Release of malaria circumsporozoite protein into the host cell cytoplasm and interaction with ribosomes

Hügel, Frank-Ulrich; Pradel, Gabriele; Frevert, Ute

doi:10.1016/0166-6851(96)02701-6

Cited by 42 publications

(51 citation statements)

References 55 publications

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“…After infection of human hepatoma cells with sporozoites, the parasites were found not to be localized in an acidified vacuole, and the released CSP did not enter the endocytic compartment of the host cell (48). In agreement with this, we found that CD8 ϩ T cell activation was not affected by chloroquine and NH 4 Cl, suggesting that an acidic compartment may not be involved in CSP processing.…”

Section: Discussionsupporting

confidence: 77%

“…The dependence of processing on the proteasome is consistent with studies which showed that sporozoites deposit the CSP in the cytoplasm of cells, beginning from the time of their attachment to the cell surface and peaking 4 -6 h after invasion (48). In addition, parasite Ags have also been shown to be inserted into the parasitophorous vacuole membrane and into the hepatocyte cytoplasm (49).…”

Section: Discussionsupporting

confidence: 69%

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Plasmodium berghei-Infected Primary Hepatocytes Process and Present the Circumsporozoite Protein to Specific CD8+ T Cells In Vitro

Bongfen

Torgler

Romero

et al. 2007

The Journal of Immunology

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A substantial and protective response against malaria liver stages is directed against the circumsporozoite protein (CSP) and involves induction of CD8+ T cells and production of IFN-γ. CSP-derived peptides have been shown to be presented on the surface of infected hepatocytes in the context of MHC class I molecules. However, little is known about how the CSP and other sporozoite Ags are processed and presented to CD8+ T cells. We investigated how primary hepatocytes from BALB/c mice process the CSP of Plasmodium berghei after live sporozoite infection and present CSP-derived peptides to specific H-2Kd-restricted CD8+ T cells in vitro. Using both wild-type and spect−/− P. berghei sporozoites, we show that both infected and traversed primary hepatocytes process and present the CSP. The processing and presentation pathway was found to involve the proteasome, Ag transport through a postendoplasmic reticulum compartment, and aspartic proteases. Thus, it can be hypothesized that infected hepatocytes can contribute in vivo to the elicitation and expansion of a T cell response.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 69%

Plasmodium berghei-Infected Primary Hepatocytes Process and Present the Circumsporozoite Protein to Specific CD8+ T Cells In Vitro

Bongfen

Torgler

Romero

et al. 2007

The Journal of Immunology

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“…In an infection model using recombinant Trypanosoma cruzi expressing an ovalbumin (OVA) epitope, it was shown that host cells were able to present OVA via the MHC-I pathway when the antigen was produced in secretory form but not the cytoplasmic or transmembrane form (22). It has also been proposed that CSP is released from the surface of sporozoites directly into the cytoplasm of host hepatocytes, where it binds to RNA-associated host cell targets (23,24). Furthermore, CSP is released from the surface of sporozoites when they travel through hepatocytes before reaching the final infected hepatocyte and appears to be presented by these traversed hepatocytes to specific T cells (25).…”

mentioning

confidence: 99%

CD8⁺T Cells Specific for a Malaria Cytoplasmic Antigen Form Clusters around Infected Hepatocytes and Are Protective at the Liver Stage of Infection

Kimura

Matsushima

et al. 2013

Infect Immun

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cFollowing Anopheles mosquito-mediated introduction into a human host, Plasmodium parasites infect hepatocytes and undergo intensive replication. Accumulating evidence indicates that CD8 ؉ T cells induced by immunization with attenuated Plasmodium sporozoites can confer sterile immunity at the liver stage of infection; however, the mechanisms underlying this protection are not clearly understood. To address this, we generated recombinant Plasmodium berghei ANKA expressing a fusion protein of an ovalbumin epitope and green fluorescent protein in the cytoplasm of the parasite. We have shown that the ovalbumin epitope is presented by infected liver cells in a manner dependent on a transporter associated with antigen processing and becomes a target of specific CD8؉ T cells from the T cell receptor transgenic mouse line OT-I, leading to protection at the liver stage of Plasmodium infection. We visualized the interaction between OT-I cells and infected hepatocytes by intravital imaging using two-photon microscopy. OT-I cells formed clusters around infected hepatocytes, leading to the elimination of the intrahepatic parasites and subsequent formation of large clusters of OT-I cells in the liver. Gamma interferon expressed in CD8 ؉ T cells was dispensable for this protective response. Additionally, we found that polyclonal ovalbumin-specific memory CD8 ؉ T cells induced by de novo immunization were able to confer sterile protection, although the threshold frequency of the protection was relatively high. These studies revealed a novel mechanism of specific CD8 ؉ T cell-mediated protective immunity and demonstrated that proteins expressed in the cytoplasm of Plasmodium parasites can become targets of specific CD8 ؉ T cells during liver-stage infection.

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“…The sporozoite invasion of the liver occurs by an elaborate process involving traversal of many liver cell types including Kupffer cells, stellate cells, endothelial cells, and hepatocytes [26,27]. It is thought that during sporozoite traversal, CSP is shed in the cytosol of the liver cells [28,29], where it becomes degraded by proteosomes and the resulting peptide fragments are exported via the TAP-dependent process [24] to the ER for loading onto nascent MHC I molecules, transport to the cell surface and eventual activation of CD8 + T cells. What remains unknown is how LS Ags that have been shown as required targets of protective immunity [30,31] are processed and presented to CD8 + T cells.…”

Section: Introductionmentioning

confidence: 99%

TAP‐mediated processing of exoerythrocytic antigens is essential for protection induced with radiation‐attenuated Plasmodium sporozoites

et al. 2016

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MHC class I dependent CD8 + T cells are essential for protection induced by radiationattenuated Plasmodium sporozoites (RAS) in murine malaria models. Apart from the mechanism of activation of CD8 + T cells specific for the circumsporozoite protein, the major sporozoite antigen (Ag), CD8 + T cells specific for other exoerythrocytic Ags that have been shown to mediate protection have not been thoroughly investigated. Specifically, mechanisms of processing and presentation of exoerythrocytic Ags, which includes liver stage (LS) Ags, remain poorly understood. We hypothesize that as exogenous proteins, LS Ags are processed by mechanisms involving either the TAP-dependent phagosomalto-cytosol or TAP-independent vacuolar pathway of cross-presentation. We used TAPdeficient mice to investigate whether LS Ag mediated induction of naïve CD8 + T cells and their recall during sporozoite challenge occur by the TAP-dependent or TAP-independent pathways. On the basis of functional attributes, CD8 + T cells were activated via the TAPindependent pathway during immunizations with Plasmodium berghei RAS; however, IFN-γ + CD8 + T cells previously induced by P. berghei RAS in TAP-deficient mice failed to be recalled against sporozoite challenge and the mice became parasitemic. On the basis of these observations, we propose that TAP-associated Ag processing is indispensable for sterile protection induced with P. berghei RAS.Keywords: Antigen presenting cells · CD8 + T cells · Liver · Plasmodium · Transporter associated with antigen processing (TAP) Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction CD8 + T cells provide a critical network of responses that underlie lasting protective immunity against viral, microbial, and parasitic infections [1]. A subset of antigen (Ag) induced CD8 + T cells acquire an effector (E) function and these CD8 + effector T (T E ) cells become poised to eliminate pathogen infected cells, Correspondence: Dr. Urszula Krzych e-mail: Urszula.Krzych1.civ@mail.mil a process that is typically MHC I dependent. The induction of Ag-specific CD8 + T cells requires ligation of the TCR by MHC I:peptide complexes that are formed during Ag processing and displayed on APCs, followed by the provision of secondary and tertiary signals, such as costimulatory molecules and cytokines, respectively [2,3]. Several distinct mechanisms of Ag processing have been described for the MHC I pathway and the utilization of a particular pathway depends in part on the Ag itself. For example, most endogenous Ags, such as viral proteins synthesized within the cytosol of infected host cells, are processed along the classical pathway involving proteosomal degradation followed by Published 2015. This article is a U.S. Government work and is in the public domain in the USA www.eji-journal.eu 886Alexander Pichugin et al. Eur. J. Immunol. 2016. 46: 885-896 TAP-dependent transfer of oligopeptides into the ER. Subsequent trimming by ER aminopeptidase associated with A...

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Release of malaria circumsporozoite protein into the host cell cytoplasm and interaction with ribosomes

Cited by 42 publications

References 55 publications

Plasmodium berghei-Infected Primary Hepatocytes Process and Present the Circumsporozoite Protein to Specific CD8+ T Cells In Vitro

Plasmodium berghei-Infected Primary Hepatocytes Process and Present the Circumsporozoite Protein to Specific CD8+ T Cells In Vitro

CD8⁺T Cells Specific for a Malaria Cytoplasmic Antigen Form Clusters around Infected Hepatocytes and Are Protective at the Liver Stage of Infection

TAP‐mediated processing of exoerythrocytic antigens is essential for protection induced with radiation‐attenuated Plasmodium sporozoites

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Release of malaria circumsporozoite protein into the host cell cytoplasm and interaction with ribosomes

Cited by 42 publications

References 55 publications

Plasmodium berghei-Infected Primary Hepatocytes Process and Present the Circumsporozoite Protein to Specific CD8+ T Cells In Vitro

Plasmodium berghei-Infected Primary Hepatocytes Process and Present the Circumsporozoite Protein to Specific CD8+ T Cells In Vitro

CD8+T Cells Specific for a Malaria Cytoplasmic Antigen Form Clusters around Infected Hepatocytes and Are Protective at the Liver Stage of Infection

TAP‐mediated processing of exoerythrocytic antigens is essential for protection induced with radiation‐attenuated Plasmodium sporozoites

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CD8⁺T Cells Specific for a Malaria Cytoplasmic Antigen Form Clusters around Infected Hepatocytes and Are Protective at the Liver Stage of Infection