Eckmann L, Laurent F, Langford T D, Hetsko M L, Smith J R, Kagnoff M F, Gillin F D
Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
J Immunol. 2000 Feb 1;164(3):1478-87. doi: 10.4049/jimmunol.164.3.1478.
Giardia lamblia infection of the human small intestine is a common protozoan cause of diarrheal disease worldwide. Although infection is luminal and generally self-limiting, and secretory Abs are thought to be important in host defense, other defense mechanisms probably affect the duration of infection and the severity of symptoms. Because intestinal epithelial cells produce NO, and its stable end products, nitrite and nitrate, are detectable mainly on the apical side, we tested the hypothesis that NO production may constitute a host defense against G. lamblia. Several NO donors, but not their control compounds, inhibited giardial growth without affecting viability, suggesting that NO is cytostatic rather than cytotoxic for G. lamblia. NO donors also inhibited giardial differentiation induced by modeling crucial environmental factors, i. e., encystation induced by bile and alkaline pH, and excystation in response to gastric pH followed by alkaline pH and protease. Despite the potent antigiardial activity of NO, G. lamblia is not simply a passive target for host-produced NO, but has strategies to evade this potential host defense. Thus, in models of human intestinal epithelium, G. lamblia inhibited epithelial NO production by consuming arginine, the crucial substrate used by epithelial NO synthase to form NO. These studies define NO and arginine as central components in a novel cross-talk between a luminal pathogen and host intestinal epithelium.
人小肠的蓝氏贾第鞭毛虫感染是全球腹泻病常见的原生动物病因。尽管感染发生在管腔且通常为自限性，并且分泌性抗体被认为在宿主防御中很重要，但其他防御机制可能会影响感染持续时间和症状严重程度。由于肠道上皮细胞会产生一氧化氮（NO），且其稳定终产物亚硝酸盐和硝酸盐主要在顶端侧可检测到，我们检验了以下假说：NO的产生可能构成宿主对蓝氏贾第鞭毛虫的防御。几种NO供体而非其对照化合物可抑制贾第虫生长而不影响其活力，这表明NO对蓝氏贾第鞭毛虫具有细胞抑制作用而非细胞毒性作用。NO供体还可抑制由模拟关键环境因素诱导的贾第虫分化，即胆汁和碱性pH诱导的包囊化，以及对胃pH随后是碱性pH和蛋白酶作出反应的脱囊化。尽管NO具有强大的抗贾第虫活性，但蓝氏贾第鞭毛虫并非简单地是宿主产生的NO的被动靶标，而是有策略来规避这种潜在的宿主防御。因此，在人肠上皮模型中，蓝氏贾第鞭毛虫通过消耗精氨酸来抑制上皮细胞产生NO，精氨酸是上皮型NO合酶用于生成NO的关键底物。这些研究将NO和精氨酸定义为管腔病原体与宿主肠上皮之间新型相互作用中的核心成分。
