6.01.2008

Host resistence to fungal pathogens

The basis of mammalian host resistance to fungal pathogens is relatively under studied. But what is the best model system for studying fungal disease? Many fungi are not host specific, that is, they have the ability to be virulent in many different hosts. Experiments can not be done in vivo in humans, but can they be done on human cell lines. Is a mouse model appropriate for understanding general mammalian immunity? Because mouse studies can be extremely expensive and a regulatory time suck, perhaps other models may be appropriate for understanding virulence in fungi (Casadevall 2005).
Recent work with C. neoformans shows that interactions with other soil organisms can be informative in screening virulence factors (Mylonakis et al. 2002). Further work in this system has revealed a specific gene required for pathogenicity in mice (Tang, et al. 2005). Other systems such as Aspergillus flavus and Candida albicans with the wax moth have also been described and show promise (Brennan et al. 2002; St. Leger et al. 2000). Another tool that is also being used to identify virulence factors in fungi is genome sequencing. Currently, several fungi are sequenced, or in the pipeline. Annotation has proven more difficult than originally thought, so the completeness of the data is limited as of now, and makes searching for "pathogenicity genes" using bioinformatic tools complicated and cumbersome.
The basis of host immunity to fungi is understood at a certain level. When mice without CD4+ lymphocytes are vaccinated with an attenuated Blastomyces dermatitidis and Histoplasma capsulatum vaccine, CD8+ T cells can induce and maintain protective immunity (W├╝thrich et al. 2003). Vaccine mediated protection was accompanied by reduced inflammation and fungal burden in the lung. In experiments with mice lacking both CD4+ and CD8+ T lymphocytes, the mice were not able to control the fungal burden very effectively with vaccination, but did show some resistance. Hence, the possibility that antibodies and/or B cells, in addition to other cell types, such as dendritic or NK cells, may play a role in the development of antifungal immunity, and has implications for vaccine development. The main result of this study is that even in the absence of CD4+ T cells, such as in AIDS patients, some immunity to fungal infections was obtained.

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