All major cholesterol-dependent cytolysins use glycans as cellular receptors.

Abstract:

:Cholesterol-dependent cytolysins (CDCs) form pores in cholesterol-rich membranes, but cholesterol alone is insufficient to explain their cell and host tropism. Here, we show that all eight major CDCs have high-affinity lectin activity that identifies glycans as candidate cellular receptors. Streptolysin O, vaginolysin, and perfringolysin O bind multiple glycans, while pneumolysin, lectinolysin, and listeriolysin O recognize a single glycan class. Addition of exogenous carbohydrate receptors for each CDC inhibits toxin activity. We present a structure for suilysin domain 4 in complex with two distinct glycan receptors, P1 antigen and αGal/Galili. We report a wide range of binding affinities for cholesterol and for the cholesterol analog pregnenolone sulfate and show that CDCs bind glycans and cholesterol independently. Intermedilysin binds to the sialyl-TF O-glycan on its erythrocyte receptor, CD59. Removing sialyl-TF from CD59 reduces intermedilysin binding. Glycan-lectin interactions underpin the cellular tropism of CDCs and provide molecular targets to block their cytotoxic activity.

journal_name

Sci Adv

journal_title

Science advances

authors

Shewell LK,Day CJ,Jen FE,Haselhorst T,Atack JM,Reijneveld JF,Everest-Dass A,James DBA,Boguslawski KM,Brouwer S,Gillen CM,Luo Z,Kobe B,Nizet V,von Itzstein M,Walker MJ,Paton AW,Paton JC,Torres VJ,Jennings MP

doi

10.1126/sciadv.aaz4926

subject

Has Abstract

pub_date

2020-05-22 00:00:00

pages

eaaz4926

issue

21

issn

2375-2548

pii

aaz4926

journal_volume

6

pub_type

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