Oral keratinocyte immune responses in HIV-associated candidiasis

Eversole, Lewis R.; Reichart, Peter A.; Ficarra, Giuseppe; Schmidt-Westhausen, Andrea Maria; Romagnoli, Paolo; Pimpinelli, Nicola

doi:10.1016/s1079-2104(97)90035-4

Cited by 61 publications

(90 citation statements)

References 36 publications

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“…The interaction of murine macrophages with CPH1-and/or EFG1-deficient C. albicans mutants has been published by Lo et al (1997). PMNs, however, are microphages and belong to the first line of host defence in oral candidosis (Eversole et al, 1997;Challacombe, 1994;Farah et al, 2001), while macrophages seem to play a more important role in deepseated or systemic infections (Vazquez-Torres & Balish, 1997). Therefore, we decided to investigate the virulence phenotype of these mutants also during interaction with PMNs as an important host-fungus interaction in oral candidosis.…”

Section: Discussionmentioning

confidence: 99%

“…For oral candidosis, epithelial cells and polymorphonuclear neutrophils (PMNs) are the first line of host defence (Eversole et al, 1997;Challacombe, 1994;Farah et al, 2001). We therefore investigated the interaction of the cph1, efg1 and cph1/efg1 mutants, their parental wild-type strain SC5314 and an EFG1 revertant with reconstituted human oral epithelium (RHE) and with PMNs.…”

Section: Introductionmentioning

confidence: 99%

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Reduced expression of the hyphal-independent Candida albicans proteinase genes SAP1 and SAP3 in the efg1 mutant is associated with attenuated virulence during infection of oral epithelium

Körting

Hube

Oberbauer

et al. 2003

Journal of Medical Microbiology

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The transition of Candida albicans from a yeast to a hyphal form is controlled by several transcriptional factors, including the key regulators Cph1 and Efg1, and is considered an important virulence attribute. These factors, especially Efg1, regulate the expression of hyphal-associated genes e.g. SAP4-SAP6. In order to investigate the relevance of these transcriptional regulators for hyphal-independent SAP genes, recently constructed cph1 and efg1 single mutants and a cph1/ efg1 double mutant lacking these factors were tested during interaction with oral epithelium and polymorphonuclear neutrophils. In contrast to the parental wild-type strain and the cph1 mutant, the efg1 and the cph1/efg1 mutants did not produce hyphal forms in all experiments and were less capable of damaging epithelial cells and neutrophil granulocytes. The attenuated epithelial lesions of these mutants were correlated not only with reduced expression of the hyphal-associated gene SAP4, but also with the lack of SAP1 and SAP3 expression previously shown to be important for oral infections. An efg1 mutant strain carrying a plasmid-borne copy of the EFG1 gene regained hyphal growth, damage of keratinocytes, granulocytes and the expression of SAP1 and SAP3. Although efg1 and cph1/efg1 mutants did not produce germ tubes during infection, expression of the hyphalassociated genes SAP5 and SAP6 was not completely abolished. A reduced capacity to stimulate an epithelial immune response manifested by a delayed onset of IL-1â, IL-8 and TNF expression was only observed in the cph1/efg1-infected tissue. These results provide further evidence for a combined regulation of different virulence factors, such as dimorphism and expression of SAP genes. Furthermore, it could be demonstrated that the lack of Efg1 also caused reduced expression of hyphal-independent SAP genes. Both the EFG1 and the CPH1 gene products are necessary for adequate induction of an immune response.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reduced expression of the hyphal-independent Candida albicans proteinase genes SAP1 and SAP3 in the efg1 mutant is associated with attenuated virulence during infection of oral epithelium

Körting

Hube

Oberbauer

et al. 2003

Journal of Medical Microbiology

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“…PMNs are frequently found at sites of Candida infections and are thought to be crucial players in controlling oral disease in vivo (25,26). We have previously demonstrated that addition of PMNs to the C. albicans-infected RHE model can protect the oral epithelium from fungal invasion and cell damage (19).…”

Section: Tlr Gene Expression In Oral Rhe Is Representative Of the Oramentioning

confidence: 99%

Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling

Weindl¹,

Naglik²,

Kaesler³

et al. 2007

J. Clin. Invest.

154

219

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Mammalian TLRs are central mediators of the innate immune system that instruct cells of the innate and adaptive response to clear microbial infections. Here, we demonstrate that human epithelial TLR4 directly protected the oral mucosa from fungal infection via a process mediated by polymorphonuclear leukocytes (PMNs). In an in vitro epithelial model of oral candidiasis, the fungal pathogen Candida albicans induced a chemoattractive and proinflammatory cytokine response but failed to directly modulate the expression of genes encoding TLRs. However, the addition of PMNs to the C. albicans-infected model strongly upregulated cytoplasmic and cellsurface epithelial TLR4 expression, which correlated directly with protection against fungal invasion and cell injury. C. albicans invasion and cell injury was restored by the addition of TLR4-specific neutralizing antibodies and knockdown of TLR4 using RNA interference, even in the presence of PMNs, demonstrating the direct role of epithelial TLR4 in the protective process. Furthermore, treatment with neutralizing antibodies specific for TNF-α resulted in strongly reduced TLR4 expression accompanied by augmented epithelial cell damage and fungal invasion. To our knowledge, this is the first description of such a PMN-dependent, TLR4-mediated protective mechanism at epithelial surfaces, which may provide significant insights into how microbial infections are managed and controlled in the oral mucosa.

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“…ϩ T cells may not be in proximity to C. albicans hyphae, which are usually confined to the upper layers of the epithelium (18,39). Accordingly, the precise role of CD8 ϩ T cells in mucosal containment of C. albicans in HIV infection, either by direct growth inhibition of Candida or, more likely, by production of cytokines which enhance the antimicrobial activity of macrophages and PMNs against C. albicans, has so far remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…However, the role of CD8 ϩ T cells in mucosal containment of C. albicans in HIV infection has not been determined. In addition, HIV-infected patients with the erythematous form of OPC have abundant neutrophilic microabscesses in the parakeratin layer of the epithelium (18,40,42). Although recruitment of polymorphonuclear leukocytes (PMNs) to the oral epithelium does not appear to be perturbed by HIV infection, investigations comparing production of reactive oxygen intermediates with phagocytosis and killing of C. albicans by PMNs from normal and HIV-infected patients have produced conflicting results (8,17,25,48,49).…”

Section: Oropharyngeal Candidiasis (Opc) Is the Most Frequent Opportumentioning

confidence: 99%

CD8⁺T Cells but Not Polymorphonuclear Leukocytes Are Required To Limit Chronic Oral Carriage ofCandida albicansin Transgenic Mice Expressing Human Immunodeficiency Virus Type 1

Marquis¹,

Lewandowski²,

Dugas³

et al. 2006

Infect Immun

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Oral keratinocyte immune responses in HIV-associated candidiasis

Cited by 61 publications

References 36 publications

Reduced expression of the hyphal-independent Candida albicans proteinase genes SAP1 and SAP3 in the efg1 mutant is associated with attenuated virulence during infection of oral epithelium

Reduced expression of the hyphal-independent Candida albicans proteinase genes SAP1 and SAP3 in the efg1 mutant is associated with attenuated virulence during infection of oral epithelium

Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling

CD8⁺T Cells but Not Polymorphonuclear Leukocytes Are Required To Limit Chronic Oral Carriage ofCandida albicansin Transgenic Mice Expressing Human Immunodeficiency Virus Type 1

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Oral keratinocyte immune responses in HIV-associated candidiasis

Cited by 61 publications

References 36 publications

Reduced expression of the hyphal-independent Candida albicans proteinase genes SAP1 and SAP3 in the efg1 mutant is associated with attenuated virulence during infection of oral epithelium

Reduced expression of the hyphal-independent Candida albicans proteinase genes SAP1 and SAP3 in the efg1 mutant is associated with attenuated virulence during infection of oral epithelium

Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling

CD8+T Cells but Not Polymorphonuclear Leukocytes Are Required To Limit Chronic Oral Carriage ofCandida albicansin Transgenic Mice Expressing Human Immunodeficiency Virus Type 1

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CD8⁺T Cells but Not Polymorphonuclear Leukocytes Are Required To Limit Chronic Oral Carriage ofCandida albicansin Transgenic Mice Expressing Human Immunodeficiency Virus Type 1