of the ALB1 gene resulted in loss of pigment and echinulation of the conidial wall as well as a significant reduction in virulence. 2). Chronic Granulomatous Disease 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 infections. The organisms to which CGD patients are most susceptible produce catalase and hence, catalase has been regarded as an important factor for microbial pathogenicity in CGD. We generated isogenic strains of A. nidulans in which one or both of the catalase genes (catA and catB ) had been deleted and tested their virulence in CGD mice produced by disruption of the p47phox gene which encodes a 47-kD subunit of the NADPH oxidase. Surprisingly, wild-type A. nidulans and the catA, catB, and catA/catB mutants were equally virulent in CGD mice. Similar to the CGD model, catalase- deficient A. nidulans strains were highly virulent in cortisone- treated BALB/c mice. Taken together, these results indicated that catalases do not play a significant role in pathogenicity of Aspergillus in CGD mice and therefore raise doubts about the central role of catalases as a fungal virulence factor in CGD. 3). CC chemokine receptor 1(CCR 1) is expressed in neutrophils, monocytes, lymphocytes and eosinophils and binds the leukocyte chemoattractant and hematopoiesis regulator macrophage inflammatory protein (MIP)-1a, as well as several related CC chemokines. Since Aspergillus is controlled principally by neutrophils, we tested the role of CCR 1 in aspergillosis by comparing mortality of CCR 1 +/+ mice and CCR 1-/- litermates challenged with A. fumigatus. As expected, the CCR 1-/- mice had accelerated mortality. These results indicate that CC chemokine receptor 1 is important for mouse neutrophil mediated host defense.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Intramural Research (Z01)
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