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Macrolides Inhibit Capsule Formation of Highly Virulent Cryptococcus gattii and Promote Innate Immune Susceptibility
Shigeki Nakamura1, Yurika Ikeda-Dantsuji2, Lianjin Jin2
1Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan shigekinak@nih.go.jp.
Abstract:
Cryptococcus gattii is a fungal pathogen, endemic in tropical and subtropical regions, the west coast of Canada, and the United States, that causes a potentially fatal infection in otherwise healthy individuals. Because the cryptococcal polysaccharide capsule is a leading virulence factor due to its resistance against innate immunity, the inhibition of capsule formation may be a promising new therapeutic strategy for C. gattii Macrolides have numerous nonantibiotic effects, including immunomodulation of mammalian cells and suppression of bacterial (but not fungal) pathogenicity. Thus, we hypothesized that a macrolide would inhibit cryptococcal capsule formation and improve the host immune response. Coincubation with clarithromycin (CAM) and azithromycin significantly reduced the capsule thickness and the amount of capsular polysaccharide of both C. gattii and C. neoformans CAM-treated C. gattii cells were significantly more susceptible to H2O2 oxidative stress and opsonophagocytic killing by murine neutrophils. In addition, more C. gattii cells were phagocytosed by murine macrophages, resulting in increased production of tumor necrosis factor alpha (TNF-α) by CAM exposure. After CAM exposure, dephosphorylation of Hog1, one of the mitogen-activated protein kinase (MAPK) signaling pathways of Cryptococcus, was observed in Western blot analysis. In addition, CAM exposure significantly reduced the mRNA expression of LAC1 and LAC2 (such mRNA expression is associated with cell wall integrity and melanin production). These results suggest that CAM may aid in inhibiting capsular formation via the MAPK signaling pathway and by suppressing virulent genes; thus, it may be a useful adjunctive agent for treatment of refractory C. gattii infection.
Insights
Macrolide antibiotics like clarithromycin (CAM) effectively inhibit the capsule formation of Cryptococcus gattii, a dangerous fungal pathogen. This inhibition enhances immune cell targeting and may offer new therapeutic strategies for C. gattii infections.
Area of Science:
- Mycology
- Immunology
- Pharmacology
Background:
- Cryptococcus gattii is a fungal pathogen causing life-threatening infections, particularly in healthy individuals.
- The polysaccharide capsule is a key virulence factor, conferring resistance to the host's immune system.
- Inhibiting capsule formation presents a potential therapeutic strategy against C. gattii.
Purpose of the Study:
- To investigate the effect of macrolides on Cryptococcus gattii capsule formation.
- To evaluate the impact of macrolides on the host immune response to C. gattii.
- To explore the molecular mechanisms underlying macrolide-mediated inhibition of C. gattii virulence.
Main Methods:
- Coincubation of C. gattii and C. neoformans with clarithromycin (CAM) and azithromycin.
- Assessment of capsule thickness and polysaccharide content.
- Evaluation of susceptibility to oxidative stress and phagocytic killing by neutrophils and macrophages.
- Analysis of TNF-α production by macrophages.
- Western blot analysis of Hog1 phosphorylation (MAPK pathway).
- Measurement of LAC1 and LAC2 mRNA expression.
Main Results:
- CAM and azithromycin significantly reduced capsule thickness and polysaccharide content in C. gattii and C. neoformans.
- CAM-treated C. gattii exhibited increased susceptibility to oxidative stress and neutrophil-mediated killing.
- Macrophages showed enhanced phagocytosis of CAM-exposed C. gattii, with increased TNF-α production.
- CAM exposure led to Hog1 dephosphorylation and reduced mRNA expression of LAC1 and LAC2.
- These suggest CAM inhibits capsular formation via the MAPK pathway and virulence genes.
Conclusions:
- Macrolides, particularly CAM, can inhibit Cryptococcus gattii capsule formation.
- CAM enhances the host immune response by increasing susceptibility to phagocytosis and oxidative stress.
- CAM may act by modulating the MAPK signaling pathway and suppressing virulence genes.
- CAM shows promise as an adjunctive therapy for refractory C. gattii infections.
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