Mechanical control of the adhesion of malaria-infected erythrocytes to the placenta

Abstract:

Pathogens use sophisticated adhesion mechanisms to remain attached to the host’s surfaces. A key example of this is the adhesion of erythrocytes infected with Plasmodium, the parasite which causes malaria, to the microvasculature. Remarkably, in the case of pregnancy-associated malaria, the adherence of parasitized erythrocytes to the placenta is enhanced by the shear of the flowing blood, suggesting a catch-bond adhesion mechanism. The adhesion is mediated by a parasite protein called VAR2CSA which anchors such infected erythrocytes to the proteoglycan matrix of the placenta. In this work, by using extensive equilibrium and force-probe molecular dynamics simulations, we elucidate the—so far unknown—molecular mechanism governing the adhesive function of VAR2CSA. We demonstrate that the elongation tension that arises from the shear of the flowing blood opens VAR2CSA into two structurally-intact domains, thereby exposing cryptic sugar binding sites. The orientation of VAR2CSA with respect to the pulling direction as well as strong sugar-protein shearing interactions favor this mode of opening. Accordingly, as the basis for a catch bond, we propose that mechanical forces strengthen the adhesion of infected erythrocytes, by increasing the number of sugar binding sites in VAR2CSA and not the bond lifetime as it would be canonically thought for a catch bond. This constitutes a new intriguing hypothesis which is of high relevance for our understanding of malaria infection and for the design of vaccines. More generally, our results put forward force-induced multivalency of mechano-responsive proteins as a key new concept for pathogen-host interactions.

SEEK ID: https://publications.h-its.org/publications/1787

DOI: 10.1016/j.bpj.2023.11.1257

Research Groups: Molecular Biomechanics

Publication type: Journal

Journal: Biophysical Journal

Publisher: Elsevier BV

Citation: Biophysical Journal,123(3):197a

Date Published: 8th Feb 2024

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Registered Mode: manually

Authors: Rita Roessner, Nicholas Michelarakis, Frauke Gräter, Camilo Aponte-Santamaría

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Citation
Roessner, R., Michelarakis, N., Gräter, F., & Aponte-Santamaria, C. (2024). Mechanical control of the adhesion of malaria-infected erythrocytes to the placenta. In Biophysical Journal (Vol. 123, Issue 3, p. 197a). Elsevier BV. https://doi.org/10.1016/j.bpj.2023.11.1257
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Created: 13th Feb 2024 at 07:58

Last updated: 5th Mar 2024 at 21:25

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