Abstract：
The opportunistic pathogen Mycobacterium abscessus subsp. abscessus (Mab) has become an emerging public health threat due to the increasing number of Mab-associated chronic pulmonary disease cases. Treatment requires multiple drug courses and is often combined with surgical resection. Cure rates are only ~50% due to treatment failure and comorbidities. Deeper understanding of the biology of Mab is required to illuminate potential avenues for the development of better therapeutics against Mab infections. The ESX-3 type VII protein secretion system of Mab has an important role in host inflammatory and pathological responses during infection. In this work, we demonstrate a functional link between ESX-3 and an iron uptake system based on an unusual mycobactin-type siderophore (designated MBT Ab) and exploit this link to implement a large screen for transposon mutants with an impaired ESX-3. Most mutants we identified carry insertions in genes encoding predicted ESX-3 secretion machinery components or potential ESX-3 substrates. The mutants overproduce MBT Ab, a trait consistent with an iron uptake defect. Our characterization of MBT Ab revealed structural features reminiscent of nocardial mycobactin-like compounds with cytotoxicity. This finding raises the possibility that MBT Ab may play roles in pathogenesis unlinked to iron homeostasis. The mutants generated herein will facilitate research to better understand the role of ESX-3 and its interplay with the siderophore system.
摘要：
机会性病原体脓肿分枝杆菌亚种。脓肿（Mab）已成为一个新兴的公共卫生威胁，由于与Mab相关的慢性肺病病例的增加。治疗需要多个药物疗程，通常与手术切除相结合。由于治疗失败和合并症,治愈率仅为~50%。需要对Mab的生物学有更深入的了解，以阐明开发针对Mab感染的更好疗法的潜在途径。Mab的ESX-3VII型蛋白分泌系统在感染期间的宿主炎症和病理反应中具有重要作用。在这项工作中,我们证明了ESX-3与基于不寻常的mycobactin型铁载体(称为MBTAb)的铁摄取系统之间的功能联系,并利用这一联系对ESX-3受损的转座子突变体进行了大屏幕筛选.我们鉴定的大多数突变体在编码预测的ESX-3分泌机制组分或潜在的ESX-3底物的基因中携带插入。突变体过度生产MBTAb，与铁摄取缺陷一致的特征。我们对MBTAb的表征揭示了结构特征，让人联想到具有细胞毒性的心脏分枝杆菌样化合物。这一发现提高了MBTAb可能在与铁稳态无关的发病机制中发挥作用的可能性。本文产生的突变体将有助于研究以更好地理解ESX-3的作用及其与铁载体系统的相互作用。
