The ModA2 Phasevarion of nontypeable Haemophilus influenzae Regulates Resistance to Oxidative Stress and Killing by Human Neutrophils.
The ModA2 Phasevarion of nontypeable Haemophilus influenzae Regulates Resistance to Oxidative Stress and Killing by Human Neutrophils.
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DOI：
10.1038/s41598-017-03552-9
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发表时间：
2017-06-09
影响因子：
4.6
通讯作者：
Bakaletz LO
中科院分区：
文献类型：
--
作者：
Brockman KL;Branstool MT;Atack JM;Robledo-Avila F;Partida-Sanchez S;Jennings MP;Bakaletz LO
无法分型的流感嗜血杆菌（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拥有一种新的遗传系统，称为相位变异体，它介导整个染色体上许多基因表达的快速和可逆变化。这是通过编码DNA甲基转移酶的单个基因（modA）的相位变异发生的，并导致两个表型不同的亚群，ON和OFF。NTHI在其人类宿主的各种微环境中遇到许多压力，因为疾病过程从无症状的鼻咽携带演变为明显的疾病。这些包括氧化应激，它存在于整个呼吸道。为了在人鼻咽中持续存在并作为整个气道的病原体，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状态导致对嗜中性粒细胞介导的杀伤的抗性降低，这导致在离体存活测定中选择modA2 OFF亚群。这些发现强调了ModA2阶段变异在适应先天宿主防御中的重要性，并揭示了为特定ModA2亚群选择的额外微环境压力。
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.