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Protective immunity differs between routes of administration of attenuated malaria parasites independent of parasite liver load.

ABSTRACT: In humans and murine models of malaria, intradermal immunization (ID-I) with genetically attenuated sporozoites that arrest in liver induces lower protective immunity than intravenous immunization (IV-I). It is unclear whether this difference is caused by fewer sporozoites migrating into the liver or by suboptimal hepatic and injection site-dependent immune responses. We therefore developed a Plasmodium yoelii immunization/boost/challenge model to examine parasite liver loads as well as hepatic and lymph node immune responses in protected and unprotected ID-I and IV-I animals. Despite introducing the same numbers of genetically attenuated parasites in the liver, ID-I resulted in lower sterile protection (53-68%) than IV-I (93-95%). Unprotected mice developed less sporozoite-specific CD8⁺ and CD4⁺ effector T-cell responses than protected mice. After immunization, ID-I mice showed more interleukin-10-producing B and T cells in livers and skin-draining lymph nodes, but fewer hepatic CD8 memory T cells and CD8⁺ dendritic cells compared to IV-I mice. Our results indicate that the lower protection efficacy obtained by intradermal sporozoite administration is not linked to low hepatic parasite numbers as presumed before, but correlates with a shift towards regulatory immune responses. Overcoming these immune suppressive responses is important not only for live-attenuated malaria vaccines but also for other live vaccines administered in the skin.

SUBMITTER: Haeberlein S

PROVIDER: S-EPMC5583236 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Protective immunity differs between routes of administration of attenuated malaria parasites independent of parasite liver load.

Haeberlein Simone S Chevalley-Maurel Séverine S Ozir-Fazalalikhan Arifa A Koppejan Hester H Winkel Beatrice M F BMF Ramesar Jai J Khan Shahid M SM Sauerwein Robert W RW Roestenberg Meta M Janse Chris J CJ Smits Hermelijn H HH Franke-Fayard Blandine B

Scientific reports 20170904 1

In humans and murine models of malaria, intradermal immunization (ID-I) with genetically attenuated sporozoites that arrest in liver induces lower protective immunity than intravenous immunization (IV-I). It is unclear whether this difference is caused by fewer sporozoites migrating into the liver or by suboptimal hepatic and injection site-dependent immune responses. We therefore developed a Plasmodium yoelii immunization/boost/challenge model to examine parasite liver loads as well as hepatic ...[more]

PMID: 28871201

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Project description:Protective immunity against preerythrocytic malaria parasite infection is difficult to achieve. Intracellular Plasmodium parasites likely minimize antigen presentation by surface-expressed major histocompatibility complex class I (MHC-I) molecules on infected cells, yet they actively remodel their host cells by export of parasite factors. Whether exported liver-stage proteins constitute better candidates for MHC-I antigen presentation to CD8(+) T lymphocytes remains unknown. Here, we systematically characterized the contribution of protein export to the magnitude of antigen-specific T-cell responses against Plasmodium berghei liver-stage parasites in C57BL/6 mice. We generated transgenic sporozoites that secrete a truncated ovalbumin (OVA) surrogate antigen only in the presence of an amino-terminal protein export element. Immunization with live attenuated transgenic sporozoites revealed that antigen export was not critical for CD8(+) T-cell priming but enhanced CD8(+) T-cell proliferation in the liver. Upon transfer of antigen-specific CD8(+) T cells, liver-stage parasites secreting the target protein were eliminated more efficiently. We conclude that Plasmodium parasites strictly control protein export during liver infection to minimize immune recognition. Strategies that enhance the discharge of parasite proteins into infected hepatocytes could improve the efficacy of candidate preerythrocytic malaria vaccines. Importance: Vaccine development against Plasmodium parasites remains a priority in malaria research. The most advanced malaria subunit vaccine candidates contain Plasmodium surface proteins with important roles for parasite vital functions. A fundamental question is whether recognition by effector CD8(+) T cells is restricted to sporozoite surface antigens or extends to parasite proteins that are synthesized during the extensive parasite expansion phase in the liver. Using a surrogate model antigen, we found that a cytoplasmic antigen is able to induce robust protective CD8(+) T-cell responses, but protein export further enhances immunogenicity and protection. Our results show that a cytoplasmic localization does not exclude a protein's candidacy for malaria subunit vaccines and that protein secretion can enhance protective immunity.

Dataset Information

Protective immunity differs between routes of administration of attenuated malaria parasites independent of parasite liver load.

Publications

Protective immunity differs between routes of administration of attenuated malaria parasites independent of parasite liver load.

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