Adenylyl cyclase alpha and cAMP signaling mediate Plasmodium sporozoite apical regulated exocytosis and hepatocyte infection.
Adenylyl cyclase alpha and cAMP signaling mediate Plasmodium sporozoite apical regulated exocytosis and hepatocyte infection.
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DOI：
10.1371/journal.ppat.1000008
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发表时间：
2008-02-29
期刊：
影响因子：
6.7
通讯作者：
Rodriguez A
中科院分区：
文献类型：
--
作者：
Ono T;Cabrita-Santos L;Leitao R;Bettiol E;Purcell LA;Diaz-Pulido O;Andrews LB;Tadakuma T;Bhanot P;Mota MM;Rodriguez A
Malaria starts with the infection of the liver of the host by Plasmodium sporozoites, the parasite form transmitted by infected mosquitoes. Sporozoites migrate through several hepatocytes by breaching their plasma membranes before finally infecting one with the formation of an internalization vacuole. Migration through host cells induces apical regulated exocytosis in sporozoites. Here we show that apical regulated exocytosis is induced by increases in cAMP in sporozoites of rodent (P. yoelii and P. berghei) and human (P. falciparum) Plasmodium species. We have generated P. berghei parasites deficient in adenylyl cyclase α (ACα), a gene containing regions with high homology to adenylyl cyclases. PbACα-deficient sporozoites do not exocytose in response to migration through host cells and present more than 50% impaired hepatocyte infectivity in vivo. These effects are specific to ACα, as re-introduction of ACα in deficient parasites resulted in complete recovery of exocytosis and infection. Our findings indicate that ACα and increases in cAMP levels are required for sporozoite apical regulated exocytosis, which is involved in sporozoite infection of hepatocytes. Malaria is transmitted through the bite of an infected mosquito that deposits Plasmodium sporozoites under the skin. These sporozoites migrate from the skin into the circulation and then enter the liver to start a new infection inside hepatocytes. Sporozoites have the capacity to traverse mammalian cells. They breach their membranes and migrate through their cytosol. This process is required for infection of the liver and triggers the exposure of adhesive proteins in the apical end of sporozoites, a process that facilitates invasion of hepatocytes. We found that elevations of cAMP inside sporozoites mediate the exposure of adhesive proteins and therefore the infection process. Mutant sporozoites that do not express adenylyl cyclase, the enzyme that synthesizes cAMP, are not able to expose the adhesive proteins and their infectivity is reduced by half. Reinsertion of adenylyl cyclase gene in the mutant sporozoites recovers their capacity to expose adhesive proteins and to infect hepatocytes, confirming the specific role of this protein in infection. These results demonstrate the importance of cAMP and the exposure of adhesive proteins in sporozoites, but also show that Plasmodium sporozoites have other mechanisms to invade host hepatocytes that are not inhibited in the mutant parasites.
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影响因子：
3.1
作者：
Gantt, S;Persson, C;Nussenzweig, V
通讯作者：
Nussenzweig, V
影响因子：
1.5
作者：
de Koning-Ward, TF;Fidock, DA;Janse, CJ
通讯作者：
Janse, CJ
影响因子：
7.8
作者：
Beraldo, Flavio H;Almeida, Fabiana M;da Silva, Aline M;Garcia, Celia R S
通讯作者：
Garcia, Celia R S
影响因子：
6.7
作者：
Huynh MH;Carruthers VB
通讯作者：
Carruthers VB
影响因子：
3.1
作者：
Charoenvit, Y;Fallarme, V;Hoffman, SL
通讯作者：
Hoffman, SL