Rhoptry neck protein 4 plays important roles during Plasmodium sporozoite infection of the mammalian liver
ABSTRACT During invasion, Plasmodium parasites secrete proteins from rhoptry and microneme apical end organelles, which have crucial roles in attaching to and invading target cells. A sporozoite stage-specific gene silencing system revealed that rhoptry neck protein 2 (RON2), RON4, and RON5 are impo...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-08-01
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| Series: | mSphere |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/msphere.00587-22 |
| _version_ | 1797730332400680960 |
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| author | Minami Baba Mamoru Nozaki Mayumi Tachibana Takafumi Tsuboi Motomi Torii Tomoko Ishino |
| author_facet | Minami Baba Mamoru Nozaki Mayumi Tachibana Takafumi Tsuboi Motomi Torii Tomoko Ishino |
| author_sort | Minami Baba |
| collection | DOAJ |
| description | ABSTRACT During invasion, Plasmodium parasites secrete proteins from rhoptry and microneme apical end organelles, which have crucial roles in attaching to and invading target cells. A sporozoite stage-specific gene silencing system revealed that rhoptry neck protein 2 (RON2), RON4, and RON5 are important for sporozoite invasion of mosquito salivary glands. Here, we further investigated the roles of RON4 during sporozoite infection of the liver in vivo. Following intravenous inoculation of RON4-knockdown sporozoites into mice, we demonstrated that sporozoite RON4 has multiple functions during sporozoite traversal of sinusoidal cells and infection of hepatocytes. In vitro infection experiments using a hepatoma cell line revealed that secreted RON4 is involved in sporozoite adhesion to hepatocytes and has an important role in the early steps of hepatocyte infection. In addition, in vitro motility assays indicated that RON4 is required for sporozoite attachment to the substrate and the onset of migration. These findings indicate that RON4 is crucial for sporozoite migration toward and invasion of hepatocytes via attachment ability and motility. IMPORTANCE Malarial parasite transmission to mammals is established when sporozoites are inoculated by mosquitoes and migrate through the bloodstream to infect hepatocytes. Many aspects of the molecular mechanisms underpinning migration and cellular invasion remain largely unelucidated. By applying a sporozoite stage-specific gene silencing system in the rodent malarial parasite, Plasmodium berghei, we demonstrated that rhoptry neck protein 4 (RON4) is crucial for sporozoite infection of the liver in vivo. Combined with in vitro investigations, it was revealed that RON4 functions during a crossing of the sinusoidal cell layer and invading hepatocytes, at an early stage of liver infection, by mediating the sporozoite capacity for adhesion and the onset of motility. Since RON4 is also expressed in Plasmodium merozoites and Toxoplasma tachyzoites, our findings contribute to understanding the conserved invasion mechanisms of Apicomplexa parasites. |
| first_indexed | 2024-03-12T11:42:46Z |
| format | Article |
| id | doaj.art-a309027566ce4609a22632b568bec990 |
| institution | Directory Open Access Journal |
| issn | 2379-5042 |
| language | English |
| last_indexed | 2024-03-12T11:42:46Z |
| publishDate | 2023-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSphere |
| spelling | doaj.art-a309027566ce4609a22632b568bec9902023-08-31T14:26:40ZengAmerican Society for MicrobiologymSphere2379-50422023-08-018410.1128/msphere.00587-22Rhoptry neck protein 4 plays important roles during Plasmodium sporozoite infection of the mammalian liverMinami Baba0Mamoru Nozaki1Mayumi Tachibana2Takafumi Tsuboi3Motomi Torii4Tomoko Ishino5Division of Molecular Parasitology, Proteo-Science Center, Ehime University , Toon, Ehime, JapanDivision of Molecular Parasitology, Proteo-Science Center, Ehime University , Toon, Ehime, JapanDivision of Molecular Parasitology, Proteo-Science Center, Ehime University , Toon, Ehime, JapanDivision of Malaria Research, Proteo-Science Center, Ehime University , Matsuyama, Ehime, JapanDivision of Molecular Parasitology, Proteo-Science Center, Ehime University , Toon, Ehime, JapanDivision of Molecular Parasitology, Proteo-Science Center, Ehime University , Toon, Ehime, JapanABSTRACT During invasion, Plasmodium parasites secrete proteins from rhoptry and microneme apical end organelles, which have crucial roles in attaching to and invading target cells. A sporozoite stage-specific gene silencing system revealed that rhoptry neck protein 2 (RON2), RON4, and RON5 are important for sporozoite invasion of mosquito salivary glands. Here, we further investigated the roles of RON4 during sporozoite infection of the liver in vivo. Following intravenous inoculation of RON4-knockdown sporozoites into mice, we demonstrated that sporozoite RON4 has multiple functions during sporozoite traversal of sinusoidal cells and infection of hepatocytes. In vitro infection experiments using a hepatoma cell line revealed that secreted RON4 is involved in sporozoite adhesion to hepatocytes and has an important role in the early steps of hepatocyte infection. In addition, in vitro motility assays indicated that RON4 is required for sporozoite attachment to the substrate and the onset of migration. These findings indicate that RON4 is crucial for sporozoite migration toward and invasion of hepatocytes via attachment ability and motility. IMPORTANCE Malarial parasite transmission to mammals is established when sporozoites are inoculated by mosquitoes and migrate through the bloodstream to infect hepatocytes. Many aspects of the molecular mechanisms underpinning migration and cellular invasion remain largely unelucidated. By applying a sporozoite stage-specific gene silencing system in the rodent malarial parasite, Plasmodium berghei, we demonstrated that rhoptry neck protein 4 (RON4) is crucial for sporozoite infection of the liver in vivo. Combined with in vitro investigations, it was revealed that RON4 functions during a crossing of the sinusoidal cell layer and invading hepatocytes, at an early stage of liver infection, by mediating the sporozoite capacity for adhesion and the onset of motility. Since RON4 is also expressed in Plasmodium merozoites and Toxoplasma tachyzoites, our findings contribute to understanding the conserved invasion mechanisms of Apicomplexa parasites.https://journals.asm.org/doi/10.1128/msphere.00587-22malariaPlasmodiumsporozoiterhoptryinvasion |
| spellingShingle | Minami Baba Mamoru Nozaki Mayumi Tachibana Takafumi Tsuboi Motomi Torii Tomoko Ishino Rhoptry neck protein 4 plays important roles during Plasmodium sporozoite infection of the mammalian liver mSphere malaria Plasmodium sporozoite rhoptry invasion |
| title | Rhoptry neck protein 4 plays important roles during Plasmodium sporozoite infection of the mammalian liver |
| title_full | Rhoptry neck protein 4 plays important roles during Plasmodium sporozoite infection of the mammalian liver |
| title_fullStr | Rhoptry neck protein 4 plays important roles during Plasmodium sporozoite infection of the mammalian liver |
| title_full_unstemmed | Rhoptry neck protein 4 plays important roles during Plasmodium sporozoite infection of the mammalian liver |
| title_short | Rhoptry neck protein 4 plays important roles during Plasmodium sporozoite infection of the mammalian liver |
| title_sort | rhoptry neck protein 4 plays important roles during plasmodium sporozoite infection of the mammalian liver |
| topic | malaria Plasmodium sporozoite rhoptry invasion |
| url | https://journals.asm.org/doi/10.1128/msphere.00587-22 |
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