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

Hongming Ma1, Lucas J Adams2, Saravanan Raju1,2

  • 1Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Nature Communications
|January 3, 2024
PubMed

Insights

Low-density lipoprotein receptor (LDLR) acts as an entry factor for alphaviruses like Eastern equine encephalitis virus (EEEV). Soluble decoy proteins targeting LDLR show potential for inhibiting alphavirus infection.

Area of Science:

  • Virology
  • Molecular Biology
  • Immunology

Background:

  • Alphaviruses utilize cellular receptors for entry, with LDLR family members previously identified.
  • Complete inhibition of alphavirus infection is not achieved by blocking known receptors, suggesting additional factors are involved.

Purpose of the Study:

  • To identify novel cellular entry factors for alphaviruses using a genome-wide screen.
  • To characterize the role of identified receptors in alphavirus binding and infection.

Main Methods:

  • CRISPR-Cas9 genome-wide loss-of-function screen in mouse neuronal cells using a chimeric alphavirus.
  • Expression analysis and binding studies of candidate receptors.
  • Development and testing of soluble decoy proteins.

Main Results:

  • Low-density lipoprotein receptor (LDLR) was identified as a novel entry factor for alphaviruses.
  • LDLR facilitates binding and infection of Eastern equine encephalitis virus (EEEV), Western equine encephalitis virus, and Semliki Forest virus.
  • A low-affinity interaction between LDLR's LA domain 3 (LA3) and alphaviruses was observed, which can be enhanced by LA3 repeats.

Conclusions:

  • LDLR serves as a low-affinity receptor for multiple alphaviruses.
  • Soluble decoy proteins targeting LDLR demonstrate efficacy in inhibiting alphavirus infection in vitro and in vivo.
  • This study provides a potential therapeutic strategy for mitigating alphavirus infections and associated diseases.

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