Gene targeting demonstrates that inducible nitric oxide synthase is not essential for resistance to oral candidiasis in mice, or for killing of <i>Candida albicans</i> by macrophages <i>in vitro</i>

Farah, Camile S.; Saunus, Jodi M.; Hu, Yan; Kazoullis, Andrea; Ashman, R. B.

doi:10.1111/j.1399-302x.2008.00462.x

Cited by 14 publications

(11 citation statements)

References 35 publications

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“…These results argue that NO production by activated macrophages during phagocytosis does not have a direct fungicidal effect on Coccidioides . Similar results were reported by Farah and coworkers [27], who observed no statistically significant difference in the ability of iNOS − / − - and WT murine strain-derived BMDM to kill C. albicans yeast in vitro . In contrast to our findings, however, they reported that macrophages from iNOS − / − mice phagocytosed a significantly greater percentage of yeast than BMDM isolated from wild type, control mice.…”

Section: Discussionsupporting

confidence: 91%

Coccidioides releases a soluble factor that suppresses nitric oxide production by murine primary macrophages

González

Hung

Cole

2011

Microbial Pathogenesis

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We studied the effect of the presence of Coccidioides on the production of nitric oxide (NO) by primary macrophages previously activated by IFN-γ and LPS. The fungal cells were isolated from cultures of arthroconidia that had been incubated for 24h in a medium that supported parasitic phase growth and were co-cultured with the macrophages. These live, first-generation parasitic cells of Coccidioides, referred to as spherule initials, suppressed NO production as well as iNOS mRNA expression by activated macrophages. Phagocytosis was not required for suppression of NO. We also showed that the culture supernatant of the spherule initials was capable of suppressing NO production, and that this activity was mediated by an as yet unidentified, secreted fungal factor(s). Heat-, paraformaldehyde- or X ray-treated spherule initials did not show this inhibitory effect. To our surprise, macrophages obtained from iNOS-deficient mice revealed phagocytic activity and killing efficiency which were comparable to that of macrophages isolated from wild type C57BL/6 mice. Although the cultured fungal pathogen can suppress NO production, this oxidative product is apparently not essential for in vitro killing of Coccidioides by activated macrophages. Our results suggest that other unidentified fungicidal mechanisms exist against Coccidioides which are apparently independent of NO production.

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Section: Discussionsupporting

confidence: 91%

Coccidioides releases a soluble factor that suppresses nitric oxide production by murine primary macrophages

González

Hung

Cole

2011

Microbial Pathogenesis

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“…In addition, we did not observe any significant differences in the levels of selected proinflammatory cytokines or chemokines between the WT and iNOS −/− mice at 7 or 11 days postchallenge. Similar results have been reported by Farah and coworkers [16] who observed that WT and iNOS −/− mice infected with Candida albicans showed equivalent levels of expression of inflammatory cytokines measured by QRT-PCR. In contrast, Livonesi et al, [14] found that iNOS −/− mice infected with Paracoccidioides brasiliensis yeast cells showed higher levels of Th1 and Th2 cytokines than the WT strain, and proposed that elevated iNOS activity contributes significantly to both protection and regulation of the inflammatory response to this fungal pathogen.…”

Section: Discussionsupporting

confidence: 91%

“…For example, NO produced by macrophages has been reported to have both host tissue damaging and anti-inflammatory effects as a result of its modulation of host secretion and function of certain cytokines, chemokines and growth factors in response to a microbial insult [2]. Previous studies of Candida infections have concluded that macrophages obtained from WT and iNOS −/− mice showed no difference in their ability to kill the pathogen in vitro [16]. Regulation of iNOS activity occurs both at the transcriptional and post-transcriptional levels.…”

Section: Discussionmentioning

confidence: 99%

“…NO has been implicated in the control of numerous infectious diseases caused by a variety of prokaryotic and eukaryotic pathogens, including Mycobacterium tuberculosis [8], Histoplasma capsulatum [9], Cryptococcus neoformans [10]; Leishmania major [11], Schistosoma mansoni [12]. On the other hand, NO has also been shown to be either detrimental or non-essential to host protection, or appears to play a dual role in infections caused by Paracoccidioides braisliensis [13,14], Sporotrix schenckii [15], Candida albicans [16] and Trypanosoma brucei [6]. Coccidioidomycosis is an endemic human respiratory disease which occurs in southwestern regions of the United States, and is caused by the dimorphic fungus Coccidioides spp.…”

Section: Introductionmentioning

confidence: 99%

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Nitric oxide synthase activity has limited influence on the control of Coccidioides infection in mice

González¹,

Hung²,

Cole³

2011

Microbial Pathogenesis

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The functions of inducible nitric oxide synthase (iNOS) activity in protection against microbial insults are still controversial. In this study, we explored the role of iNOS in protection against Coccidioides infection in mice. We observed that wild-type (WT) and iNOS−/− mice showed similar percent survival and fungal burden in their lungs at days 7 and 11 after intranasal challenge with Coccidioides. Vaccinated WT and iNOS−/− mice revealed comparable fungal burden in their lungs and spleen at 7 and 11 days postchallenge. However, at 11 days the non-vaccinated, iNOS-deficient mice had significantly higher fungal burden in their spleen compared to WT mice. Additionally, higher numbers of lung-infiltrated neutrophils, macrophages and dendritic cells were observed in WT mice at day 11 postchallenge compared to iNOS−/− mice. Moreover, no difference in numbers of T, B, NK or regulatory T cells, or concentrations of selected cytokines and chemokines were detected in lungs of both mouse strains at 7 and 11 days postchallenge. Although iNOS-derived NO production appears to influence the inflammatory response and dissemination of the fungal pathogen, our results suggest that iNOS activity does not play a significant role in the control of coccidioidal infection in mice and that other, still undefined mechanisms of host protection are involved.

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“…The inducible nitric oxide synthase (iNOS or NOS2) is the major source of NO that is generated by phagocytes as an antimicrobial defence. Interestingly data from NOS2 knockout mice suggests that this enzyme is dispensible for clearance of oral candidiasis and for killing by macrophages (Farah et al, 2009). In addition nitrosative stress response genes were not found to be upregulated in C .…”

Section: Discussionmentioning

confidence: 99%

Alternative oxidase induction protects Candida albicans from respiratory stress and promotes hyphal growth

Duvenage

Walker

Bojarczuk

et al. 2018

Preprint

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21The human fungal pathogen Candida albicans possesses two genes expressing a 22 cyanide-insensitive Alternative Oxidase (Aox) enzymes in addition to classical and 23 parallel electron transfer chains (ETC). In this study, we examine the role of Aox in C. 24 albicans under conditions of respiratory stress, which may be inflicted during its 25 interaction with the human host or co-colonising bacteria. We find that the level of Aox 26 expression is sufficient to modulate resistance to classical ETC inhibition under 27 respiratory stress and are linked to gene expression changes that can promote both 28 survival and pathogenicity. For example we demonstrate that Aox function is important 29 for the regulation of filamentation in C. albicans and observe that cells lacking Aox 30 function lose virulence in a zebrafish infection model. Our investigations also identify 31 that pyocyanin, a phenazine produced by the co-colonising bacterium 32 Pseudomonas aeruginosa, inhibits Aox-based respiration in C. albicans. These results 33 suggest that Aox plays important roles within respiratory stress response pathways 34 which C. albicans may utilise both as a commensal organism and as a pathogen. 35 36 37C. albicans is a commensal yeast which is found in the majority of the population. 38

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Gene targeting demonstrates that inducible nitric oxide synthase is not essential for resistance to oral candidiasis in mice, or for killing of Candida albicans by macrophages in vitro

Abstract: These data suggest that iNOS-derived NO is not required for resistance to oral candidiasis in vivo, and that bone marrow-derived macrophages may have iNOS-independent means of generating reactive nitrogen species.

Cited by 14 publications

References 35 publications

Coccidioides releases a soluble factor that suppresses nitric oxide production by murine primary macrophages

Coccidioides releases a soluble factor that suppresses nitric oxide production by murine primary macrophages

Nitric oxide synthase activity has limited influence on the control of Coccidioides infection in mice

Alternative oxidase induction protects Candida albicans from respiratory stress and promotes hyphal growth

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