High Levels of Interleukin-10 Impair Resistance to Pulmonary Coccidioidomycosis in Mice in Part through Control of Nitric Oxide Synthase 2 Expression

Jiménez, María del Pilar; Walls, Lorraine; Fierer, Joshua

doi:10.1128/iai.01985-05

Cited by 38 publications

(42 citation statements)

References 65 publications

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“…4 and 6). This was a surprising result, because B6 mice make more IL-10 than resistant DBA/2 mice (67), and high levels of IL-10 are detrimental in this infection (17). One possible explanation is that the mutant mice also made more of some potentially protective cytokines, such as IFN-␥, GM-CSF, and IL-17 and IL-23.…”

Section: Discussionmentioning

confidence: 89%

“…In further support of genetic factors being important in determining the immune response to infection and therefore susceptibility, we discovered that inbred mice also vary greatly in their susceptibility to coccidioidomycosis (15). Susceptible mice make more interleukin 4 (IL-4) and 17), and IL-10-deficient C57BL/6 (B6) mice are more resistant to infection than B6 mice (18).…”

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confidence: 99%

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Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice

et al. 2014

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We investigated the roles of the mannose receptor (MR) and Dectin-2 in resistance to pulmonary coccidioidomycosis in C57BL/6 (B6) mice and in the interaction of myeloid cells with spherules, using B6 mice with targeted mutations in Mrc1 and Clec4n. Spherules are the tissue form of Coccidioides, and we determined that the MR on bone marrow-derived dendritic cells (BMDC) was important for recognition of spherules (formalin-killed spherules [FKS]) and for secretion of interleukin 10 (IL-10) and proinflammatory cytokines in response to FKS by both elicited macrophages and BMDC. Infected MR knockout (KO) mice produced more IL-10 in their lungs than did B6 mice, and MR KO mice also made more protective Th-17 cytokines. In contrast to the MR, Dectin-2 was not required for recognition of FKS by BMDC or for the production of cytokines by BMDC in response to FKS. However, Dectin-2 KO was required for stimulation of elicited peritoneal macrophages. Despite that, lung cytokine levels were not significantly different in Dectin-2 KO mice and B6 mice 14 days after infection, except for IL-1␤, which was higher in Dectin-2 KO lungs. Although both Dectin-2 ؊/؊ and MR ؊/؊ myeloid cells had reduced proinflammatory cytokine responses to FKS in vitro, neither MR nor Dectin-2 deficiency reduced the resistance of B6 mice to pulmonary coccidioidomycosis.

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Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice

et al. 2014

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“…The images were obtained from the CDC (http://phil.cdc.gov/phil/details.asp). This figure was previously published in the Journal of Fungi [70]. …”

Section: Dimorphismmentioning

confidence: 99%

“…A broad-spectrum NOS inhibitor increased the susceptibility of DBA/2 mice to C. immitis [69]. In contrast, a Nos2 mutant mouse strain was not more susceptible [70]. However, that mutation was made in C57BL/6 mice, which themselves make very little NO in response this infection [69].…”

Section: Immunologymentioning

confidence: 99%

Coccidioides immitis and posadasii; A review of their biology, genomics, pathogenesis, and host immunity

Kirkland

Fierer

2018

Virulence

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Coccidioides immitis and C. posadasii are two highly pathogenic dimorphic fungal species that are endemic in the arid areas of the new world, including the region from west Texas to southern and central California in the USA that cause coccidioidomycosis (also known as Valley Fever). In highly endemic regions such as southern Arizona, up to 50% of long term residents have been infected. New information about fungal population genetics, ecology, epidemiology, and host-pathogen interactions is becoming available. However, our understanding of some aspects of coccidioidomycosis is still incomplete, including the extent of genetic variability of the fungus, the genes involved in virulence, and how the changes in gene expression during the organism’s dimorphic life cycle are related to the transformation from a free-living mold to a parasitic spherule. Unfortunately, efforts to develop an effective subunit vaccine have not yet been productive, although two potential live fungus vaccines have been developed.

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“…Work with the pathogenic fungi Histoplasma capsula-tum (2,24), Paracoccidioides brasiliensis (17,22), Coccidioides immitis (15), and Cryptococcus neoformans (31) has shown that the macrophage nitric oxide-producing enzyme, inducible nitric oxide synthase (iNOS), promotes host clearance of invading fungi. Conversely, each of these fungal pathogens has evolved the means to subvert nitric oxide production or resist killing by nitric oxide (6,10,13,23,25,30,32,37).…”

mentioning

confidence: 99%

Blastomyces dermatitidis Yeast Cells Inhibit Nitric Oxide Production by Alveolar Macrophage Inducible Nitric Oxide Synthase

Rocco

Carmen²,

Klein³

2011

Infect Immun

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The ability of pathogens to evade host antimicrobial mechanisms is crucial to their virulence. The dimorphic fungal pathogen Blastomyces dermatitidis can infect immunocompetent patients, producing a primary pulmonary infection that can later disseminate to other organs. B. dermatitidis possesses a remarkable ability to resist killing by alveolar macrophages. To date, no mechanism to explain this resistance has been described. Here, we focus on macrophage production of the toxic molecule nitric oxide as a potential target of subversion by B. dermatitidis yeast cells. We report that B. dermatitidis yeast cells reduce nitric oxide levels in the supernatants of activated alveolar macrophages. This reduction is not due to detoxification of nitric oxide, but rather to suppression of macrophage nitric oxide production. We show that B. dermatitidis yeast cells do not block upregulation of macrophage inducible nitric oxide synthase (iNOS) expression or limit iNOS access to its arginine substrate. Instead, B. dermatitidis yeast cells appear to inhibit iNOS enzymatic activity. Further investigation into the genetic basis of this potential virulence mechanism could lead to the identification of novel antifungal drug targets.

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High Levels of Interleukin-10 Impair Resistance to Pulmonary Coccidioidomycosis in Mice in Part through Control of Nitric Oxide Synthase 2 Expression

Cited by 38 publications

References 65 publications

Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice

Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice

Coccidioides immitis and posadasii; A review of their biology, genomics, pathogenesis, and host immunity

Blastomyces dermatitidis Yeast Cells Inhibit Nitric Oxide Production by Alveolar Macrophage Inducible Nitric Oxide Synthase

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