烟曲霉是一种主要的侵袭性霉菌病原体,也是侵袭性曲霉病最常见的病原体。目前可用的侵袭性曲霉病治疗方法在数量和功效上都受到限制。我们最近的工作发现,β-葡聚糖合酶抑制剂,棘白菌素,对具有分离起始网络(SIN)激酶活性缺陷的烟曲霉菌株具有杀真菌性。已知这些药物对正常隔离的菌株具有真菌抑制作用。令人惊讶的是,SIN激酶突变株也未能侵入肺组织,并且在免疫抑制小鼠模型中的毒力显着降低。因此,抑制丝状真菌中的分隔是降低毒力和改善当前抗真菌治疗的令人兴奋的治疗前景。然而,SIN在病原真菌中仍未被研究。为了解决这个知识差距,我们表征了烟曲霉SIN的推定调节成分。这些包括GTPase,SpgA,它是双组分GTP酶激活蛋白,ByrA/BubA,和激酶激活剂,SepM和MobA.删除spgA,byra,或bubA没有明显的隔膜或棘白菌素易感性表型。相比之下,我们的数据显示,sepM或mobA的缺失在很大程度上破坏了它们的SIN激酶结合配偶体,sepL和sidB,分别。减少隔膜形成,棘白菌素高度敏感,而毒力的降低是由于任一基因的缺失而产生的。这些发现提供了强有力的支持证据,表明隔片不仅对于承受棘白菌素的细胞壁破坏作用至关重要,而且对于建立侵袭性疾病也至关重要。因此,药物SIN抑制可能是未来抗真菌药物开发的令人兴奋的策略.IMPORTANCESepta是棘白菌素敏感性和普遍存在的真菌病原体烟曲霉的组织入侵生长的重要结构决定因素。因此,分离机器的成分代表了有希望的新型抗真菌靶标,以改善棘白菌素的活性并降低毒力。然而,关于烟曲霉的隔膜调节知之甚少。这里,我们表征了烟曲霉败血症起始网络的预测调控成分。我们表明,激酶激活剂SepM和MobA对于适当的间隔和棘白菌素抗性至关重要,MobA发挥了重要作用。mobA的空突变体在小鼠模型中显示出显着降低的毒力,强调了该途径在烟曲霉发病机制中的重要性。
Aspergillus fumigatus is a major invasive mold pathogen and the most frequent etiologic agent of invasive aspergillosis. The currently available treatments for invasive aspergillosis are limited in both number and efficacy. Our recent work has uncovered that the β-glucan synthase inhibitors, the echinocandins, are fungicidal against strains of A. fumigatus with defects in septation initiation network (SIN) kinase activity. These drugs are known to be fungistatic against strains with normal septation. Surprisingly, SIN kinase mutant strains also failed to invade lung tissue and were significantly less virulent in immunosuppressed mouse models. Inhibiting septation in filamentous fungi is therefore an exciting therapeutic prospect to both reduce virulence and improve current antifungal therapy. However, the SIN remains understudied in pathogenic fungi. To address this knowledge gap, we characterized the putative regulatory components of the A. fumigatus SIN. These included the GTPase, SpgA, it\'s two-component GTPase-activating protein, ByrA/BubA, and the kinase activators, SepM and MobA. Deletion of spgA, byrA, or bubA resulted in no overt septation or
echinocandin susceptibility phenotypes. In contrast, our data show that deletion of sepM or mobA largely phenocopies disruption of their SIN kinase binding partners, sepL and sidB, respectively. Reduced septum formation,
echinocandin hypersusceptibility, and reduced virulence were generated by loss of either gene. These findings provide strong supporting evidence that septa are essential not only for withstanding the cell wall disrupting effects of echinocandins but are also critical for the establishment of invasive disease. Therefore, pharmacological SIN inhibition may be an exciting strategy for future antifungal drug development.IMPORTANCESepta are important structural determinants of
echinocandin susceptibility and tissue invasive growth for the ubiquitous fungal pathogen Aspergillus fumigatus. Components of the septation machinery therefore represent promising novel antifungal targets to improve
echinocandin activity and reduce virulence. However, little is known about septation regulation in A. fumigatus. Here, we characterize the predicted regulatory components of the A. fumigatus septation initiation network. We show that the kinase activators SepM and MobA are vital for proper septation and
echinocandin resistance, with MobA playing an essential role. Null mutants of mobA displayed significantly reduced virulence in a mouse model, underscoring the importance of this pathway for A. fumigatus pathogenesis.