Mucormycosis, caused by Rhizopus species, is a life-threatening fungal infection that occurs in patients immunocompromised by diabetic ketoacidosis (DKA), cytotoxic chemotherapy, immunosuppressive therapy, hematologic malignancies, or severe trauma. Inhaled Rhizopus spores cause pulmonary infections in patients with hematologic malignancies, while patients with DKA are much more prone to rhinoorbital/cerebral mucormycosis. Here, we show that Rhizopus delemar interacts with glucose-regulated protein 78 (GRP78) on nasal epithelial cells via its spore coat protein CotH3 to invade and damage the nasal epithelial cells. Expression of the two proteins is significantly enhanced by high glucose, iron, and ketone body levels (hallmark features of DKA), potentially leading to frequently lethal rhinoorbital/cerebral mucormycosis. In contrast, R. delemar CotH7 recognizes integrin β1 as a receptor on alveolar epithelial cells, causing the activation of epidermal growth factor receptor (EGFR) and leading to host cell invasion. Anti-integrin β1 antibodies inhibit R. delemar invasion of alveolar epithelial cells and protect mice from pulmonary mucormycosis. Our results show that R. delemar interacts with different mammalian receptors depending on the host cell type. Susceptibility of patients with DKA primarily to rhinoorbital/cerebral disease can be explained by host factors typically present in DKA and known to upregulate CotH3 and nasal GRP78, thereby trapping the fungal cells within the rhinoorbital milieu, leading to subsequent invasion and damage. Our studies highlight that mucormycosis pathogenesis can potentially be overcome by the development of novel customized therapies targeting niche-specific host receptors or their respective fungal ligands.

中文翻译：

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在毛霉菌病期间，GRP78和整联蛋白在宿主细胞侵袭中发挥不同的作用。

根霉菌种引起的毛霉菌病是威胁生命的真菌感染，发生于糖尿病酮症酸中毒（DKA），细胞毒性化学疗法，免疫抑制疗法，血液系统恶性肿瘤或严重创伤而免疫受损的患者中。吸入性根瘤菌孢子在血液系统恶性肿瘤患者中引起肺部感染，而DKA患者则更容易发生鼻眶/脑黏膜真菌病。在这里，我们显示根霉通过其孢子外壳蛋白CotH3与鼻上皮细胞上的葡萄糖调节蛋白78（GRP78）相互作用，侵袭并破坏鼻上皮细胞。高葡萄糖，铁和酮体水平（DKA的标志性特征）显着增强了这两种蛋白的表达，有可能导致经常致死的鼻眶/脑黏膜真菌病。与此相反，德氏根霉CotH7识别整合素β1作为肺泡上皮细胞的受体，引起表皮生长因子受体（EGFR）的激活并导致宿主细胞的入侵。抗整联蛋白β1抗体抑制R. delemar对肺泡上皮细胞的侵袭，并保护小鼠免受肺毛霉菌病的侵害。我们的结果表明，R。delemar取决于宿主细胞类型，它与不同的哺乳动物受体相互作用。DKA患者主要对鼻眶/脑疾病的易感性可以通过通常存在于DKA中且已知会上调CotH3和鼻GRP78的宿主因子来解释，从而将真菌细胞捕获在鼻眶环境中，从而导致随后的侵袭和破坏。我们的研究突出表明，通过针对小生境特异性宿主受体或它们各自的真​​菌配体的新型定制疗法的开发，可以潜在地克服毛霉菌病的发病机理。