Department of Internal Medicine, Division of Infectious Diseases University of Texas Medical School at Houston, Houston, TX 77030, USA.
Clin Infect Dis. 2011 Jun;52(11):1332-41. doi: 10.1093/cid/cir228.
Under normal conditions, the expression of CD14, which is the principal receptor for bacterial lipopolysaccharide, is down-regulated in the intestinal mucosa but increases in response to inflammatory stimuli. The aim of the present study was to investigate whether fecal CD14 levels increased in response to infection with diarrheagenic Escherichia coli and whether single nucleotide polymorphisms (SNPs) in the CD14 gene were associated with an increased susceptibility to traveler's diarrhea (TD) in US visitors to Mexico.
Six SNPs located at the promoter, exon, and untranslated regions of CD14 were typed in a prospective cohort study of 1360 visitors to Mexico at risk for TD. Stools from visitors with TD were studied for enteric pathogens by culture, colony hybridization, and polymerase chain reaction. Fecal soluble CD14 (sCD14) was measured in a subgroup of 203 adults with diarrhea and 66 healthy controls by enzyme-linked immunosorbent assay.
The minor allele frequencies for CD14 SNPs were significantly different among the various racial and ethnic groups studied. Two SNPs in the promoter region of CD14 (-159 C > T; rs2569190 and -4191 C > T; rs5744441) were found to be associated with TD in White visitors. The -159 TT genotype was associated with a higher risk for TD (Relative risk [RR], 1.21; 95% confidence interval [CI], 1.05-1.38; P = .008), whereas individuals with the -4191 TT genotype were protected from infection (RR, 0.82; 95% CI, 0.71-0.92; P = .006). Subjects with TD excreted higher levels of fecal CD14 than did healthy controls (33,480 pg/mL vs 6178 pg/mL; P < .02). Fecal sCD14 levels were higher in stool samples from visitors with TD and the -159 TT genotype than they were in visitors with the CC/CT genotypes (P = .02), and stool samples from subjects with the -4191 CC genotype had higher fecal sCD14 levels than did stool samples from visitors with the CT/TT (P = .005) genotype. In a multivariate analysis with haplotypes constructed with the 6 SNPs studied, subjects with the haplotype containing the -159 C and the -4191 T allele were less likely to acquire TD (P = .015).
Our study suggests that CD14 levels increase in response to bacterial diarrhea and that polymorphisms in the CD14 gene influence susceptibility to TD. Intestinal CD14 plays an important role in the innate immune response to enteric pathogens.
在正常情况下，肠道黏膜中 CD14 的表达（CD14 是细菌脂多糖的主要受体）受到下调，但在炎症刺激下会增加。本研究旨在探讨腹泻性大肠埃希菌感染是否会导致粪便 CD14 水平升高，以及 CD14 基因中的单核苷酸多态性（SNP）是否与美国旅行者腹泻（TD）的易感性增加有关。
在一项对 1360 名前往墨西哥的有 TD 风险的游客进行的前瞻性队列研究中，对位于 CD14 启动子、外显子和非翻译区的 6 个 SNP 进行了分型。通过培养、菌落杂交和聚合酶链反应对 TD 患者的粪便进行肠道病原体检测。通过酶联免疫吸附试验（ELISA）测量 203 名腹泻成人和 66 名健康对照者粪便可溶性 CD14（sCD14）。
在所研究的不同种族和民族群体中，CD14 SNP 的次要等位基因频率存在显著差异。CD14 启动子区域的两个 SNP（-159 C > T；rs2569190 和 -4191 C > T；rs5744441）与白人游客的 TD 相关。-159 TT 基因型与 TD 风险增加相关（相对风险 [RR]，1.21；95%置信区间 [CI]，1.05-1.38；P =.008），而 -4191 TT 基因型则可预防感染（RR，0.82；95% CI，0.71-0.92；P =.006）。TD 患者粪便中 CD14 的含量高于健康对照者（33480 pg/mL 比 6178 pg/mL；P <.02）。TD 患者粪便中 sCD14 水平高于携带 -159 TT 基因型的患者（P =.02），而携带 -4191 CC 基因型的患者粪便中 sCD14 水平高于携带 CT/TT 基因型的患者（P =.005）。在包含所研究的 6 个 SNP 的单体型构建的多变量分析中，携带包含 -159 C 和 -4191 T 等位基因的单体型的患者不太可能感染 TD（P =.015）。
我们的研究表明，细菌腹泻会导致 CD14 水平升高，而 CD14 基因中的多态性会影响 TD 的易感性。肠道 CD14 在肠道病原体的固有免疫反应中起着重要作用。
