Cellular mechanisms of host resistance against oral Candida Albicans infections in a murine model

Farah, Camile Selim (2000). Cellular mechanisms of host resistance against oral Candida Albicans infections in a murine model PhD Thesis, School of Dentistry, The University of Queensland.

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Author Farah, Camile Selim
Thesis Title Cellular mechanisms of host resistance against oral Candida Albicans infections in a murine model
School, Centre or Institute School of Dentistry
Institution The University of Queensland
Publication date 2000
Thesis type PhD Thesis
Total pages 270
Language eng
Subjects 1105 Dentistry
Formatted abstract

The general objectives of this work were to compare the development and resolution of oral Candida albicans infection in genetically defined strains of mice, and to identify the cellular mechanisms that determine the different patterns of oral infection and clearance.

A murine model of oral candidiasis was established. Various inbred strains of mice were inoculated orally with C. albicans yeasts, and the infection was monitored over a period of 21 days. Results indicated that CBA/CaH mice were more susceptible, and BALB/c mice were more resistant to this infection compared to other strains tested. The infection was short-lived, and the different strains cleared the infection in a similar fashion.

As inbred strains showed variations in colonisation, the role of non-immune salivary factors in host defence was explored. Whole saliva and submandibular salivary gland extract exhibited significant candidacidal activity. This appeared to correlate with the presence of low molecular weight salivary proteins similar to human histatins, a family of histidine-rich polypeptides with proven anti-candidal activity. The candidacidal capacity of saliva and gland extract was comparable in all mouse strains tested, and therefore did not account for the differences in colonisation levels.

The C5 status of the mice, and their MHC haplotypes appeared to play no role in susceptibility to oral infection. The cytokine profile offered by intra-cytoplasmic staining was complicated, and did not reveal a particular pattern of cytokine expression in these mice. Consistent with the published literature, infected mice demonstrated DTH responses after footpad challenge with heat-killed Candida. This confirmed that the yeast elicited cell-mediated immune responses in our model.

The significance of cell-mediated immunity in host recovery from primary infection was further analysed in an immunodeficient mouse model. T cell deficient nude mice (Hfhll<nu>/Hfhll<nu>) lacking T lymphocytes were infected orally with C. albicans. These mice became heavily colonised with the yeast and developed a chronic oral candidal infection which persisted for several months. Histological sections demonstrated hyphae penetrating the oral epithelium of the palate, tongue, and gingival tissues. Epithelial micro-abscess formation, consisting mainly of polymorphonuclear leukocytes, was a constant feature of the oral infection in these immunodeficient mice.

Thymus transplantation, and the adoptive transfer of either naive or immune lymphocytes, resulted in the clearance of the yeast from the oral cavity of infected T cell deficient mice. Elimination of the yeast from the oral tissues of these animals was subsequently shown to be mediated by CD4+ T cells, that were able to infiltrate the oral tissues. High levels of IL-12 and moderate levels of IFN-Ƴ were dominant features of the cytokine profile in the draining lymph nodes of these mice, whereas IL-6, IFN-Ƴ, TNF-α. and MIF (macrophage migration inhibition factor) gene expression was detected in the oral tissues of infected nu/nu mice after lymphocyte reconstitution. DTH responses were demonstrated in nu/nu mice reconstituted with CD4+ but not CDS+ T cells.

A role for T cells in the host response against C. albicans was confirmed in euthymic inbred mice by monoclonal antibody depletion of CD4+ and CDS+ cell populations, in conjunction with head and neck irradiation. Head and neck irradiation increased the levels of colonisation in treated mice, but the infection was prolonged only in animals also depleted of CD4+ T cells. The cytokine profile displayed by irradiated and non-irradiated mice infected with C. albicans was similar to that described above.

Monoclonal antibody depletion of neutrophils from the systemic circulation, and cytotoxic inactivation of macrophages, increased the severity of the oral infection, and revealed a role for both of these phagocytic cell types in host defence against oral candidiasis. It would appear that the clearance of an oral C. albicans infection is dependent on CD4+ T cell augmentation of monocyte and neutrophil function, possibly mediated by cytokines such as IL- 12, IFN- Ƴ and MIF.

Enhancement of host responses against oral candidiasis was provided by active immunisation of mice via the oral, but not the systemic route. Both the fungal load and duration of colonisation were decreased following a primary oral challenge. Humoral immunity conferred by passive immunisati9n with immune serum failed to confer any protection at the oral mucosal surface.

In conclusion, the work reported in this thesis has shown that host resistance against oral Candida albicans infections is directed by cell-mediated immune responses at the mucosal surface. T lymphocytes, CD4+ T cells in particular, play a prominent role in this process, probably by augmenting the ability of phagocytic cells, such as neutrophils and macrophages, to clear the yeast from the oral mucosa.

Keyword Candida albicans

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
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Created: Mon, 28 Oct 2013, 11:52:50 EST by Yu-lin Huang on behalf of Scholarly Communication and Digitisation Service