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Biomolecular events involved in the establishment of brain anticandidal resistance
R Mazzolla1, R Barluzzi, M Puliti
1Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.
Abstract:
Using a murine model, we have demonstrated the establishment of cerebral resistance to local lethal challenge with Candida albicans strain CA-6, by previous intracerebral (i.c.) infection with the low-virulent strain PCA-2. Here we show that i.c. infection with PCA-2 is effective in drastically reducing brain colonization following secondary infection with CA-6. As assessed by colony forming unit assay and histopathological analysis, microbial counts are impaired, granuloma formation and hyphal growth are also reduced in brains of PCA-2- and CA-6-infected mice with respect to CA-6-challenged mice. Furthermore, using PCR studies, we found that, while PCA-2 (i.e. healing infection) induces transient cytokine gene expression in the mouse brain, CA-6 lethal challenge results in long-lasting (until mouse death) high levels of all cytokine gene transcripts assessed. Finally brains from mice that will resist CA-6 challenge, because of previous infection with PCA-2, also exhibit a transient induction of all cytokine genes. Only IL-1 beta remains highly expressed at all time- points tested. Overall, these results provide evidence that healing and non-healing C. albicans i.c. infections differ in the immune reaction(s) locally evoked, at least in terms of cytokine gene expression, strongly suggesting cytokine involvement in the establishment of brain anticandidal resistance.
Insights
Previous infection with a low-virulent Candida albicans strain (PCA-2) establishes cerebral resistance against lethal Candida albicans (CA-6) challenge by modulating immune responses and reducing brain colonization.
Area of Science:
- Immunology
- Mycology
- Neuroscience
Background:
- Candida albicans is an opportunistic fungal pathogen that can cause severe central nervous system infections.
- Establishing effective cerebral resistance against fungal pathogens remains a significant clinical challenge.
- Understanding the immune mechanisms underlying brain antifungal immunity is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the establishment of cerebral resistance to Candida albicans following prior infection with a low-virulent strain.
- To elucidate the role of cytokine gene expression in the development of brain antifungal immunity.
- To differentiate the immune responses between healing and non-healing cerebral candidiasis.
Main Methods:
- Murine model of intracerebral (i.c.) infection with Candida albicans strains CA-6 (lethal) and PCA-2 (low-virulent).
- Colony forming unit (CFU) assay and histopathological analysis to assess fungal burden and tissue damage.
- Polymerase Chain Reaction (PCR) studies to evaluate cytokine gene expression in brain tissue.
Main Results:
- Previous i.c. infection with PCA-2 significantly reduced brain colonization by CA-6 in a secondary infection model.
- PCA-2 pre-infection diminished microbial counts, granuloma formation, and hyphal growth compared to CA-6 challenge alone.
- Healing PCA-2 infections induced transient cytokine gene expression, while lethal CA-6 infections caused sustained high levels; resistant mice showed transient induction, with IL-1 beta remaining high.
Conclusions:
- Prior infection with a low-virulent C. albicans strain effectively induces cerebral resistance against a subsequent lethal challenge.
- Differential cytokine gene expression patterns correlate with the outcome of cerebral candidiasis, distinguishing healing from non-healing infections.
- These findings strongly suggest a critical role for local immune responses, particularly cytokine involvement, in establishing brain antifungal resistance.