de Moura Vinicius C N, Verma Deepshikha, Everall Isobel, Brown Karen P, Belardinelli Juan M, Shanley Crystal, Stapleton Megan, Parkhill Julian, Floto R Andres, Ordway Diane J, Jackson Mary
Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States.
Molecular Immunity Unit, Medical Research Council (MRC)-Laboratory of Molecular Biology, University of Cambridge Department of Medicine, Cambridge, United Kingdom.
Front Microbiol. 2021 Jul 14;12:706207. doi: 10.3389/fmicb.2021.706207. eCollection 2021.
Chronic pulmonary infections caused by non-tuberculous mycobacteria of the complex (MABSC) are emerging as a global health problem and pose a threat to susceptible individuals with structural lung disease such as cystic fibrosis. The molecular mechanisms underlying the pathogenicity and intrinsic resistance of MABSC to antibiotics remain largely unknown. The involvement of Msp-type porins in the virulence and biocide resistance of some rapidly growing non-tuberculous mycobacteria and the finding of deletions and rearrangements in the porin genes of serially collected MABSC isolates from cystic fibrosis patients prompted us to investigate the contribution of these major surface proteins to MABSC infection. Inactivation by allelic replacement of the each of the two Msp-type porin genes of CIP108297, and , led to a marked increase in the virulence and pathogenicity of both mutants in murine macrophages and infected mice. Neither of the mutants were found to be significantly more resistant to antibiotics. These results suggest that adaptation to the host environment rather than antibiotic pressure is the key driver of the emergence of porin mutants during infection.
由非结核分枝杆菌复合群（MABSC）引起的慢性肺部感染正成为一个全球性的健康问题，并对患有诸如囊性纤维化等结构性肺病的易感个体构成威胁。MABSC致病性和对抗生素固有抗性的分子机制在很大程度上仍不清楚。Msp型孔蛋白参与了一些快速生长的非结核分枝杆菌的毒力和对杀菌剂的抗性，并且在从囊性纤维化患者连续收集的MABSC分离株的孔蛋白基因中发现了缺失和重排，这促使我们研究这些主要表面蛋白对MABSC感染的作用。通过等位基因替换使CIP108297的两个Msp型孔蛋白基因中的每一个失活，导致两个突变体在小鼠巨噬细胞和感染小鼠中的毒力和致病性显著增加。未发现这两个突变体中的任何一个对抗生素有明显更强的抗性。这些结果表明，在感染过程中，适应宿主环境而非抗生素压力是孔蛋白突变体出现的关键驱动因素。
