Open Access

ARTICLE

Myeloid differentiation factor 88 (MyD88) is required for murine resistance to Candida albicans and is critically involved in Candida-induced production of cytokines

Eva Villamón¹, Daniel Gozalbo¹, Patricia Roig¹, Celia Murciano¹, José Enrique O’Connor², Didier Fradelizi³, M. Luisa Gil¹

1 Departamento de Microbiología y Ecología;
2 Departamento de Bioquímica y Biología Molecular, Universitat de València, C/ Dr. Moliner 50, 46100 Burjasot, Valencia, Spain
3 Departement d’Immunologie, INSERM 567, CNRS UMR 8104, Université Paris 5, Institut Cochin, 27, rue Faubourg-Saint-Jacques, 75674 Paris Cedex 14, France

* Corresponding Author: M. Luisa Gil,

European Cytokine Network 2004, 15(3), 263-271.

Abstract

We have studied the role of myeloid differentiation factor 88 (MyD88), the universal Toll-like receptor (TLR) adaptor protein, in murine defenses against We have studied the role of myeloid differentiation factor 88 (MyD88), the universal Toll-like receptor (TLR) adaptor protein, in murine defenses against Candida albicans. MyD88-deficient mice, experimen-tally infected in vivo, had a very significant impaired survival, and a higher tissue fungal burden when compared with control mice. The recruitment of neutrophils to the site of infection was also significantly diminished in MyD88^-/- mice. In vitro production of proinflammatory cytokines such as TNF-α, IFN-γ and IL-12p70, by antigen-stimulated splenocytes from mice intravenously infected with the low-virulence C. albicans PCA2 strain, could not be detected in MyD88^-/- mice. This default of production of Th1 cytokines in MyD88-deficient mice correlated with a greatly diminished frequency of IFN-γ-producing CD4 + T lymphocytes. Also, the frequency of IFN-γ-producing CD8 + T lymphocytes was lower in MyD88^-/- mice than in control mice. Although C. albicans-specific antibody titers in PCA2-infected mice appeared more quickly in MyD88^-/- mice than in control mice, the MyD88^-/- group was not able to maintain the Candida-specific IgM nor IgG titers at the third week of infection. The complexity of antigens recognized by sera from MyD88^-/- mice was quite similar to that from infected control mice. Taken together, these data show that MyD88^-/- mice are extremely susceptible to C. albicans infections, suggesting that MyD88-dependent signaling pathways are essential for both the innate and adaptive immune responses to C. albicans. MyD88-deficient mice, experimen-tally infected in vivo, had a very significant impaired survival, and a higher tissue fungal burden when compared with control mice. The recruitment of neutrophils to the site of infection was also significantly diminished in MyD88^-/- mice. In vitro production of proinflammatory cytokines such as TNF-α, IFN-γ and IL-12p70, by antigen-stimulated splenocytes from mice intravenously infected with the low-virulence C. albicans PCA2 strain, could not be detected in MyD88^-/- mice. This default of production of Th1 cytokines in MyD88-deficient mice correlated with a greatly diminished frequency of IFN-γ-producing CD4 + T lymphocytes. Also, the frequency of IFN-γ-producing CD8 + T lymphocytes was lower in MyD88^-/- mice than in control mice. Although C. albicans-specific antibody titers in PCA2-infected mice appeared more quickly in MyD88^-/- mice than in control mice, the MyD88^-/- group was not able to maintain the Candida-specific IgM nor IgG titers at the third week of infection. The complexity of antigens recognized by sera from MyD88^-/- mice was quite similar to that from infected control mice. Taken together, these data show that MyD88^-/- mice are extremely susceptible to C. albicans infections, suggesting that MyD88-dependent signaling pathways are essential for both the innate and adaptive immune responses to C. albicans.

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