Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio, 43205, USA.
Institute for Glycomics, Griffith University, Gold Coast, Queensland, 4222, Australia.
Sci Rep. 2017 Jun 9;7(1):3161. doi: 10.1038/s41598-017-03552-9.
Nontypeable Haemophilus influenzae (NTHI) is the causative agent of multiple respiratory tract infections. Several human pathogens, including NTHI, possess a novel genetic system, termed the phasevarion, which mediates a rapid and reversible change in the expression of many genes throughout the chromosome. This occurs by phase variation of a single gene (modA) that encodes a DNA methyltransferase and results in two phenotypically distinct subpopulations, ON and OFF. NTHI encounters many pressures within the various microenvironments of its human host as the disease course evolves from one of asymptomatic nasopharyngeal carriage to overt disease. These include oxidative stresses, which are present throughout the respiratory tract. To persist in the human nasopharynx and as a pathogen throughout the airways, NTHI must be able to mitigate toxic levels of oxidative stress. Here we show that expression of ModA2, modA2 ON status, resulted in increased sensitivity to oxidative stress. Furthermore, the modA2 ON status resulted in decreased resistance to neutrophil-mediated killing, which resulted in selection for the modA2 OFF subpopulation in an ex vivo survival assay. These findings highlight the importance of the ModA2 phasevarion in adaptation to innate host defences and reveal an additional microenvironmental pressure that selected for a specific ModA2 subpopulation.
无乳链球菌（NTHI）是多种呼吸道感染的病原体。包括 NTHI 在内的几种人类病原体具有一种新型遗传系统，称为相变异子，可介导染色体上许多基因的快速和可逆表达变化。这是通过编码 DNA 甲基转移酶的单个基因（modA）的相变异而发生的，导致两个表型明显不同的亚群，ON 和 OFF。NTHI 在其人类宿主的各种微环境中遇到许多压力，因为疾病从无症状鼻咽携带发展为显性疾病。这些压力包括氧化应激，它存在于整个呼吸道中。为了在人类鼻咽部和呼吸道中持续存在，NTHI 必须能够减轻氧化应激的毒性水平。在这里，我们表明 ModA2 的表达、modA2 ON 状态导致对氧化应激的敏感性增加。此外，modA2 ON 状态导致对中性粒细胞介导的杀伤的抵抗力降低，这导致在体外生存试验中选择 modA2 OFF 亚群。这些发现强调了 ModA2 相变异子在适应先天宿主防御中的重要性，并揭示了选择特定 ModA2 亚群的另一个微环境压力。
