SARS-CoV-2 Protein Fuels Lung Inflammation by Hijacking Macrophages

Even now, scientists are still untangling how the SARS-CoV-2 virus can leave such lasting damage in the lungs. Severe COVID-19 is not simply a matter of infected airway cells. In the sickest patients, the virus can help set off a destructive inflammatory loop, in which immune cells that should be fighting infection instead become part of the problem.

A new study from researchers at Gladstone Institutes and the University of California, San Francisco (UCSF), identifies one viral protein, ORF8, as a key driver of that process. The paper, “Secreted ORF8 reprograms macrophages to enhance SARS-CoV-2 infection of lung epithelial cells,” was published in Science Advances.

The work builds on earlier efforts by Gladstone and UCSF scientists to map interactions between SARS-CoV-2 proteins and human proteins in search of viral vulnerabilities that could be targeted with drugs. ORF8 had emerged as an intriguing but puzzling candidate. In isolated lung cells, ORF8 appeared to limit viral replication, yet SARS-CoV-2 variants lacking ORF8 have tended to cause milder disease.

To resolve that contradiction, Melanie Ott, MD, PhD, director of the Gladstone Infectious Disease Institute, and colleagues focused on macrophages, immune cells that help shape the body’s response to infection and inflammation. The team exposed macrophages to ORF8, studied how the cells responded to SARS-CoV-2 infection, and then tested how those immune-cell changes affected nearby alveolar type II lung epithelial cells. They also evaluated ORF8’s effects in mice infected with SARS-CoV-2.

The researchers found that ORF8 increased macrophage expression of angiotensin converting enzyme 2, or ACE2, the receptor SARS-CoV-2 uses to enter cells, making the immune cells more permissive to infection. Once infected, ORF8-exposed macrophages were more likely to lose antiviral function, undergo inflammatory cell death, and release signals that promoted lung inflammation and made surrounding lung epithelial cells more vulnerable to viral replication.

“We were surprised to see how effectively ORF8 turns our own immune defenses against us,” said first author Yusuke Matsui, MD, PhD, a staff research scientist in Ott’s lab. “ORF8 is hijacking macrophages to enhance infection of the surrounding tissue.”

In co-culture experiments, the presence of macrophages changed ORF8’s effect on infection. As the authors wrote in the paper, macrophage co-culture “overrides ORF8’s previously reported inhibition of AT2 [human alveolar type II] infection, restoring infectious viral production.” In mice, SARS-CoV-2 carrying ORF8 caused greater lung inflammation, viral burden, and scarring than virus lacking the protein, supporting the idea that ORF8 helps create a feedforward circuit linking immune-cell infection to lung pathology.

The work also highlights a potential therapeutic target. Researchers tested brodalumab, an antibody already FDA-approved for psoriasis that blocks IL-17RA, the receptor previously linked to ORF8. In mice, IL-17RA blockade countered “ORF8 activity, lowering viral burden and attenuating pulmonary inflammation and fibrosis,” the authors wrote. Ott said the findings could support more targeted treatments for severe COVID-19. “By showing that this single viral protein is the main bridge between viral growth and tissue damage, we’ve found a clear target for new treatments,” she added.

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