CSP—A Model for In Vivo Presentation of Plasmodium berghei Sporozoite Antigens by Hepatocytes

Balam, Saidou; Romero, Jacqueline; Bongfen, Silayuv E.; Guillaume, Philippe; Corradin, Giampietro

doi:10.1371/journal.pone.0051875

Cited by 25 publications

(35 citation statements)

References 29 publications

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“…Some of these molecules are polarized toward the basolateral surface of the hepatocyte, thereby maximizing the potential for lymphocyte interaction and activation 15 . Furthermore, both in vitro and in vivo evidence indicates that hepatocytes can present antigen to naive T cells [35][36][37][38] . Electron microscopy has revealed that hepatocytes and naive T cells physically interact in an ICAM-1-dependent and MHC-dependent fashion 15 .…”

Section: Hepatocytesmentioning

confidence: 99%

Immune surveillance by the liver

2013

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Receiving both portal vein blood and arterial blood, the liver is an important and critical component in the defense against blood-borne infection. To accomplish this role, the liver contains numerous innate and adaptive immune cells that specialize in detection and capture of pathogens from the blood. Further, these immune cells participate in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes within the vasculature. Finally, this role in host defense must be tightly regulated to ensure that inappropriate immune responses are not raised against nonpathogenic exogenous blood-borne molecules, such as those derived from food. It is this balance between activation and tolerance that characterizes the liver as a frontline immunological organ.

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Section: Hepatocytesmentioning

confidence: 99%

Immune surveillance by the liver

2013

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“…CSP coats the sporozoite surface, is shed from the motile sporozoite (9), and is transported to the hepatocyte cytoplasm (10). CSP is a target of protective class I-dependent CTL responses (10)(11)(12). Depending on the mouse model, CSP can also elicit important CD4 + T-cell responses (13,14) and MHC class IIdependent IgG responses (15).…”

mentioning

confidence: 99%

“…Depending on the mouse model, CSP can also elicit important CD4 + T-cell responses (13,14) and MHC class IIdependent IgG responses (15). In some systems, large numbers of adoptively transferred CSP-specific T-cell clones or endogenously generated CTLs can protect mice against sporozoite challenge (8,12,14,16,17). However, it remains unclear whether CSP-specific CTLs in naïve subjects can be primed to achieve protection with existing vaccination approaches.…”

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confidence: 99%

A T-cell response to a liver-stagePlasmodiumantigen is not boosted by repeated sporozoite immunizations

Murphy

Kas²,

Stone³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Development of an antimalarial subunit vaccine inducing protective cytotoxic T lymphocyte (CTL)-mediated immunity could pave the way for malaria eradication. Experimental immunization with sporozoites induces this type of protective response, but the extremely large number of proteins expressed by Plasmodium parasites has so far prohibited the identification of sufficient discrete T-cell antigens to develop subunit vaccines that produce sterile immunity. Here, using mice singly immunized with Plasmodium yoelii sporozoites and high-throughput screening, we identified a unique CTL response against the parasite ribosomal L3 protein. Unlike CTL responses to the circumsporozoite protein (CSP), the population of L3-specific CTLs was not expanded by multiple sporozoite immunizations. CSP is abundant in the sporozoite itself, whereas L3 expression does not increase until the liver stage. The response induced by a single immunization with sporozoites reduces the parasite load in the liver so greatly during subsequent immunizations that L3-specific responses are only generated during the primary exposure. Functional L3-specific CTLs can, however, be expanded by heterologous prime-boost regimens. Thus, although repeat sporozoite immunization expands responses to preformed antigens like CSP that are present in the sporozoite itself, this immunization strategy may not expand CTLs targeting parasite proteins that are synthesized later. Heterologous strategies may be needed to increase CTL responses across the entire spectrum of Plasmodium liver-stage proteins.

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“…In support of the former notion, it has been proposed that hepatocytes only present antigens that are secreted into the cytoplasm after invasion or during cell traversal (29, 30). Recent genome-wide immune profiling approaches in the two murine models provided evidence for each of these propositions (22, 31).…”

Section: Introductionmentioning

confidence: 97%

Antigen Export during Liver Infection of the Malaria Parasite Augments Protective Immunity

Montagna

Beigier-Bompadre

Becker

et al. 2014

mBio

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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.

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CSP—A Model for In Vivo Presentation of Plasmodium berghei Sporozoite Antigens by Hepatocytes

Cited by 25 publications

References 29 publications

Immune surveillance by the liver

Immune surveillance by the liver

A T-cell response to a liver-stagePlasmodiumantigen is not boosted by repeated sporozoite immunizations

Antigen Export during Liver Infection of the Malaria Parasite Augments Protective Immunity

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