Deregulated Production of Protective Cytokines in Response to<i>Candida albicans</i>Infection in Patients with Chronic Mucocutaneous Candidiasis

Lilić, Desa; Gravenor, I; Robson, Neil C.; Lammas, David A.; Drysdale, P; Calvert, Jane; Cant, Andrew J.; Abinun, Mario

doi:10.1128/iai.71.10.5690-5699.2003

Cited by 72 publications

(50 citation statements)

References 33 publications

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“…Therefore, cytokines from Th1 cells have been associated with resistance to C. albicans infection, while Th2 appears to increase susceptibility to infection. This hypothesis is supported by a study which showed that patients with chronic mucocutaneous candidiasis exhibit Th2 cytokine production during the immune response to C. albicans (20). Furthermore, TNF-␣, released by both hematopoietic and nonhematopoietic cells, has been shown to play a vital role in host defense in systemic candidiasis (5).…”

supporting

confidence: 61%

Exogenous Farnesol Interferes with the Normal Progression of Cytokine Expression during Candidiasis in a Mouse Model

Navarathna

Nickerson²,

Duhamel

et al. 2007

Infect Immun

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Candida albicans, a dimorphic fungus composed of yeast and mycelial forms, is the most common human fungal pathogen. Th1 cytokines such as interleukin-2 (IL-2), gamma interferon (IFN-␥), and tumor necrosis factor alpha (TNF-␣), which are induced by macrophage IL-12, are critical to resistance against systemic candidiasis, while Th2 cytokines such as IL-4 and IL-5 are less critical. Farnesol is a quorum-sensing molecule produced by C. albicans that controls the formation of mycelia but is also a virulence factor. To determine whether farnesol enhances the virulence of C. albicans by modulating the production of Th1 and Th2 cytokines, mice were pretreated with farnesol prior to intravenous infection with a sublethal dose of farnesol-producing C. albicans. Production of IL-2, IL-4, IL-5, TNF-␣, IFN-␥, and IL-12 was evaluated by bead-array flow cytometry and enzyme-linked immunosorbent assay. Mice exhibited an elevation in serum TNF-␣ levels at 48 h and an elevation in IFN-␥ and IL-12 levels at 6 to 12 h after infection with C. albicans. Pretreatment with farnesol significantly reduced the elevation of both IFN-␥ and IL-12 but not TNF-␣. In contrast, mice pretreated with farnesol exhibited an unexpected elevation in IL-5 levels. To determine whether farnesol has a direct effect on macrophage production of IL-12, peritoneal macrophages were pretreated with farnesol prior to stimulation with IFN-␥ plus lipopolysaccharide (LPS). Farnesol inhibited production of both IL-12 p40 and p70 from IFN-␥/LPS-stimulated macrophages. Therefore, the role of farnesol in systemic candidiasis is likely due to its ability to inhibit the critical Th1 cytokines IFN-␥ and IL-12 and perhaps to enhance a Th2 cytokine, IL-5.Candida albicans is a dimorphic commensal fungus and a medically important opportunistic pathogen, particularly in immunocompromised individuals (37). Previous work showed that yeast-mycelium dimorphism in C. albicans is regulated in part by secretion of a lipophilic molecule identified as farnesol (15). Farnesol prevents mycelial development in a quorumsensing or cell density-dependent manner, and it was the first quorum-sensing molecule (QSM) discovered in a eukaryotic organism. This work was recently reviewed by Nickerson et al. (33). However, all of the work on farnesol as a QSM has been done in vitro, leaving open the question of what role farnesol or farnesol analogs have in vivo. In this regard, Hornby et al. (15) proposed two competing hypotheses. The first was that the shift from yeast to mycelium was a critical step in pathogenesis and that exogenous farnesol could block this transition, thus acting in a therapeutic manner. The alternate hypothesis was that the lipophilic farnesol excreted during infection would interact with host cells in a manner that promoted virulence. The latter idea was supported by our work on the pathogenicity of C. albicans cells pretreated with subinhibitory concentrations (0.5 to 1 M) of fluconazole (29). These cells secreted 10 times more farnesol than did untreated cells, and they ...

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supporting

confidence: 61%

Exogenous Farnesol Interferes with the Normal Progression of Cytokine Expression during Candidiasis in a Mouse Model

Navarathna

Nickerson²,

Duhamel

et al. 2007

Infect Immun

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“…Such evidence includes the following: (1) IL-10 knock-out mice infected with Trypanosoma cruzi and Toxoplasma gondii die rapidly because of a massive and sustained inflammatory response [129,130], and are predisposed to have an exaggerated Th1 immune response in the context of Plasmodium chabaudi chabaudi malaria [131] and Listeria monocytogenes meningoencephalitis [132]. (2) In contrast, elevated concentrations of IL-10, or an imbalance between IL-10 and IL-12 in favor of IL-10, have been associated with persistent infection-induced inflammation, resulting in the development of invasive and chronic disease, such as human visceral leishmaniasis [133], chronic human Candida albicans infections [134], as well as paracoccidioidomycosis [135][136][137][138][139][140]. (3) Upon LPS challenge, IL-10 deficient mice display an uncontrolled production of TNF-a [141], are extremely vulnerable to the generalized Shwartzman reaction [141], and are more sensitive to lethal acute endotoxin shock (which occurs with a 20-fold lower dose of LPS) [141].…”

Section: Il-10: a Cytokine That Dampens Inflammationmentioning

confidence: 99%

The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: A role for interleukin-10

Gotsch

Romero

Kusanovic

et al. 2008

The Journal of Maternal-Fetal & Neonatal Medicine

119

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Objective. The anti-inflammatory limb of the immune response is crucial for dampening inflammation. Spontaneous parturition at term and preterm labor (PTL) are mediated by inflammation in the cervix, membranes, and myometrium. This study focuses on the changes in the amniotic fluid concentrations of the anti-inflammatory cytokine interleukin (IL)-10. The objectives of this study were to determine whether there is a relationship between amniotic fluid concentrations of IL-10 and gestational age, parturition (at term and preterm), and intra-amniotic infection/inflammation (IAI). Study design. A cross-sectional study was conducted including 301 pregnant women in the following groups: (1) midtrimester of pregnancy who delivered at term (n ¼ 112); (2) mid-trimester who delivered preterm neonates (n ¼ 30); (3) term not in labor without IAI (n ¼ 40); (4) term in labor without IAI (n ¼ 24); (5) term in labor with IAI (n ¼ 20); (6) PTL without IAI who delivered at term (n ¼ 31); (7) PTL without IAI who delivered preterm (n ¼ 30); (8) PTL with IAI who delivered preterm (n ¼ 14). IL-10 concentrations in amniotic fluid were determined by a specific and sensitive immunoassay. Nonparametric statistics were used for analysis. Results.(1) IL-10 was detectable in amniotic fluid and its median concentration did not change with gestational age from mid-trimester to term. (2) Patients in labor at term had a significantly higher median amniotic fluid IL-10 concentration than that of patients at term not in labor (p ¼ 0.04). (3) Women at term in labor with IAI had a significantly higher median amniotic fluid IL-10 concentration than that of patients at term in labor without IAI (p ¼ 0.02). (4) Women with PTL and IAI who delivered preterm had a significantly higher median amniotic fluid concentration of IL-10 than those without IAI who delivered preterm and than those who delivered at term (p ¼ 0.009 and p 5 0.001, respectively). (5) Among patients with preterm labor without IAI, those who delivered preterm had a significantly higher median amniotic fluid IL-10 concentration than those who delivered at term (p ¼ 0.03). Conclusions. The anti-inflammatory cytokine IL-10 is detectable in the amniotic fluid of normal pregnant women. Spontaneous parturition at term and in preterm gestation is associated with increased amniotic fluid concentrations of IL-10. IAI (preterm and at term) is also associated with increased amniotic fluid concentrations of IL-10. We propose that IL-10 has a role in the regulation of the immune response in vivo by initiating actions that dampen inflammation.

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“…The role of inhibitory cytokines, such as IL-10, is crucial in down-regulation of type 1 cytokines (IL-12, IL-18, and IFN-γ), as well as inflammatory cytokines (IL-6 and TNF-α). 40) Th17 cells produce proinflammatory cytokines like IL-17A, IL-17F, IL-21 and IL-22, and are involved in the clearance of several extracellular bacteria and fungi. 41) The protective roles of IL-17A in a murine model of infection with C. albicans have been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Vaccination with Recombinant Non-transmembrane Domain of Protein Mannosyltransferase 4 Improves Survival during Murine Disseminated Candidiasis

Wang

Yan

et al. 2015

Biological & Pharmaceutical Bulletin

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Candida albicans is the most common cause of invasive fungal infections in humans. The C. albicans cell wall proteins play an important role in crucial host-fungus interactions and might be ideal vaccine targets to induce protective immune response in host. Meanwhile, protein that is specific to C. albicans is also an ideal target of vaccine. In this study, 11 proteins involving cell wall biosynthesis, yeast-to-hypha formation, or specific to C. albicans were chosen and were successfully cloned, purified and verified. The immune protection of vaccination with each recombinant protein respectively in preventing systemic candidiasis in BALB/c mice was assessed. The injection of rPmt4p vaccination significantly increased survival rate, decreased fungal burdens in the heart, liver, brain, and kidneys, and increased serum levels of both immunoglobulin G (IgG) and IgM against rPmt4p in the immunized mice. Histopathological assessment demonstrated that rPmt4p vaccination protected the tissue structure, and decreased the infiltration of inflammatory cells. Passive transfer of the rPmt4p immunized serum increased survival rate against murine systemic candidiasis and significantly reduced organ fungal burden. The immune serum enhanced mouse neutrophil killing activity by directly neutralizing rPmt4p effects in vitro. Levels of interleukin (IL)-4, IL-10, IL-12p70, IL-17A and tumor necrosis factor (TNF)-α in serum were higher in the immunized mice compared to those in the adjuvant control group. In conclusion, our results suggested that rPmt4p vaccination may be considered as a potential vaccine candidate against systemic candidiasis.

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Deregulated Production of Protective Cytokines in Response toCandida albicansInfection in Patients with Chronic Mucocutaneous Candidiasis

Cited by 72 publications

References 33 publications

Exogenous Farnesol Interferes with the Normal Progression of Cytokine Expression during Candidiasis in a Mouse Model

Exogenous Farnesol Interferes with the Normal Progression of Cytokine Expression during Candidiasis in a Mouse Model

The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: A role for interleukin-10

Vaccination with Recombinant Non-transmembrane Domain of Protein Mannosyltransferase 4 Improves Survival during Murine Disseminated Candidiasis

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