Evidence map›Paper›PMID 42728375›Full record

ArticleEMBO reports2026

Circulating cholesterol fuels SARS-CoV-2 replication via ORF3a.

Jennifer M Hayashi, Taha Y Taha, Irene P Chen, Rahul K Suryawanshi, Danielle L Swaney, Maria McCavitt-Malvido, Mauricio Montano, Abdullah M Syed, Mir M Khalid, Camille R Simoneau and 12 more

Abstract read
PubMed Publisher
In one paragraph

Article in EMBO reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors.

Jennifer M Hayashi *J. David Gladstone Institutes, San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-7153-9212
Taha Y Taha *J. David Gladstone Institutes, San Francisco, CA, USA.
Irene P ChenJ. David Gladstone Institutes, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-5766-9253
Rahul K SuryawanshiJ. David Gladstone Institutes, San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-8374-669X
Danielle L SwaneyJ. David Gladstone Institutes, San Francisco, CA, USA.
Maria McCavitt-MalvidoJ. David Gladstone Institutes, San Francisco, CA, USA.
Mauricio MontanoJ. David Gladstone Institutes, San Francisco, CA, USA.
Abdullah M SyedJ. David Gladstone Institutes, San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-9156-9662
Mir M KhalidJ. David Gladstone Institutes, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-1862-6795
Camille R SimoneauJ. David Gladstone Institutes, San Francisco, CA, USA.
Pei-Yi ChenJ. David Gladstone Institutes, San Francisco, CA, USA.
Kristoffer E LeonJ. David Gladstone Institutes, San Francisco, CA, USA.
Chia-Lin TsouJ. David Gladstone Institutes, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-1205-2970
Erica StevensonJ. David Gladstone Institutes, San Francisco, CA, USA.
Martin GordonJ. David Gladstone Institutes, San Francisco, CA, USA.
Natalie R ChaplinElectron Microscope Laboratory, University of California, Berkeley, CA, USA.ORCID http://orcid.org/0009-0004-8714-2921
Danielle M JorgensElectron Microscope Laboratory, University of California, Berkeley, CA, USA.
Zhongde WangDepartment of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT, USA.ORCID http://orcid.org/0000-0003-2441-4729
Andreas S PuschnikBiohub, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-9605-9458
Jennifer A DoudnaJ. David Gladstone Institutes, San Francisco, CA, USA.
Nevan J KroganJ. David Gladstone Institutes, San Francisco, CA, USA.ORCID http://orcid.org/0000-0003-4902-337X
Melanie OttJ. David Gladstone Institutes, San Francisco, CA, USA. melanie.ott@gladstone.ucsf.edu.ORCID http://orcid.org/0000-0002-5697-1274

Funding

HHS | National Institutes of Health (NIH) NIAID F31AI1646671HHS | National Institutes of Health (NIH) NIAID R01AI097552HHS | National Institutes of Health (NIH) NIAID U19AI171110HHS | National Institutes of Health (NIH) NIDA DP1DA038043
6 · The paper itself

Abstract

High levels of "bad" cholesterol increase the risk of cardiovascular disease and are also linked to more severe COVID-19, though the reason has been unclear. We show that low-density lipoprotein (LDL) directly enhances SARS-CoV-2 RNA replication, especially in the Beta variant. The viral accessory protein ORF3a is both necessary and sufficient to increase cholesterol uptake in cell culture and hamster models. ORF3a stabilizes the host LDL receptor by displacing the PCSK9 chaperone, leading to greater cholesterol entry into cells. While wild-type ORF3a disrupts endosomal acidification and limits cholesterol recycling through interaction with VPS39 (part of the HOPS complex), the Beta variant does not, allowing more efficient cholesterol recovery and stronger LDL responsiveness. Overall, our findings show that SARS-CoV-2 can directly link its replication to host cholesterol levels via ORF3a. This mechanism may help guide antiviral strategies, particularly for individuals with high cholesterol.

Identifiers

PMID42728375

What OpenQuestion holds

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.