Department of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, Maryland, USA.
Department of Molecular Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Infect Immun. 2020 Aug 19;88(9). doi: 10.1128/IAI.00237-20.
The opportunistic pathogen is responsible for much of the morbidity and mortality associated with cystic fibrosis (CF), a condition that predisposes patients to chronic lung infections. lung infections are difficult to treat because adapts to the CF lung, can develop multidrug resistance, and can form biofilms. Despite the clinical significance of , modeling infections in CF has been challenging. Here, we characterize -transgenic (Tg) BALB/c mice as lung infection models. -Tg mice overexpress the epithelial Na channel (ENaC) in their lungs, driving increased sodium absorption that causes lung pathology similar to CF. We intranasally infected -Tg mice and wild-type littermates with the laboratory strain PAO1 and CF clinical isolates and then assessed differences in bacterial clearance, cytokine responses, and histological features up to 12 days postinfection. -Tg mice carried higher bacterial burdens when infected with biofilm-grown rather than planktonic PAO1; -Tg mice also cleared infections more slowly than their wild-type littermates. Infection with PAO1 elicited significant increases in proinflammatory and Th17-linked cytokines on day 3. -Tg mice infected with nonmucoid early CF isolates maintained bacterial burdens and mounted immune responses similar to those of PAO1-infected -Tg mice. In contrast, -Tg mice infected with a mucoid CF isolate carried high bacterial burdens, produced significantly more interleukin 1β (IL-1β), IL-13, IL-17, IL-22, and KC, and showed severe immune cell infiltration into the bronchioles. Taken together, these results show the promise of -Tg mice as models of early colonization in the CF lung.
机会性病原体是导致囊性纤维化（CF）相关发病率和死亡率的主要原因，这种疾病使患者容易发生慢性肺部感染。肺部感染难以治疗，因为它可以适应 CF 肺部，可以产生多药耐药性，并可以形成生物膜。尽管机会性病原体具有临床意义，但在 CF 中模拟感染一直具有挑战性。在这里，我们将过表达上皮钠离子通道（ENaC）的 -Tg BALB/c 小鼠作为 CF 肺部感染模型。-Tg 小鼠的肺部过度表达 ENaC，导致钠吸收增加，引起类似于 CF 的肺部病理学。我们通过鼻腔感染 -Tg 小鼠和野生型同窝仔鼠，使用实验室菌株 PAO1 和 CF 临床分离株，然后评估感染后 12 天内细菌清除率、细胞因子反应和组织学特征的差异。与浮游 PAO1 相比，生物膜生长的 PAO1 感染 -Tg 小鼠时携带更高的细菌负荷；-Tg 小鼠的感染清除速度也比野生型同窝仔鼠慢。PAO1 感染引起第三天促炎和 Th17 相关细胞因子显著增加。感染非粘液性早期 CF 分离株的 -Tg 小鼠维持细菌负荷，并产生与 PAO1 感染的 -Tg 小鼠相似的免疫反应。相比之下，感染粘液性 CF 分离株的 -Tg 小鼠携带高细菌负荷，产生显著更多的白细胞介素 1β（IL-1β）、IL-13、IL-17、IL-22 和 KC，并显示严重的免疫细胞浸润到细支气管。总之，这些结果表明 -Tg 小鼠作为 CF 肺部早期定植的模型具有潜力。
