This growth phase of Aspergillus fumigatus is inhibited by lactoferrin-mediated iron depletion [28]. In contrast, inhibition of the hyphal form of Aspergillus fumigatus requires NADPH oxidase [28, 30]. Aspergillus PND-1186 cell line nidulans lacking the catalase genes are capable of causing disease in gp47phox KO mice, which suggested that reactive oxygen intermediates

might not be inhibiting the organism directly [30]. It has been suggested that activation of intracellular proteases by reactive oxygen intermediates is important for killing Candida and several types of bacteria [31]. There is one report that MK-8931 nmr administration of pentraxin 3 protected gp47phox mice from experimental Aspergillus fumigatus infection, suggesting that this molecule in important for resistance to Aspergillus fumigatus and may be lacking in CGD mice [32]. The only evidence that primary pathogenic fungi are more virulent in CGD mice is a study with Sporothrix schenckii [33]. These investigators found that gp91phox KO mice infected with Sporothrix schenckii intradermally died within three months, whereas control mice survived this infection. They also found that PMN from gp91phox KO mice were not able to control the growth of Sporothrix schenckii as well as the controls. We have not been able to find any published data on Blastomyces dermatitidis, C. immitis or

Histoplasma capsulatum MLN2238 in vivo experimental infections in CGD mice. People with chronic granulomatous disease have increased susceptibility to Aspergillus infections and, to a lesser extent, infections due to other opportunistic fungi [34]. There have been no reports of increased susceptibility to the primary pathogenic fungi Coccidioides, Histoplasma

capsulatum, Blastomyces dermatitidis or Sporothrix schenckii. One expert states that these infections are not a problem in chronic granulomatous disease [34]. One CGD patient has been observed to recover uneventfully from pulmonary coccidioidomycosis without anti-fungal therapy (J. Galgiani, very personal communication). The observation that NADPH oxidase is not required for a protective immune response to experimental coccidioidomycosis raises the question of what immune mechanisms used to kill spherules and endospores in vivo. One potential protective immune effector mechanism is oxidative stress due to nitric oxide. We have previously reported that IL-10 exacerbates the course of experimental coccidioidomycois and inhibits nitric oxide synthase [35]. On the other hand, a very recent study suggests that Coccidioides is resistant to killing by NO and that mice with a deletion mutation in inducible nitric oxide synthase are able to kill Coccidioides [36]. Coccidioides spherules can be very large (more than 60 μM in diameter) and therefore difficult to phagocytose. Perhaps inhibiting the growth of the endospore controls the growth of the organism. Understanding the mechanisms of protective immunity is important for optimally preventing and treating infections with this pathogenic fungus.