Department of Biological Sciences, University of Calgary, Calgary, AB, Canada Inflammation Research Network, University of Calgary, Calgary, AB, Canada Host-Parasite Interactions, University of Calgary, Calgary, AB, Canada.
Inflammation Research Network, University of Calgary, Calgary, AB, Canada Department of Medicine, University of Calgary, Calgary, AB, Canada.
Infect Immun. 2014 Jul;82(7):2772-87. doi: 10.1128/IAI.01771-14. Epub 2014 Apr 14.
Giardia duodenalis (syn. G. intestinalis, G. lamblia) infections are a leading cause of waterborne diarrheal disease that can also result in the development of postinfectious functional gastrointestinal disorders via mechanisms that remain unclear. Parasite numbers exceed 10(6) trophozoites per centimeter of gut at the height of an infection. Yet the intestinal mucosa of G. duodenalis-infected individuals is devoid of signs of overt inflammation. G. duodenalis infections can also occur concurrently with infections with other proinflammatory gastrointestinal pathogens. Little is known of whether and how this parasite can attenuate host inflammatory responses induced by other proinflammatory stimuli, such as a gastrointestinal pathogen. Identifying hitherto-unrecognized parasitic immunomodulatory pathways, the present studies demonstrated that G. duodenalis trophozoites attenuate secretion of the potent neutrophil chemoattractant interleukin-8 (CXCL8); these effects were observed in human small intestinal mucosal tissues and from intestinal epithelial monolayers, activated through administration of proinflammatory interleukin-1β or Salmonella enterica serovar Typhimurium. This attenuation is caused by the secretion of G. duodenalis cathepsin B cysteine proteases that degrade CXCL8 posttranscriptionally. Furthermore, the degradation of CXCL8 via G. duodenalis cathepsin B cysteine proteases attenuates CXCL8-induced chemotaxis of human neutrophils. Taken together, these data demonstrate for the first time that G. duodenalis trophozoite cathepsins are capable of attenuating a component of their host's proinflammatory response induced by a separate proinflammatory stimulus.
十二指肠贾第鞭毛虫（又名 G. 肠型、G. 兰伯氏鞭毛虫）感染是导致水源性腹泻病的主要原因，也可通过机制导致感染后功能性胃肠疾病。在感染高峰期，寄生虫数量超过每厘米肠道 10（6）个滋养体。然而，十二指肠贾第鞭毛虫感染个体的肠道黏膜没有明显炎症的迹象。十二指肠贾第鞭毛虫感染也可能与其他促炎胃肠道病原体同时发生。目前尚不清楚该寄生虫是否以及如何减轻宿主对其他促炎刺激物（如胃肠道病原体）引起的炎症反应。本研究旨在确定迄今为止尚未被识别的寄生虫免疫调节途径，结果表明十二指肠贾第鞭毛虫滋养体可减弱强效中性粒细胞趋化因子白细胞介素 8（CXCL8）的分泌；这些效应在人小肠黏膜组织和经促炎白细胞介素 1β或鼠伤寒沙门氏菌激活的肠上皮单层中观察到。这种减弱是由十二指肠贾第鞭毛虫组织蛋白酶 B 半胱氨酸蛋白酶分泌引起的，该蛋白酶可使 CXCL8 在转录后降解。此外，通过十二指肠贾第鞭毛虫组织蛋白酶 B 半胱氨酸蛋白酶降解 CXCL8 可减弱 CXCL8 诱导的人中性粒细胞趋化性。综上所述，这些数据首次表明，十二指肠贾第鞭毛虫滋养体组织蛋白酶能够减弱宿主对另一促炎刺激物诱导的促炎反应的一部分。
