Non-typeable Haemophilus influenzae (NTHi) causes multiple diseases of the human airway and is a predominant bacterial pathogen of acute otitis media and otitis media in which treatment fails. NTHi utilizes a system of phase variable epigenetic regulation, termed the phasevarion, to facilitate adaptation and survival within multiple sites of the human host. The NTHi phasevarion influences numerous disease-relevant phenotypes such as biofilm formation, antibiotic resistance, and opsonization. We have previously identified an advantageous selection for a specific phasevarion status, which significantly affects severity and chronicity of experimental otitis media. In this study, we utilized pure cultures of NTHi variants in which modA was either locked ON or locked OFF, and thus modA was unable to phase vary. These locked variants were used to assess the progression of experimental otitis media and define the specific immune response induced by each subpopulation. Although the initial disease caused by each subpopulation was similar, the immune response elicited by each subpopulation was unique. The modA2 OFF variant induced significantly greater activation of macrophages both in vitro and within the middle ear during disease. In contrast, the modA2 ON variant induced a greater neutrophil extracellular trap response, which led to greater killing of the modA2 ON variant. These data suggest that not only does the NTHi phasevarion facilitate adaptation, but also allows the bacteria to alter immune responses during disease. Understanding these complex bacterial-host interactions and the regulation of bacterial factors responsible is critical to the development of better diagnostic, treatment, and preventative strategies for these bacterial pathogens.
中文翻译:
在不可分型的流感嗜血杆菌的细菌表观遗传开关修改中耳炎期间宿主免疫反应。
不可分类 嗜血杆菌流感(NTHi)引起人的呼吸道多种疾病,是急性中耳炎和中耳炎的主要细菌病原体,治疗失败。NTHi利用相变表观遗传调控系统(称为相变)来促进人类宿主多个部位的适应和生存。NTHi相变影响许多与疾病相关的表型,例如生物膜形成,抗生素抗性和调理作用。我们先前已经确定了针对特定相变状态的有利选择,该相变状态显着影响实验性中耳炎的严重性和慢性性。在这项研究中,我们利用了NTHi变体的纯培养物,其中模式 被锁定为ON或锁定为OFF,因此 模式无法阶段变化。这些锁定的变体用于评估实验性中耳炎的进展,并定义由每个亚群诱导的特异性免疫应答。尽管由每个亚群引起的初始疾病是相似的,但是由每个亚群引起的免疫反应是独特的。的modA2 OFF变体诱导巨噬细胞的活化明显增强 体外以及疾病期间中耳内部。相反,modA2 ON变体诱导更大的嗜中性白细胞胞外捕获反应,从而导致更大的杀伤力。 modA2ON变体。这些数据表明,NTHi相变不仅促进适应,而且还允许细菌在疾病期间改变免疫应答。了解这些复杂的细菌-宿主相互作用以及负责的细菌因子的调控对于开发更好的这些细菌病原体的诊断,治疗和预防策略至关重要。