Rolin Olivier, Muse Sarah J, Safi Chetan, Elahi Shokrollah, Gerdts Volker, Hittle Lauren E, Ernst Robert K, Harvill Eric T, Preston Andrew
Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA.
Infect Immun. 2014 Feb;82(2):491-9. doi: 10.1128/IAI.01260-12. Epub 2013 Oct 14.
Pathogen transmission cycles require many steps: initial colonization, growth and persistence, shedding, and transmission to new hosts. Alterations in the membrane components of the bacteria, including lipid A, the membrane anchor of lipopolysaccharide, could affect any of these steps via its structural role protecting bacteria from host innate immune defenses, including antimicrobial peptides and signaling through Toll-like receptor 4 (TLR4). To date, lipid A has been shown to affect only the within-host dynamics of infection, not the between-host dynamics of transmission. Here, we investigate the effects of lipid A modification in a mouse infection and transmission model. Disruption of the Bordetella bronchiseptica locus (BB4268) revealed that ArnT is required for addition of glucosamine (GlcN) to B. bronchiseptica lipid A. ArnT modification of lipid A did not change its TLR4 agonist activity in J774 cells, but deleting arnT decreased resistance to killing by cationic antimicrobial peptides, such as polymyxin B and β-defensins. In the standard infection model, mutation of arnT did not affect B. bronchiseptica colonization, growth, persistence throughout the respiratory tract, recruitment of neutrophils to the nasal cavity, or shedding of the pathogen. However, the number of bacteria necessary to colonize a host (50% infective dose [ID50]) was 5-fold higher for the arnT mutant. Furthermore, the arnT mutant was defective in transmission between hosts. These results reveal novel functions of the ArnT lipid A modification and highlight the sensitivity of low-dose infections and transmission experiments for illuminating aspects of infectious diseases between hosts. Factors such as ArnT can have important effects on the burden of disease and are potential targets for interventions that can interrupt transmission.
初始定植、生长与持续存在、脱落以及传播至新宿主。细菌膜成分的改变，包括脂多糖的膜锚定成分脂质A，可能通过其保护细菌免受宿主固有免疫防御（包括抗菌肽和通过Toll样受体4（TLR4）的信号传导）的结构作用，影响这些步骤中的任何一个。迄今为止，脂质A仅被证明会影响宿主内的感染动态，而非宿主间的传播动态。在此，我们在小鼠感染与传播模型中研究脂质A修饰的影响。支气管败血波氏杆菌位点（BB4268）的破坏表明，将氨基葡萄糖（GlcN）添加到支气管败血波氏杆菌脂质A中需要ArnT。脂质A的ArnT修饰并未改变其在J774细胞中的TLR4激动剂活性，但删除arnT会降低对阳离子抗菌肽（如多粘菌素B和β-防御素）杀伤的抗性。在标准感染模型中，arnT突变不影响支气管败血波氏杆菌的定植、生长、在整个呼吸道的持续存在、中性粒细胞向鼻腔的募集或病原体的脱落。然而，arnT突变体定植宿主所需的细菌数量（50%感染剂量[ID50]）比野生型高5倍。此外，arnT突变体在宿主间传播方面存在缺陷。这些结果揭示了ArnT脂质A修饰的新功能，并突出了低剂量感染和传播实验对于阐明宿主间传染病方面的敏感性。诸如ArnT等因素可能对疾病负担产生重要影响，并且是可中断传播的干预措施的潜在靶点。
