The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has b...The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has been reported to alter overall cellular metabolism, there is little known about the consequences of extended exposure to the toxin. Here, we describe studies to address this gap in knowledge, which have revealed that mitochondrial dysfunction and fragmentation are followed by a time-dependent recovery of mitochondrial structure, mitochondrial transmembrane potential, and cellular ATP levels. Cells exposed to VacA also initially demonstrated a reduction in oxidative phosphorylation, as well as increase in compensatory aerobic glycolysis. These metabolic alterations were reversed in cells with limited toxin exposure, congruent with the recovery of mitochondrial transmembrane potential and the absence of cytochrome c release from the mitochondria. Taken together, these results are consistent with a model that mitochondrial structure and function are restored in VacA-intoxicated cells.展开更多
目的:观察黄芪含药血清能否有效抑制体外幽门螺杆菌(hel i cobact er pyl ori,Hp)空泡毒素(VacA)的活性,从而探讨其抗菌机制。方法:将HP菌株培养上清液制成粗制VacA蛋白,经倍比稀释后(1∶32～1∶1),选择1∶2滴度与不同浓度黄芪含药血清...目的:观察黄芪含药血清能否有效抑制体外幽门螺杆菌(hel i cobact er pyl ori,Hp)空泡毒素(VacA)的活性,从而探讨其抗菌机制。方法:将HP菌株培养上清液制成粗制VacA蛋白,经倍比稀释后(1∶32～1∶1),选择1∶2滴度与不同浓度黄芪含药血清共同作用于胃癌SGC-7901细胞,观察胃癌细胞形态变化,采用中性红摄入法(NRU)评价空泡活性。结果:黄芪含药血清对VacA活性有显著抑制作用,含药血清小剂量组NRU检测其空泡活性A550=0.228±0.029,显微镜下计数空泡形成率为78.75%±8.539%,与阴性对照组比较差异有显著性(P<0.05),随血清含药浓度的增加A550和空泡形成率逐渐降低;含药血清大剂量组A550=0.127±0.047,空泡形成率为32.25%±10.21%,与阴性对照组比较差异有极显著性(P<0.01),与阳性对照奥美拉唑组比较差异无显著性(P>0.05);含药血清大剂量组与中剂量组A550比较,差异无显著性(P>0.05),与小剂量组比较差异有显著性(P<0.05),可见黄芪含药血清对空泡毒素的抑制作用具有浓度依赖性。结论:黄芪对HP VacA活性具有明显的抑制作用,且该抑制作用具有一定的浓度依赖性。展开更多
AIM: To better understand the pathogenic role of Helicobacter pylori (H. pylori) in pre-eclampsia (PE), and whether it is associated or not with fetal growth retardation (FGR). METHODS: Maternal blood samples were col...AIM: To better understand the pathogenic role of Helicobacter pylori (H. pylori) in pre-eclampsia (PE), and whether it is associated or not with fetal growth retardation (FGR). METHODS: Maternal blood samples were collected from 62 consecutive pregnant women with a diagnosis of PE and/or FGR, and from 49 women with uneventful pregnancies (controls). Serum samples were evaluated by immunoblot assay for presence of specific antibodies against H. pylori antigens [virulence: cytotoxin-associated antigen A (CagA); ureases; heat shock protein B; flagellin A; persistence: vacuolating cytotoxin A (VacA)]. Maternal complete blood count and liver enzymes levels were assessed at delivery by an automated analyzer. RESULTS: A significantly higher percentage of H. pyloriseropositive women were found among PE cases (85.7%) compared to controls (42.9%, P < 0.001). There were no differences between pregnancies complicated by FGR without maternal hypertension (46.2%) and controls. Importantly, persistent and virulent infections (VacA/ CagA seropositive patients, intermediate leukocyte blood count and aspartate aminotransferase levels) were exclusively associated with pre-eclampsia complicated by FGR, while virulent but acute infections (CagA positive/ VacA negative patients, highest leukocyte blood count and aspartate aminotransferase levels) specifically correlated with PE without FGR. CONCLUSION: Our data strongly indicate that persistent and virulent H. pylori infections cause or contribute to PE complicated by FGR, but not to PE without feto-placental compromise.展开更多
Helicobacter pylori(H. pylori) is perhaps the most ubiquitous and successful human pathogen, since it colonizes the stomach of more than half of humankind. Infection with this bacterium is commonly acquired during chi...Helicobacter pylori(H. pylori) is perhaps the most ubiquitous and successful human pathogen, since it colonizes the stomach of more than half of humankind. Infection with this bacterium is commonly acquired during childhood. Once infected, people carry the bacteria for decades or even for life, if not treated. Persistent infection with this pathogen causes gastritis, peptic ulcer disease and is also strongly associated with the development of gastric cancer. Despite induction of innate and adaptive immune responses in the infected individual, the host is unable to clear the bacteria. One widely accepted hallmark of H. pylori is that it successfully and stealthily evades host defense mechanisms. Though the gastric mucosa is well protected against infection, H. pylori is able to reside under the mucus, attach to gastric epithelial cells and cause persistent infection by evading immune responses mediated by host. In this review, we discuss how H. pylori avoids innate and acquired immune response elements, uses gastric epithelial cells as mediators to manipulate host T cell responses and uses virulence factors to avoid adaptive immune responses by T cells to establish a persistent infection. We also discuss in this review how the genetic diversity of this pathogen helps for its survival.展开更多
文摘The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has been reported to alter overall cellular metabolism, there is little known about the consequences of extended exposure to the toxin. Here, we describe studies to address this gap in knowledge, which have revealed that mitochondrial dysfunction and fragmentation are followed by a time-dependent recovery of mitochondrial structure, mitochondrial transmembrane potential, and cellular ATP levels. Cells exposed to VacA also initially demonstrated a reduction in oxidative phosphorylation, as well as increase in compensatory aerobic glycolysis. These metabolic alterations were reversed in cells with limited toxin exposure, congruent with the recovery of mitochondrial transmembrane potential and the absence of cytochrome c release from the mitochondria. Taken together, these results are consistent with a model that mitochondrial structure and function are restored in VacA-intoxicated cells.
文摘目的:观察黄芪含药血清能否有效抑制体外幽门螺杆菌(hel i cobact er pyl ori,Hp)空泡毒素(VacA)的活性,从而探讨其抗菌机制。方法:将HP菌株培养上清液制成粗制VacA蛋白,经倍比稀释后(1∶32～1∶1),选择1∶2滴度与不同浓度黄芪含药血清共同作用于胃癌SGC-7901细胞,观察胃癌细胞形态变化,采用中性红摄入法(NRU)评价空泡活性。结果:黄芪含药血清对VacA活性有显著抑制作用,含药血清小剂量组NRU检测其空泡活性A550=0.228±0.029,显微镜下计数空泡形成率为78.75%±8.539%,与阴性对照组比较差异有显著性(P<0.05),随血清含药浓度的增加A550和空泡形成率逐渐降低;含药血清大剂量组A550=0.127±0.047,空泡形成率为32.25%±10.21%,与阴性对照组比较差异有极显著性(P<0.01),与阳性对照奥美拉唑组比较差异无显著性(P>0.05);含药血清大剂量组与中剂量组A550比较,差异无显著性(P>0.05),与小剂量组比较差异有显著性(P<0.05),可见黄芪含药血清对空泡毒素的抑制作用具有浓度依赖性。结论:黄芪对HP VacA活性具有明显的抑制作用,且该抑制作用具有一定的浓度依赖性。
基金Supported by The Italian Ministry of Health, Programma per la Ricerca Sanitaria 2007, Programma Strategico, Salute della donna/Area materno infantile, No. RFPS-2007-4-638281
文摘AIM: To better understand the pathogenic role of Helicobacter pylori (H. pylori) in pre-eclampsia (PE), and whether it is associated or not with fetal growth retardation (FGR). METHODS: Maternal blood samples were collected from 62 consecutive pregnant women with a diagnosis of PE and/or FGR, and from 49 women with uneventful pregnancies (controls). Serum samples were evaluated by immunoblot assay for presence of specific antibodies against H. pylori antigens [virulence: cytotoxin-associated antigen A (CagA); ureases; heat shock protein B; flagellin A; persistence: vacuolating cytotoxin A (VacA)]. Maternal complete blood count and liver enzymes levels were assessed at delivery by an automated analyzer. RESULTS: A significantly higher percentage of H. pyloriseropositive women were found among PE cases (85.7%) compared to controls (42.9%, P < 0.001). There were no differences between pregnancies complicated by FGR without maternal hypertension (46.2%) and controls. Importantly, persistent and virulent infections (VacA/ CagA seropositive patients, intermediate leukocyte blood count and aspartate aminotransferase levels) were exclusively associated with pre-eclampsia complicated by FGR, while virulent but acute infections (CagA positive/ VacA negative patients, highest leukocyte blood count and aspartate aminotransferase levels) specifically correlated with PE without FGR. CONCLUSION: Our data strongly indicate that persistent and virulent H. pylori infections cause or contribute to PE complicated by FGR, but not to PE without feto-placental compromise.
基金Supported by National Institutes of Health grants K22AI68712,R56DK090090-01American Gastroenterological Association Research Scholar Award,NIH 1U54RR02614+3 种基金The University of Texas Medical Branch Clinical and Translational Sciences AwardThe American cancer society RSG-10-159-01-LIB,NIH 8UL1TR000041The University of New Mexico clinical and Translational Science CenterTaslima T Lina is funded by Sealy Centre for Vaccine Development Pre-doctoral fellowship and McLaughlin Pre-doctoral Fellowship,UTMB
文摘Helicobacter pylori(H. pylori) is perhaps the most ubiquitous and successful human pathogen, since it colonizes the stomach of more than half of humankind. Infection with this bacterium is commonly acquired during childhood. Once infected, people carry the bacteria for decades or even for life, if not treated. Persistent infection with this pathogen causes gastritis, peptic ulcer disease and is also strongly associated with the development of gastric cancer. Despite induction of innate and adaptive immune responses in the infected individual, the host is unable to clear the bacteria. One widely accepted hallmark of H. pylori is that it successfully and stealthily evades host defense mechanisms. Though the gastric mucosa is well protected against infection, H. pylori is able to reside under the mucus, attach to gastric epithelial cells and cause persistent infection by evading immune responses mediated by host. In this review, we discuss how H. pylori avoids innate and acquired immune response elements, uses gastric epithelial cells as mediators to manipulate host T cell responses and uses virulence factors to avoid adaptive immune responses by T cells to establish a persistent infection. We also discuss in this review how the genetic diversity of this pathogen helps for its survival.
