GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis
GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis
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DOI：
10.1128/mbio.01087-20
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发表时间：
2020-05-01
期刊：
影响因子：
6.4
通讯作者：
Ibrahim, Ashraf S.
中科院分区：
文献类型：
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作者：
Alqarihi, Abdullah;Gebremariam, Teclegiorgis;Ibrahim, Ashraf S.
毛霉菌病由根霉属引起，是一种危及生命的真菌感染，发生在因糖尿病酮症酸中毒（DKA）、细胞毒性化疗、免疫抑制治疗、血液恶性肿瘤或严重创伤而免疫功能低下的患者中。吸入根霉孢子会导致血液恶性肿瘤患者肺部感染，而DKA患者更容易发生鼻眶/脑毛霉菌病。在这里，我们表明德勒马根霉通过其孢子外壳蛋白CotH 3与鼻上皮细胞上的葡萄糖调节蛋白78（GRP 78）相互作用，从而入侵和损伤鼻上皮细胞。这两种蛋白质的表达通过高葡萄糖、铁和酮体水平（DKA的标志性特征）显著增强，可能导致经常致命的鼻眶/脑毛霉菌病。相反，R. delemar CotH 7识别整联蛋白β 1作为肺泡上皮细胞上的受体，引起表皮生长因子受体（EGFR）的活化并导致宿主细胞侵袭。抗整联蛋白β 1抗体抑制R.肺泡上皮细胞的delemar侵袭和保护小鼠免受肺毛霉菌病。结果表明，R.根据宿主细胞类型，delemar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DKA中通常存在的宿主因子来解释，并且已知宿主因子上调CotH 3和鼻GRP 78，从而将真菌细胞捕获在鼻眶环境中，导致随后的侵袭和损伤。我们的研究强调，毛霉菌病的发病机制，可以潜在地克服针对利基特异性宿主受体或其各自的真菌ligands.IMPORTANCE毛霉菌病引起的根霉属真菌感染的发展是一种真菌感染，往往致命的预后。孢子的吸入是进入的主要途径，鼻腔和肺泡上皮细胞是第一批遇到真菌的细胞。在恶性血液病患者或正在接受细胞毒化疗的患者中，根霉引起肺部感染。另一方面，DKA患者主要患有鼻眶/脑毛霉菌病。同一种真菌引起的疾病类型如此不同的原因尚不清楚。在这里，我们表明，独特的易感性DKA受试者鼻眶/脑毛霉菌病可能是由于鼻上皮细胞GRP 78和真菌CotH 3之间的特定相互作用，其表达增加的宿主因子存在于DKA。相反，肺毛霉菌病是通过吸入的表达CotH 7的孢子与整合素β 1受体相互作用而引发的，整合素β 1受体激活EGFR以诱导真菌侵入宿主细胞。这些结果为DKA与血液系统恶性肿瘤患者不同的疾病表现提供了合理的解释，并为开发针对这些致命形式的毛霉菌病的治疗干预措施提供了基础。
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 beta 1 as a receptor on alveolar epithelial cells, causing the activation of epidermal growth factor receptor (EGFR) and leading to host cell invasion. Anti-integrin beta 1 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.IMPORTANCE Mucormycosis caused by Rhizopus species is a fungal infection with often fatal prognosis. Inhalation of spores is the major route of entry, with nasal and alveolar epithelial cells among the first cells that encounter the fungi. In patients with hematologic malignancies or those undergoing cytotoxic chemotherapy, Rhizopus causes pulmonary infections. On the other hand, DKA patients predominantly suffer from rhinoorbital/cerebral mucormycosis. The reason for such disparity in disease types by the same fungus is not known. Here, we show that the unique susceptibility of DKA subjects to rhinoorbital/cerebral mucormycosis is likely due to specific interaction between nasal epithelial cell GRP78 and fungal CotH3, the expression of which increases in the presence of host factors present in DKA. In contrast, pulmonary mucormycosis is initiated via interaction of inhaled spores expressing CotH7 with integrin beta 1 receptor, which activates EGFR to induce fungal invasion of host cells. These results introduce a plausible explanation for disparate disease manifestations in DKA versus those in hematologic malignancy patients and provide a foundation for development of therapeutic interventions against these lethal forms of mucormycosis.