Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan
Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.
Antimicrob Agents Chemother. 2019 May 24;63(6). doi: 10.1128/AAC.02364-18. Print 2019 Jun.
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 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 and CAM-treated cells were significantly more susceptible to HO oxidative stress and opsonophagocytic killing by murine neutrophils. In addition, more 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 , was observed in Western blot analysis. In addition, CAM exposure significantly reduced the mRNA expression of and (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 infection.
荚膜组织胞浆菌是一种真菌病原体，存在于热带和亚热带地区、加拿大西海岸和美国，它会导致原本健康的个体患上潜在致命的感染。由于 cryptococcal 多糖荚膜是一种主要的毒力因子，因为它能抵抗先天免疫，因此抑制荚膜形成可能是治疗 大环内酯类药物具有许多非抗生素作用，包括对哺乳动物细胞的免疫调节和抑制细菌（但不是真菌）的致病性。因此，我们假设大环内酯类药物会抑制 cryptococcal 荚膜形成并改善宿主免疫反应。与克拉霉素（CAM）和阿奇霉素共同孵育可显著降低 和 的荚膜厚度和荚膜多糖含量。CAM 处理的 细胞对 HO 氧化应激和鼠中性粒细胞的调理吞噬杀伤作用明显更敏感。此外，更多的 细胞被鼠巨噬细胞吞噬，导致 CAM 暴露后 TNF-α 的产生增加。CAM 暴露后，Western blot 分析观察到 MAPK 信号通路中的一种丝裂原活化蛋白激酶（MAPK）途径的 Hog1 去磷酸化。此外，CAM 暴露还显著降低了 和 （与细胞壁完整性和黑色素产生相关的 mRNA 表达）的 mRNA 表达。这些结果表明，CAM 可能通过 MAPK 信号通路和抑制毒力基因来帮助抑制荚膜形成；因此，它可能是治疗难治性 感染的有用辅助剂。
