Hypersusceptibility of cystic fibrosis mice to chronic Pseudomonas aeruginosa oropharyngeal colonization and lung infection
Hypersusceptibility of cystic fibrosis mice to chronic Pseudomonas aeruginosa oropharyngeal colonization and lung infection
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DOI：
10.1073/pnas.0437901100
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发表时间：
2003-02-18
影响因子：
11.1
通讯作者：
Pier, GB
中科院分区：
文献类型：
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作者：
Coleman, FT;Mueschenborn, S;Pier, GB
迄今为止，尚未开发出能够模拟人类慢性绿脓杆菌肺部感染CF主要临床表型的转基因囊性纤维化（CF）小鼠模型。在转基因CF跨膜传导调节因子（cftr）小鼠群体中，我们发现当饮用水中存在环境中的铜绿假单胞菌时，饲养在同一笼中的WT、杂合和纯合CF小鼠在口咽部长期定殖。从饮用水中消除铜绿假单胞菌导致大多数WT和CF杂合子小鼠的清除，但纯合子小鼠没有。对于实验评价，特定动物饲养技术和经口感染途径的组合显示cftr（-/-）小鼠而不是WT小鼠可以被铜绿假单胞菌长期定殖，随后发生肺移位，产生指示慢性肺部感染的病理学图片。在某些情况下，从肺中回收铜绿假单胞菌的粘液样分离株，表明存在转化为粘液样的条件。WT小鼠肺中人CFTR的过表达显著加速了铜绿假单胞菌的清除速率，表明肺CFTR水平在防御感染中起重要作用。不能表达表面多糖藻酸盐或全局调节剂GacA的铜绿假单胞菌突变体在小鼠中定殖的能力不足。CIF小鼠对铜绿假单胞菌外膜抗原产生了强有力的免疫应答。总之，我们发现在适当的条件下，转基因CF小鼠对铜绿假单胞菌定植和感染高度敏感，可用于评估肺病理生理学、细菌毒力和开发旨在治疗CF肺病的疗法。
No transgenic cystic fibrosis (CF) mouse model developed to date mimics the major clinical phenotype found in humans with CF, chronic Pseudomonas aeruginosa lung infection. in a transgenic CF transmembrane conductance regulator (cftr) mouse colony, we found WT, heterozygous, and homozygous CF mice housed in the same cage became chronically colonized in the oropharynx with environmental A aeruginosa when the bacterium was present in drinking water. Elimination of A aeruginosa from drinking water resulted in clearance in most WT and CF heterozygous, but not homozygous mice. For experimental evaluation, a combination of specific animal husbandry techniques and an oral infection route showed cftr(-/-) mice but not WT mice can be chronically colonized by P. aeruginosa with subsequent lung translocation, yielding a pathologic picture indicative of chronic lung infection. In some instances, mucoid isolates of P. aeruginosa were recovered from lungs, indicating conditions were present for conversion to mucoidy. Overexpression of human CFTR in the lungs of WT mice markedly accelerated the clearance rate of P. aeruginosa, demonstrating that lung levels of CFTR play an important role in defense against infection. A aeruginosa mutants unable to express the surface polysaccharide alginate or the global regulator GacA were deficient in their ability to colonize the mice. CIF mice made potent immune responses to A aeruginosa outer membrane antigens. Overall, we found that under the proper conditions, transgenic CF mice are hypersusceptible to P. aeruginosa colonization and infection and can be used for evaluations of lung pathophysiology, bacterial virulence, and development of therapies aimed at treating CF lung disease.