Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural Universitygrid.412243.2, Harbin, Heilongjiang, China.
Infect Immun. 2022 Mar 17;90(3):e0067221. doi: 10.1128/iai.00672-21. Epub 2022 Feb 7.
The protozoan parasite Giardia duodenalis inhabits the upper small intestine of mammals, including humans, and causes a disease known as giardiasis, which can lead to diarrhea, abdominal cramps, and bloating. G. duodenalis was known as a causative factor of intestinal epithelial cell (IEC) apoptosis. Cyclooxygenase-2 (COX-2) has been identified as an influencing factor of pathogen infection by participating in immune response, while its role in host defense against infection is not clear. Here, we initially observed the involvement of COX-2 in the regulation of -induced IEC apoptosis. Inhibition of COX-2 activity could promote induced reduction of IEC viability, increase of reactive oxygen species (ROS) production, and decrease of nitric oxide (NO) release, which would exacerbate IEC apoptosis. In addition, during -IEC interactions, COX-2 inhibition was able to accelerate caspase-3 activation and poly(ADP-ribose) polymerase (PARP) cleavage and inhibit the expressions of some anti-apoptotic proteins like cIAP-2 and survivin. In contrast, COX-2 overexpression could reduce -induced IEC apoptosis. We further investigated the regulatory mechanisms affecting COX-2 expression in terms of anti-apoptosis. The results showed that p38/ERK/AKT/NF-κB signaling could regulate COX-2-mediated ROS/NO production and anti-IEC apoptosis during infection. We also found that COX-2-mediated anti-IEC apoptosis induced by was related to Toll-like receptor 4 (TLR4)-dependent activation of p38-NF-κB signaling. Collectively, this study identified COX-2 as a promoter for apoptotic resistance during -IEC interactions and determined the potential regulators, furthering our knowledge of anti- host defense mechanisms.
原虫寄生虫贾第鞭毛虫寄生于哺乳动物（包括人类）的上小肠，引起一种称为贾第虫病的疾病，可导致腹泻、腹痛和腹胀。已知 G. 十二指肠是肠上皮细胞 (IEC) 凋亡的致病因素。环氧化酶-2 (COX-2) 已被确定为通过参与免疫反应影响病原体感染的一个因素，而其在宿主防御感染方面的作用尚不清楚。在这里，我们最初观察到 COX-2 参与调节诱导的 IEC 凋亡。COX-2 活性的抑制可促进诱导的 IEC 活力降低、活性氧 (ROS) 产生增加和一氧化氮 (NO) 释放减少，从而加剧 IEC 凋亡。此外，在 -IEC 相互作用过程中，COX-2 抑制能够加速半胱天冬酶-3 的激活和多聚（ADP-核糖）聚合酶 (PARP) 的裂解，并抑制一些抗凋亡蛋白如 cIAP-2 和 survivin 的表达。相比之下，COX-2 的过表达可以减少诱导的 IEC 凋亡。我们进一步研究了影响抗凋亡 COX-2 表达的调节机制。结果表明，p38/ERK/AKT/NF-κB 信号通路可以调节感染过程中 COX-2 介导的 ROS/NO 产生和抗 IEC 凋亡。我们还发现，由诱导的 COX-2 介导的抗 IEC 凋亡与 TLR4 依赖性 p38-NF-κB 信号通路的激活有关。总的来说，这项研究确定了 COX-2 是在 -IEC 相互作用过程中促进凋亡抵抗的促进因子，并确定了潜在的调节因子，进一步了解了抗宿主防御机制。
