Pier G B, Grout M, Zaidi T, Meluleni G, Mueschenborn S S, Banting G, Ratcliff R, Evans M J, Colledge W H
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature. 1998 May 7;393(6680):79-82. doi: 10.1038/30006.
Homozygous mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF). In the heterozygous state, increased resistance to infectious diseases may maintain mutant CFTR alleles at high levels in selected populations. Here we investigate whether typhoid fever could be one such disease. The disease is initiated when Salmonella typhi enters gastrointestinal epithelial cells for submucosal translocation. We found that S. typhi, but not the related murine pathogen S. typhimurium, uses CFTR for entry into epithelial cells. Cells expressing wild-type CFTR internalized more S. typhi than isogenic cells expressing the most common CFTR mutation, a phenylalanine deleted at residue 508 (delta508). Monoclonal antibodies and synthetic peptides containing a sequence corresponding to the first predicted extracellular domain of CFTR inhibited uptake of S. typhi. Heterozygous deltaF508 Cftr mice translocated 86% fewer S. typhi into the gastrointestinal submucosa than wild-type Cftr mice; no translocation occurred in deltaF508 Cftr homozygous mice. The Cftr genotype had no effect on the translocation of S. typhimurium. Immunoelectron microscopy revealed that more CFTR bound to S. typhi in the submucosa of Cftr wild-type mice than in deltaF508 heterozygous mice. We conclude that diminished levels of CFTR in heterozygotes may decrease susceptibility to typhoid fever.
囊性纤维化跨膜传导调节因子（CFTR）的纯合突变会导致囊性纤维化（CF）。在杂合状态下，对传染病抵抗力的增强可能会使突变的CFTR等位基因在特定人群中维持在较高水平。在此，我们研究伤寒是否可能是这类疾病之一。伤寒是由伤寒杆菌进入胃肠道上皮细胞进行黏膜下转移引发的。我们发现，伤寒杆菌而非相关的鼠病原体鼠伤寒杆菌利用CFTR进入上皮细胞。表达野生型CFTR的细胞内化的伤寒杆菌比表达最常见CFTR突变（第508位氨基酸残基苯丙氨酸缺失，即Δ508）的同基因细胞更多。含有与CFTR第一个预测细胞外结构域相对应序列的单克隆抗体和合成肽可抑制伤寒杆菌的摄取。杂合的ΔF508 Cftr小鼠向胃肠道黏膜下转移的伤寒杆菌比野生型Cftr小鼠少86%；在ΔF508 Cftr纯合小鼠中未发生转移。Cftr基因型对鼠伤寒杆菌的转移没有影响。免疫电子显微镜显示，与ΔF508杂合小鼠相比，Cftr野生型小鼠黏膜下与伤寒杆菌结合的CFTR更多。我们得出结论，杂合子中CFTR水平降低可能会降低对伤寒的易感性。
