The low-density lipoprotein receptor promotes infection of multiple encephalitic alphaviruses

Hongming Ma, Lucas J. Adams, Saravanan Raju, Alan Sariol, Natasha M. Kafai, Hana Janova, William B. Klimstra, Daved H. Fremont and Michael S. Diamond ()
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Hongming Ma: Washington University School of Medicine
Lucas J. Adams: Washington University School of Medicine
Saravanan Raju: Washington University School of Medicine
Alan Sariol: Washington University School of Medicine
Natasha M. Kafai: Washington University School of Medicine
Hana Janova: Washington University School of Medicine
William B. Klimstra: The University of Pittsburgh
Daved H. Fremont: Washington University School of Medicine
Michael S. Diamond: Washington University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Members of the low-density lipoprotein receptor (LDLR) family, including LDLRAD3, VLDLR, and ApoER2, were recently described as entry factors for different alphaviruses. However, based on studies with gene edited cells and knockout mice, blockade or abrogation of these receptors does not fully inhibit alphavirus infection, indicating the existence of additional uncharacterized entry factors. Here, we perform a CRISPR-Cas9 genome-wide loss-of-function screen in mouse neuronal cells with a chimeric alphavirus expressing the Eastern equine encephalitis virus (EEEV) structural proteins and identify LDLR as a candidate receptor. Expression of LDLR on the surface of neuronal or non-neuronal cells facilitates binding and infection of EEEV, Western equine encephalitis virus, and Semliki Forest virus. Domain mapping and binding studies reveal a low-affinity interaction with LA domain 3 (LA3) that can be enhanced by concatenation of LA3 repeats. Soluble decoy proteins with multiple LA3 repeats inhibit EEEV infection in cell culture and in mice. Our results establish LDLR as a low-affinity receptor for multiple alphaviruses and highlight a possible path for developing inhibitors that could mitigate infection and disease.

Date: 2024
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DOI: 10.1038/s41467-023-44624-x

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