Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT, USA.
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Nature. 2021 Aug;596(7870):114-118. doi: 10.1038/s41586-021-03722-w. Epub 2021 Jul 14.
Pathogenic fungi reside in the intestinal microbiota but rarely cause disease. Little is known about the interactions between fungi and the immune system that promote commensalism. Here we investigate the role of adaptive immunity in promoting mutual interactions between fungi and host. We find that potentially pathogenic Candida species induce and are targeted by intestinal immunoglobulin A (IgA) responses. Focused studies on Candida albicans reveal that the pathogenic hyphal morphotype, which is specialized for adhesion and invasion, is preferentially targeted and suppressed by intestinal IgA responses. IgA from mice and humans directly targets hyphal-enriched cell-surface adhesins. Although typically required for pathogenesis, C. albicans hyphae are less fit for gut colonization and we show that immune selection against hyphae improves the competitive fitness of C. albicans. C. albicans exacerbates intestinal colitis and we demonstrate that hyphae and an IgA-targeted adhesin exacerbate intestinal damage. Finally, using a clinically relevant vaccine to induce an adhesin-specific immune response protects mice from C. albicans-associated damage during colitis. Together, our findings show that adaptive immunity suppresses harmful fungal effectors, with benefits to both C. albicans and its host. Thus, IgA uniquely uncouples colonization from pathogenesis in commensal fungi to promote homeostasis.
肠道微生物群中存在致病性真菌，但它们很少引起疾病。人们对促进共生的真菌与免疫系统之间的相互作用知之甚少。在这里，我们研究了适应性免疫在促进真菌与宿主之间相互作用中的作用。我们发现，潜在的致病性念珠菌属物种会引发并成为肠道免疫球蛋白 A（IgA）反应的靶标。对白色念珠菌的重点研究表明，专门用于粘附和入侵的致病性菌丝形态被肠道 IgA 反应优先靶向和抑制。来自小鼠和人类的 IgA 直接靶向富含菌丝的细胞表面粘附素。尽管通常是致病所必需的，但白色念珠菌的菌丝在肠道定植方面适应性较差，我们表明针对菌丝的免疫选择可提高白色念珠菌的竞争适应性。白色念珠菌会加剧肠道结肠炎，我们证明菌丝和 IgA 靶向的粘附素会加剧肠道损伤。最后，使用一种临床相关的疫苗来诱导针对特定粘附素的免疫反应，可以在结肠炎期间保护小鼠免受白色念珠菌相关的损伤。总之，我们的研究结果表明，适应性免疫抑制了有害的真菌效应物，这对白色念珠菌及其宿主都有益。因此，IgA 独特地将定植与共生真菌的发病机制分离，以促进体内平衡。
