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J Thromb Haemost. 2019 Dec 19. doi: 10.1111/jth.14713. [Epub ahead of print]

Plasmodium falciparum histidine rich protein HRPII inhibits the anti-inflammatory function of antithrombin.

Author information

1
Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA.
2
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
3
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Abstract

BACKGROUND:

It has been reported that histidine-rich protein II (HRPII), secreted by the malaria parasite, Plasmodium falciparum (Pf), inhibits the heparin-dependent anticoagulant activity of antithrombin (AT) in vitro and in plasma-based assay systems.

OBJECTIVE:

The objective of this study was to test the hypothesis that HRPII may also interact with the AT-binding vascular glycosaminoglycans (GAGs), thereby inhibiting the anti-inflammatory signaling function of the serpin.

METHODS:

We expressed HRPII in bacteria, purified it to homogeneity and studied its effect on endothelial cell signaling in the absence and presence of AT employing established signaling assays.

RESULTS:

We demonstrate that a low concentration of HRPII potently disrupts the barrier permeability function of endothelial cells. Moreover, HRPII competitively inhibits the protective effect of AT by a concentration-dependent manner. Similarly, AT inhibits the pro-inflammatory activity of HRPII by a concentration-dependent manner. The siRNA knockdown of 3-O-sulfotransferase 1 (3-OST-1), the enzyme responsible for the essential 3-O-sulfation of the AT-binding GAGs, downregulates the pro-inflammatory function of HRPII in endothelial cells, supporting the hypothesis that HRPII competitively inhibits the interaction of AT with 3-OS containing vascular GAGs. Histidine-rich protein II elicits its barrier-disruptive effect by the Src-dependent phosphorylation of vascular endothelial (VE)-cadherin and AT counteracts this effect. We further demonstrate that inorganic polyphosphates bind HRPII with a high affinity to amplify the pro-inflammatory signaling function of HRPII in both cellular and in vivo permeability models.

CONCLUSION:

We postulate that Pf-derived HRPII and polyphosphate can contribute to the pathogenesis of malaria infection by downregulating the AT-dependent anti-inflammatory and anticoagulant pathways.

KEYWORDS:

Plasmodium falciparum ; HRPII; antithrombin; glycosaminoglycans; signaling

PMID:
31858717
DOI:
10.1111/jth.14713

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