Knockout of the rodent malaria parasite chitinase PbCHT1 reduces infectivity to mosquitoes
Knockout of the rodent malaria parasite chitinase PbCHT1 reduces infectivity to mosquitoes
复制标题
DOI：
10.1128/iai.69.6.4041-4047.2001
复制
发表时间：
2001-06-01
影响因子：
3.1
通讯作者：
Sinden, RE
中科院分区：
文献类型：
--
作者：
Dessens, JT;Mendoza, J;Sinden, RE
在蚊子传播过程中，疟原虫必须穿过一种称为围营养基质（PM）的含几丁质的结构，该结构围绕着蚊子中肠中受感染的血粉。反过来，动动物产生多种几丁质酶活性，可能旨在破坏这种物理屏障，以允许动动物入侵中肠上皮。疟原虫几丁质酶活性是几丁质酶抑制剂异糖脒阻断人类和禽类疟疾传播的靶标。在这里，我们鉴定并表征了啮齿类疟原虫伯氏疟原虫的第一个几丁质酶基因。我们表明，该基因名为 PbCHT1，是禽类疟疾寄生虫鸡疟原虫 PgCHT1 的结构直系同源物，也是人类疟原虫 PfCHT1 的旁系同源物。疟疾寄生虫 恶性疟原虫，PbCHT1 的靶向破坏可将史氏按蚊中的寄生虫感染性降低高达 90%，在动合动物饲料中也观察到感染性降低（这是一种在 PM 形成之前发生中肠入侵的人为情况），这表明 PbCHT1 除了破坏 PM 之外还发挥着其他作用。 PbCHT1无效突变体在体外没有残留的动合子衍生的几丁质酶活性；表明 P. berghei ookinetes 仅表达一种几丁质酶基因。此外，PbCHT1 活性似乎对异糖脒抑制不敏感，这一观察结果引发了关于使用别糖脒及其类似成分作为潜在的疟疾传播阻断药物的问题。总而言之，这些发现表明啮齿动物、鸟类和人类疟疾寄生虫几丁质酶之间存在根本差异，这对疟原虫-蚊子相互作用的进化具有影响。
During mosquito transmission, malaria ookinetes must cross a chitin-containing structure known as the peritrophic matrix (PM), which surrounds the infected blood meal in the mosquito midgut. In turn, ookinetes produce multiple chitinase activities presumably aimed at disrupting this physical barrier to allow ookinete invasion of the midgut epithelium. Plasmodium chitinase activities are demonstrated targets for human and avian malaria transmission blockade with the chitinase inhibitor allosamidin, Here, we identify and characterize the first chitinase gene of a rodent malaria parasite, Plasmodium berghei, We show that the gene, named PbCHT1, is a structural ortholog of PgCHT1 of the avian malaria parasite Plasmodium gallinaceum and a paralog of PfCHT1 of the human malaria parasite Plasmodium falciparum, Targeted disruption of PbCHT1 reduced parasite infectivity in Anopheles stephensi mosquitoes by up to 90%, Reductions in infectivity were also observed in ookinete feeds-an artificial situation where midgut invasion occurs before PM formation-suggesting that PbCHT1 plays a role other than PM disruption. PbCHT1 null mutants had no residual ookinete-derived chitinase activity in vitro; suggesting that P. berghei ookinetes express only one chitinase gene. Moreover, PbCHT1 activity appeared insensitive to allosamidin inhibition, an observation that raises questions about the use of allosamidin and components like it as potential malaria transmission-blocking drugs. Taken together, these findings suggest a fundamental divergence among rodent, avian, and human malaria parasite chitinases, with implications for the evolution of Plasmodium-mosquito interactions.