Epithelial GM-CSF Induction by <i>Candida glabrata</i>

Li, L.; Dongari-Bagtzoglou, Anna

doi:10.1177/0022034509341266

Cited by 36 publications

(29 citation statements)

References 32 publications

(34 reference statements)

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“…observations are consistent with the findings of Li et al (21,22) and Schaller et al (39) for C. glabrata-infected epithelial models, where GM-CSF is likewise upregulated, while the overall cytokine response is low. Thus, the observed mononuclear cell infiltrates are likely the result of increased local GM-CSF concentrations.…”

Section: Discussionsupporting

confidence: 93%

Candida glabrata Persistence in Mice Does Not Depend on Host Immunosuppression and Is Unaffected by Fungal Amino Acid Auxotrophy

et al. 2010

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Candida glabrata has emerged as an important fungal pathogen of humans, causing life-threatening infections in immunocompromised patients. In contrast, mice do not develop disease upon systemic challenge, even with high infection doses. In this study we show that leukopenia, but not treatment with corticosteroids, leads to fungal burdens that are transiently increased over those in immunocompetent mice. However, even immunocompetent mice were not capable of clearing infections within 4 weeks. Tissue damage and immune responses to microabscesses were mild as monitored by clinical parameters, including blood enzyme levels, histology, myeloperoxidase, and cytokine levels. Furthermore, we investigated the suitability of amino acid auxotrophic C. glabrata strains for in vitro and in vivo studies of fitness and/or virulence. Histidine, leucine, or tryptophan auxotrophy, as well as a combination of these auxotrophies, did not influence in vitro growth in rich medium. The survival of all auxotrophic strains in immunocompetent mice was similar to that of the parental wild-type strain during the first week of infection and was only mildly reduced 4 weeks after infection, suggesting that C. glabrata is capable of utilizing a broad range of host-derived nutrients during infection. These data suggest that C. glabrata histidine, leucine, or tryptophan auxotrophic strains are suitable for the generation of knockout mutants for in vivo studies. Notably, our work indicates that C. glabrata has successfully developed immune evasion strategies enabling it to survive, disseminate, and persist within mammalian hosts.

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Section: Discussionsupporting

confidence: 93%

Candida glabrata Persistence in Mice Does Not Depend on Host Immunosuppression and Is Unaffected by Fungal Amino Acid Auxotrophy

et al. 2010

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“…Our data are in line with some studies demonstrating minimal or no invasion of oral epithelial cells [2, 3] and lack of cytokine production [5] with non- C. albicans species, but in contrast to others that have demonstrated invasion and/or cytokine production by C. tropicalis , C. parapsilosis or C. glabrata [4, 20–23]. An important and common feature of these latter studies, though, is that invasion and cytokine production by the non- C. albicans species was significantly lower than that induced by C. albicans .…”

Section: Discussionsupporting

confidence: 92%

Activation of MAPK/c-Fos induced responses in oral epithelial cells is specific to Candida albicans and Candida dubliniensis hyphae

Moyes

Murciano²,

Runglall³

et al. 2011

Med Microbiol Immunol

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Oral epithelial cells detect the human pathogenic fungus Candida albicans via NF-κB and a bi-phasic mitogen-activated protein kinase (MAPK) signaling response. However, discrimination between C. albicans yeast and hyphal forms is mediated only by the MAPK pathway, which constitutes activation of the MAPK phosphatase MKP1 and the c-Fos transcription factor and is targeted against the hyphal form. Given that C. albicans is not the only Candida species capable of filamentation or causing mucosal infections, we sought to determine whether this MAPK/MKP1/c-Fos mediated response mechanism was activated by other pathogenic Candida species, including C. dubliniensis, C. tropicalis, C. parapsilosis, C. glabrata and C. krusei. Although all Candida species activated the NF-κB signaling pathway, only C. albicans and C. dubliniensis were capable of inducing MKP1 and c-Fos activation, which directly correlated with hypha formation. However, only C. albicans strongly induced cytokine production (G-CSF, GM-CSF, IL-6 and IL-1α) and cell damage. Candida dubliniensis, C. tropicalis and C. parapsilosis were also capable of inducing IL-1α and this correlated with mild cell damage and was dependent upon fungal burdens. Our data demonstrate that activation of the MAPK/MKP1/c-Fos pathway in oral epithelial cells is specific to C. dubliniensis and C. albicans hyphae.

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“…These data are in agreement with experimental mice infections, where an upregulation of GM-CSF on day 2 postinfection was observed, although the overall cytokine response was low (7). Furthermore, findings of Li et al (39,57) and Schaller et al (38) suggested that C. glabrata predominantly induces the release of GM-CSF from epithelial cells, whereas induction of other proinflammatory cytokines remained low, especially in comparison with C. albicans. GM-CSF is a potent activator of macrophages and induces differentiation of precursor cells as well as the recruitment of macrophages to sites of infection.…”

Section: Discussionsupporting

confidence: 86%

The Facultative Intracellular Pathogen Candida glabrata Subverts Macrophage Cytokine Production and Phagolysosome Maturation

Seider

Brunke

Schild

et al. 2011

The Journal of Immunology

184

226

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Although Candida glabrata is an important human pathogenic yeast, its pathogenicity mechanisms are largely unknown. Immune evasion strategies seem to play key roles during infection, since very little inflammation is observed in mouse models. Furthermore, C. glabrata multiplies intracellularly after engulfment by macrophages. In this study, we sought to identify the strategies that enable C. glabrata to survive phagosome biogenesis and antimicrobial activities within human monocyte-derived macrophages. We show that, despite significant intracellular proliferation, macrophage damage or apoptosis was not apparent, and production of reactive oxygen species was inhibited. Additionally, with the exception of GM-CSF, levels of pro- and anti-inflammatory cytokines were only marginally increased. We demonstrate that adhesion to and internalization by macrophages occur within minutes, and recruitment of endosomal early endosomal Ag 1 and lysosomal-associated membrane protein 1 indicates phagosome maturation. However, phagosomes containing viable C. glabrata, but not heat-killed yeasts, failed to recruit cathepsin D and were only weakly acidified. This inhibition of acidification did not require fungal viability, but it had a heat-sensitive surface attribute. Therefore, C. glabrata modifies the phagosome into a nonacidified environment and multiplies until the host cells finally lyse and release the fungi. Our results suggest persistence of C. glabrata within macrophages as a possible immune evasion strategy.

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Epithelial GM-CSF Induction by Candida glabrata

Cited by 36 publications

References 32 publications

Candida glabrata Persistence in Mice Does Not Depend on Host Immunosuppression and Is Unaffected by Fungal Amino Acid Auxotrophy

Candida glabrata Persistence in Mice Does Not Depend on Host Immunosuppression and Is Unaffected by Fungal Amino Acid Auxotrophy

Activation of MAPK/c-Fos induced responses in oral epithelial cells is specific to Candida albicans and Candida dubliniensis hyphae

The Facultative Intracellular Pathogen Candida glabrata Subverts Macrophage Cytokine Production and Phagolysosome Maturation

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