Chauvin David, Hust Michael, Schütte Mark, Chesnay Adélaïde, Parent Christelle, Moreira Gustavo Marçal Schmidt Garcia, Arroyo Javier, Sanz Ana Belén, Pugnière Martine, Martineau Pierre, Chandenier Jacques, Heuzé-Vourc'h Nathalie, Desoubeaux Guillaume
INSERM, Centre d'Étude des Pathologies Respiratoires, U1100, Tours, France.
Department Faculté de Médecine, Université de Tours, Tours, France.
Front Microbiol. 2019 Mar 26;10:600. doi: 10.3389/fmicb.2019.00600. eCollection 2019.
is an airborne opportunistic fungal pathogen responsible for severe infections. Among them, invasive pulmonary aspergillosis has become a major concern as mortality rates exceed 50% in immunocompromised hosts. In parallel, allergic bronchopulmonary aspergillosis frequently encountered in cystic fibrosis patients, is also a comorbidity factor. Current treatments suffer from high toxicity which prevents their use in weakened subjects, resulting in impaired prognostic. Because of their low toxicity and high specificity, anti-infectious therapeutic antibodies could be a new alternative to conventional therapeutics. In this study, we investigated the potential of cell wall transglycosylases of to be therapeutic targets for therapeutic antibodies. We demonstrated that the Crf target was highly conserved, regardless of the pathophysiological context; whereas the gene was found to be 100% conserved in 92% of the isolates studied, Crf proteins were expressed in 98% of the strains. In addition, we highlighted the role of Crf proteins in fungal growth, using a deletion mutant for gene, for which a growth decrease of 23.6% was observed after 48 h. It was demonstrated that anti-Crf antibodies neutralized the enzymatic activity of recombinant Crf protein, and delayed fungal growth by 12.3% when added to spores. In a neutropenic rat model of invasive pulmonary aspergillosis, anti-Crf antibodies elicited a significant recruitment of neutrophils, macrophages and T CD4 lymphocytes but it was not correlated with a decrease of fungal burden in lungs and improvement in survival. Overall, our study highlighted the potential relevance of targeting Crf cell wall protein (CWP) with therapeutic antibodies.
是一种导致严重感染的空气传播机会性真菌病原体。其中，侵袭性肺曲霉病已成为一个主要问题，因为免疫功能低下宿主的死亡率超过50%。同时，囊性纤维化患者中经常遇到的过敏性支气管肺曲霉病也是一个合并症因素。目前的治疗方法毒性高，这使得它们无法用于身体虚弱的患者，导致预后受损。由于其低毒性和高特异性，抗感染治疗性抗体可能成为传统治疗方法的新替代方案。在本研究中，我们研究了曲霉细胞壁转糖基酶作为治疗性抗体治疗靶点的潜力。我们证明，无论病理生理背景如何，Crf靶点高度保守；虽然在所研究的92%的分离株中发现基因100%保守，但Crf蛋白在98%的菌株中表达。此外，我们使用基因缺失突变体突出了Crf蛋白在真菌生长中的作用，在48小时后观察到其生长下降了23.6%。结果表明，抗Crf抗体中和了重组Crf蛋白的酶活性，并且当添加到孢子中时，使真菌生长延迟了12.3%。在侵袭性肺曲霉病的中性粒细胞减少大鼠模型中，抗Crf抗体引起了中性粒细胞、巨噬细胞和T CD4淋巴细胞的显著募集，但这与肺部真菌负荷的降低和生存率的提高无关。总体而言，我们的研究突出了用治疗性抗体靶向Crf细胞壁蛋白（CWP）的潜在相关性。
