Plasmodium Circumsporozoite Protein Promotes the Development of the Liver Stages of the Parasite

Singh, Agam Prasad; Buscaglia, Carlos A.; Wang, Qian; Levay, Agata; Nussenzweig, Daniel R.; Walker, John R.; Winzeler, Elizabeth A.; Fujii, Hodaka; Fontoura, Beatriz M. A.; Nussenzweig, Victor

doi:10.1016/j.cell.2007.09.013

Cited by 187 publications

(193 citation statements)

References 51 publications

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“…In addition, wounded cells contain free sporozoite-derived proteins in the cytoplasm, which might potently interfere with important host cell functions. Indeed, recently it has been shown that overexpression of CSP antagonizes NF-B translocation to the nucleus in infected cells upon TNF-␣ stimulation, which consequently inhibits the expression of proinflammatory molecules (37). This seems to contradict our observations.…”

Section: Discussioncontrasting

confidence: 99%

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Sporozoite-Mediated Hepatocyte Wounding Limits Plasmodium Parasite Development via MyD88-Mediated NF-κB Activation and Inducible NO Synthase Expression

Torgler

Bongfen

Romero

et al. 2008

The Journal of Immunology

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Plasmodium sporozoites traverse several host cells before infecting hepatocytes. In the process, the plasma membranes of the cells are ruptured, resulting in the release of cytosolic factors into the microenvironment. This released endogenous material is highly stimulatory/immunogenic and can serve as a danger signal initiating distinct responses in various cells. Thus, our study aimed at characterizing the effect of cell material leakage during Plasmodium infection on cultured mouse primary hepatocytes and HepG2 cells. We observed that wounded cell-derived cytosolic factors activate NF-κB, a main regulator of host inflammatory responses, in cells bordering wounded cells, which are potential host cells for final parasite infection. This activation of NF-κB occurred shortly after infection and led to a reduction of infection load in a time-dependent manner in vitro and in vivo, an effect that could be reverted by addition of the specific NF-κB inhibitor BAY11-7082. Furthermore, no NF-κB activation was observed when Spect−/− parasites, which are devoid of hepatocyte traversing properties, were used. We provide further evidence that NF-κB activation causes the induction of inducible NO synthase expression in hepatocytes, and this is, in turn, responsible for a decrease in Plasmodium-infected hepatocytes. Furthermore, primary hepatocytes from MyD88−/− mice showed no NF-κB activation and inducible NO synthase expression upon infection, suggesting a role of the Toll/IL-1 receptor family members in sensing cytosolic factors. Indeed, lack of MyD88 significantly increased infection in vitro and in vivo. Thus, host cell wounding due to parasite migration induces inflammation which limits the extent of parasite infection.

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Section: Discussioncontrasting

confidence: 99%

“…To date, it is unclear whether it might be a candidate to limit a TLR-mediated immune response against the parasite. As already discussed above, an additional candidate is the CSP (37).…”

Section: Discussionmentioning

confidence: 99%

Sporozoite-Mediated Hepatocyte Wounding Limits Plasmodium Parasite Development via MyD88-Mediated NF-κB Activation and Inducible NO Synthase Expression

Torgler

Bongfen

Romero

et al. 2008

The Journal of Immunology

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“…In a real-time PCR mix of 50 lL, cDNA equivalent of 0.5 lg RNA was used. Real-time PCR mix also contained P. berghei 18S rRNA specific primers and SYBR green dye (29). Real-time PCR was performed in a BioRad icycler and the copy numbers were calculated, using known amount of plasmid standard having the amplification target sequence (29).…”

Section: In Vitro Inhibition Studiesmentioning

confidence: 99%

“…Real-time PCR mix also contained P. berghei 18S rRNA specific primers and SYBR green dye (29). Real-time PCR was performed in a BioRad icycler and the copy numbers were calculated, using known amount of plasmid standard having the amplification target sequence (29). Parasite growth and percentage inhibition were calculated by dividing the 18S rRNA copy numbers of experimental group with that of the untreated control group.…”

Section: In Vitro Inhibition Studiesmentioning

confidence: 99%

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Triclosan inhibit the growth of the late liver‐stage of Plasmodium

Singh

Surolia

2009

IUBMB Life

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SummaryAnnually, approximately two million human deaths are caused worldwide by malaria, most of them being children. Plasmodium falciparum is the leading cause of cerebral malaria, the most severe and fatal form of disease. Moreover, the emergence of resistant strains to the existing drugs has worsened the situation. Currently, primaquine is the only drug available for eliminating liver-stage parasites. Because of the emergence of resistant parasite strains, it becomes necessary to find new targets unique to the malaria parasites. In the Plasmodium species, the discovery of a distinct Type-II fatty-acid synthesis pathway has created an opportunity to target this pathway for the development of new inhibitors of malaria parasite growth. The present study explored the growth inhibition potential of triclosan in the case of liver-stage parasites. Liver-stage of Plasmodium is an excellent target for intervention due to very small parasite load as well as possibility of eliminating parasites before it can cause blood-stage infection. Here we report that triclosan inhibits the development of the Plasmodium liver-stage parasites.2009 IUBMB IUBMB Life, 61(9): 923-928, 2009

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Identification and characterization of nuclear localization signals in the circumsporozoite protein of Plasmodium falciparum

Shrikondawar,

Chennoju,

Ghosh

et al. 2024

FEBS Letters

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Secretory proteins of Plasmodium exhibit differential spatial and functional activity within the host cell nucleus. However, the nuclear localization signals (NLSs) for these proteins remain largely uncharacterized. In this study, we have identified and characterized two NLSs in the circumsporozoite protein of Plasmodium falciparum (Pf‐CSP). Both NLSs in the Pf‐CSP contain clusters of lysine and arginine residues essential for specific interactions with the conserved tryptophan and asparagine residues of importin‐α, facilitating nuclear translocation of Pf‐CSP. While the two NLSs of Pf‐CSP function independently and are both crucial for nuclear localization, a single NLS of Pf‐CSP leads to weak nuclear localization. These findings shed light on the mechanism of nuclear penetrability of secretory proteins of Plasmodium proteins.

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Plasmodium Circumsporozoite Protein Promotes the Development of the Liver Stages of the Parasite

Cited by 187 publications

References 51 publications

Sporozoite-Mediated Hepatocyte Wounding Limits Plasmodium Parasite Development via MyD88-Mediated NF-κB Activation and Inducible NO Synthase Expression

Sporozoite-Mediated Hepatocyte Wounding Limits Plasmodium Parasite Development via MyD88-Mediated NF-κB Activation and Inducible NO Synthase Expression

Triclosan inhibit the growth of the late liver‐stage of Plasmodium

Identification and characterization of nuclear localization signals in the circumsporozoite protein of Plasmodium falciparum

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