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ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome

DOI: 10.1126/sciadv.abl8213 DOI Help

Authors: Alexander T. Baker (Mayo Clinic; Arizona State University; Cardiff University) , Ryan J. Boyd (Arizona State University,) , Daipayan Sarkar (Arizona State University; Michigan State University) , Alicia Teijeira-Crespo (Cardiff University) , Chun Kit Chan (University of Illinois) , Emily Bates (Cardiff University) , Kasim Waraich (MRC-University of Glasgow Centre for Virus Research) , John Vant (Arizona State University) , Eric Wilson (Arizona State University) , Chloe D. Truong (Arizona State University) , Magdalena Lipka-Lloyd (Cardiff University) , Petra Fromme (Arizona State University) , Josh Vermaas (Michigan State University) , Dewight Williams (Arizona State University) , Leeann Machiesky (AstraZeneca) , Meike Heurich (Cardiff University) , Bolni M. Nagalo (Mayo Clinic) , Lynda Coughlan (University of Maryland School of Medicine) , Scott Umlauf (AstraZeneca) , Po-Lin Chiu (Arizona State University) , Pierre J. Rizkallah (Cardiff University) , Taylor S. Cohen (AstraZeneca) , Alan L. Parker (Cardiff University) , Abhishek Singharoy (Arizona State University) , Mitesh J. Borad (Mayo Clinic; Mayo Clinic Cancer Center)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Science Advances , VOL 7

State: Published (Approved)
Published: December 2021
Diamond Proposal Number(s): 20147

Open Access Open Access

Abstract: Vaccines derived from chimpanzee adenovirus Y25 (ChAdOx1), human adenovirus type 26 (HAdV-D26), and human adenovirus type 5 (HAdV-C5) are critical in combatting the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic. As part of the largest vaccination campaign in history, ultrarare side effects not seen in phase 3 trials, including thrombosis with thrombocytopenia syndrome (TTS), a rare condition resembling heparin-induced thrombocytopenia (HIT), have been observed. This study demonstrates that all three adenoviruses deployed as vaccination vectors versus SARS-CoV-2 bind to platelet factor 4 (PF4), a protein implicated in the pathogenesis of HIT. We have determined the structure of the ChAdOx1 viral vector and used it in state-of-the-art computational simulations to demonstrate an electrostatic interaction mechanism with PF4, which was confirmed experimentally by surface plasmon resonance. These data confirm that PF4 is capable of forming stable complexes with clinically relevant adenoviruses, an important step in unraveling the mechanisms underlying TTS.

Diamond Keywords: COVID-19; Viruses; Thrombosis

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 06/12/2021 12:57

Documents:
sciadv.abl8213.pdf

Discipline Tags:

Vaccines Pathogens Infectious Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)