Vandeputte Patrick, Dugé de Bernonville Thomas, Le Govic Yohann, Le Gal Solène, Nevez Gilles, Papon Nicolas, Bouchara Jean-Philippe
Groupe d'Etude des Interactions Hôte-Pathogène, EA 3142, SFR ICAT 4208, UNIV Angers, UNIV Brest, Institut de Biologie en Santé-IRIS, Angers, France.
Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire d'Angers, Angers, France.
Comput Struct Biotechnol J. 2020 Nov 10;18:3468-3483. doi: 10.1016/j.csbj.2020.10.034. eCollection 2020.
species rank second among the filamentous fungi colonizing the lungs of patients with cystic fibrosis (CF). Apart from the context of immunodeficiency (lung transplantation), the colonization of the CF airways by these fungi usually remains asymptomatic. Why the colonization of the lower airways by species is fairly tolerated by CF patients while these fungi are able to induce a marked inflammatory reaction in other clinical contexts remains questionable. In this regards, we were interested here in exploring the transcriptional reprogramming that accompanies the adaptation of these fungi to the particular microenvironment encountered in the airways of CF patients. Cultivation of in conditions mimicking the microenvironment in the CF lungs was shown to induce marked transcriptional changes. This includes notably the down-regulation of enzymes involved in the synthesis of some major components of the plasma membrane which may reflect the ability of the fungus to evade the host immune response by lowering the biosynthesis of some major antigenic determinants or inhibiting their targeting to the cell surface through alterations of the membrane fluidity. In addition, this analysis revealed that some genes encoding enzymes involved in the biosynthesis of some mycotoxins were down-regulated suggesting that, during the colonization process, reduces the production of some toxic secondary metabolites to prevent exacerbation of the immune system response. Finally, a strong up-regulation of many genes encoding enzymes involved in the degradation of aromatic compounds was observed, suggesting that these catabolic properties would predispose the fungus to particular patterns of human pathogenicity. Together these data provide new insights into the adaptative mechanisms developed by in the CF lungs, which should be considered for identification of potential targets for drug development, but also for the experimental conditions to be used in susceptibility testing of clinical isolates to current antifungals.
曲霉属在定植于囊性纤维化（CF）患者肺部的丝状真菌中排名第二。除了免疫缺陷（肺移植）的情况外，这些真菌在CF气道中的定植通常无症状。为什么CF患者对曲霉属在其下呼吸道的定植耐受性较好，而这些真菌在其他临床情况下却能引发明显的炎症反应，这仍然是个问题。在这方面，我们感兴趣的是探索这些真菌适应CF患者气道中特定微环境时伴随的转录重编程。在模拟CF肺部微环境的条件下培养曲霉属，结果显示会诱导显著的转录变化。这尤其包括参与质膜某些主要成分合成的酶的下调，这可能反映了真菌通过降低一些主要抗原决定簇的生物合成或通过改变膜流动性来抑制它们靶向细胞表面，从而逃避宿主免疫反应的能力。此外，该分析还显示，一些编码参与某些霉菌毒素生物合成的酶的基因被下调，这表明在定植过程中，曲霉属会减少一些有毒次生代谢产物的产生，以防止免疫系统反应加剧。最后，观察到许多编码参与芳香族化合物降解的酶的基因强烈上调，这表明这些分解代谢特性会使该真菌具有特定的人类致病模式。这些数据共同为曲霉属在CF肺部发展的适应机制提供了新的见解，这不仅应被考虑用于确定药物开发的潜在靶点，还应被考虑用于临床分离株对当前抗真菌药物敏感性测试所使用的实验条件。
