Druggable redox pathways against Mycobacterium abscessus in cystic fibrosis patient-derived airway organoids.

IF 6.7 1区 医学 Q1 Immunology and Microbiology
PLoS Pathogens Pub Date : 2023-08-24 eCollection Date: 2023-08-01 DOI:10.1371/journal.ppat.1011559
Stephen Adonai Leon-Icaza, Salimata Bagayoko, Romain Vergé, Nino Iakobachvili, Chloé Ferrand, Talip Aydogan, Célia Bernard, Angelique Sanchez Dafun, Marlène Murris-Espin, Julien Mazières, Pierre Jean Bordignon, Serge Mazères, Pascale Bernes-Lasserre, Victoria Ramé, Jean-Michel Lagarde, Julien Marcoux, Marie-Pierre Bousquet, Christian Chalut, Christophe Guilhot, Hans Clevers, Peter J Peters, Virginie Molle, Geanncarlo Lugo-Villarino, Kaymeuang Cam, Laurence Berry, Etienne Meunier, Céline Cougoule
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引用次数: 0

Abstract

Mycobacterium abscessus (Mabs) drives life-shortening mortality in cystic fibrosis (CF) patients, primarily because of its resistance to chemotherapeutic agents. To date, our knowledge on the host and bacterial determinants driving Mabs pathology in CF patient lung remains rudimentary. Here, we used human airway organoids (AOs) microinjected with smooth (S) or rough (R-)Mabs to evaluate bacteria fitness, host responses to infection, and new treatment efficacy. We show that S Mabs formed biofilm, and R Mabs formed cord serpentines and displayed a higher virulence. While Mabs infection triggers enhanced oxidative stress, pharmacological activation of antioxidant pathways resulted in better control of Mabs growth and reduced virulence. Genetic and pharmacological inhibition of the CFTR is associated with better growth and higher virulence of S and R Mabs. Finally, pharmacological activation of antioxidant pathways inhibited Mabs growth, at least in part through the quinone oxidoreductase NQO1, and improved efficacy in combination with cefoxitin, a first line antibiotic. In conclusion, we have established AOs as a suitable human system to decipher mechanisms of CF-driven respiratory infection by Mabs and propose boosting of the NRF2-NQO1 axis as a potential host-directed strategy to improve Mabs infection control.

Abstract Image

Abstract Image

Abstract Image

囊性纤维化患者来源的气道类器官中针对脓肿分枝杆菌的可Druggable氧化还原途径。
脓肿分枝杆菌(Mabs)导致囊性纤维化(CF)患者的寿命缩短,主要是因为其对化疗药物的耐药性。到目前为止,我们对CF患者肺部中驱动Mabs病理的宿主和细菌决定因素的了解仍然很初级。在这里,我们使用微注射光滑(S)或粗糙(R-)Mabs的人类气道类器官(AOs)来评估细菌适应性、宿主对感染的反应和新的治疗效果。我们发现S Mabs形成生物膜,R Mabs形成脐带蛇,并表现出更高的毒力。虽然Mabs感染会引发氧化应激增强,但抗氧化途径的药理学激活会更好地控制Mabs的生长并降低毒力。CFTR的遗传和药理学抑制与S和R Mabs更好的生长和更高的毒力有关。最后,抗氧化途径的药理学激活抑制了Mabs的生长,至少部分通过醌氧化还原酶NQO1,并与一线抗生素头孢西丁联合提高了疗效。总之,我们已经确定AOs是一种合适的人类系统,可以解读Mabs引起CF驱动的呼吸道感染的机制,并提出增强NRF2-NQO1轴作为一种潜在的宿主导向策略,以改善Mabs感染控制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PLoS Pathogens
PLoS Pathogens 生物-病毒学
CiteScore
11.40
自引率
3.00%
发文量
598
审稿时长
2 months
期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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