PXD069220-1

PXD069220 is an original dataset announced via ProteomeXchange.

Title	Secreted ORF8 reprograms macrophages to enhance SARS-CoV-2 infection of lung epithelial cells
Description	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets the respiratory epithelium, yet severe disease features diffuse lung injury and hyperinflammatory syndromes driven by dysregulated immune activation. Emerging evidence indicates that resident and infiltrating immune cells in the lung can encounter the virus early in infection and, under specific conditions, become infected. This process amplifies local inflammation and facilitates viral propagation in the lower airways and distal lung regions, where angiotensin converting enzyme 2 (ACE2) expression is limited. However, how epithelial and immune cell compartments interact to produce the hallmark pulmonary pathology of SARS-CoV-2 infection remains unresolved. Here we show that secreted ORF8, a SARS-CoV-2 accessory protein, drives inflammatory lung pathology by increasing macrophage permissively to infection, triggering pyroptosis, and amplifying viral replication in alveolar epithelial cells. Co-culture of macrophages with human alveolar type II (AT2) cells overrides ORF8’s previously reported inhibition of AT2 infection, restoring productive viral replication. In vivo, IL-17RA blockade with brodalumab counteracts ORF8 activity, lowering viral burden and attenuating pulmonary inflammation and fibrosis. These findings reveal a paracrine role for ORF8 in reprogramming macrophages, thereby establishing a feedforward proviral circuit that accelerates lung pathology in COVID-19 and are particularly relevant given the recurrent emergence of SARS-CoV-2 variants with either intact or deleted ORF8 since the beginning of the pandemic.
HostingRepository	PRIDE
AnnounceDate	2026-08-07
AnnouncementXML	Submission_2026-08-07_14:24:02.950.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Robyn Kaake
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-08 16:29:43	ID requested
⏵ 1	2026-08-07 14:24:03	announced

Dataset with its publication pending

submitter keyword: SARS-CoV-2

ORF8

macrophage

ACE2

pyroptosis

IL-1β

brodalumab

Robyn Midori Kaake
contact affiliation	Univeristy of California San Francisco (UCSF), Department of Bioengineering and Therapeutic Sciences, USA, San Francisco
contact email	robyn.kaake@gladstone.ucsf.edu
lab head
Robyn Kaake
contact affiliation	Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA
contact email	robyn.kaake@gladstone.ucsf.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/08/PXD069220

PRIDE project URI

• PRIDE
  1. PXD069220
     1. Label: PRIDE project
     2. Name: Secreted ORF8 reprograms macrophages to enhance SARS-CoV-2 infection of lung epithelial cells