Department of Microbiology, University of California Davis, Davis, California, United States of America.
PLoS Pathog. 2011 Aug;7(8):e1002167. doi: 10.1371/journal.ppat.1002167. Epub 2011 Aug 4.
Giardia trophozoites attach to the intestinal microvilli (or inert surfaces) using an undefined "suction-based" mechanism, and remain attached during cell division to avoid peristalsis. Flagellar motility is a key factor in Giardia's pathogenesis and colonization of the host small intestine. Specifically, the beating of the ventral flagella, one of four pairs of motile flagella, has been proposed to generate a hydrodynamic force that results in suction-based attachment via the adjacent ventral disc. We aimed to test this prevailing "hydrodynamic model" of attachment mediated by flagellar motility. We defined four distinct stages of attachment by assessing surface contacts of the trophozoite with the substrate during attachment using TIRF microscopy (TIRFM). The lateral crest of the ventral disc forms a continuous perimeter seal with the substrate, a cytological indication that trophozoites are fully attached. Using trophozoites with two types of molecularly engineered defects in flagellar beating, we determined that neither ventral flagellar beating, nor any flagellar beating, is necessary for the maintenance of attachment. Following a morpholino-based knockdown of PF16, a central pair protein, both the beating and morphology of flagella were defective, but trophozoites could still initiate proper surface contacts as seen using TIRFM and could maintain attachment in several biophysical assays. Trophozoites with impaired motility were able to attach as well as motile cells. We also generated a strain with defects in the ventral flagellar waveform by overexpressing a dominant negative form of alpha2-annexin::GFP (D122A, D275A). This dominant negative alpha2-annexin strain could initiate attachment and had only a slight decrease in the ability to withstand normal and shear forces. The time needed for attachment did increase in trophozoites with overall defective flagellar beating, however. Thus while not directly required for attachment, flagellar motility is important for positioning and orienting trophozoites prior to attachment. Drugs affecting flagellar motility may result in lower levels of attachment by indirectly limiting the number of parasites that can position the ventral disc properly against a surface and against peristaltic flow.
贾第鞭毛虫滋养体使用一种未定义的“基于吸力”的机制附着在肠微绒毛(或惰性表面)上,并在细胞分裂过程中保持附着,以避免蠕动。鞭毛运动是贾第鞭毛虫发病机制和宿主小肠定植的关键因素。具体来说,四个运动鞭毛中的一对腹面鞭毛的摆动已被提出产生一种水动力,通过相邻的腹面盘导致基于吸力的附着。我们旨在测试这种由鞭毛运动介导的附着的流行“流体动力学模型”。我们通过使用 TIRF 显微镜(TIRFM)在附着过程中评估滋养体与基质的表面接触,定义了附着的四个不同阶段。腹面盘的侧脊与基质形成连续的周边密封,这是滋养体完全附着的细胞学指征。使用两种分子工程化的鞭毛摆动缺陷型滋养体,我们确定腹面鞭毛的摆动,甚至任何鞭毛的摆动,对于维持附着都不是必需的。在基于 morpholino 的 PF16(中央对蛋白)敲低后,中央对蛋白的鞭毛的摆动和形态都有缺陷,但滋养体仍然可以通过 TIRFM 看到正确的表面接触,并可以在几种生物物理测定中保持附着。运动能力受损的滋养体能够附着,就像运动细胞一样。我们还通过过表达显性负形式的 alpha2-连接蛋白::GFP(D122A,D275A)产生了一种具有缺陷的腹面鞭毛波形的菌株。这种显性负 alpha2-连接蛋白菌株可以启动附着,并且仅略微降低了承受正常和剪切力的能力。然而,在总体鞭毛摆动缺陷的滋养体中,附着所需的时间确实增加了。因此,尽管鞭毛运动不是附着的直接必需条件,但它对于在附着之前定位和定向滋养体很重要。影响鞭毛运动的药物可能会通过间接限制能够正确将腹面盘定位在表面上并抵抗蠕动流的寄生虫数量来导致附着水平降低。