Stopping COVID-19 by targeting out-of-control immune cells

SARS-CoV-2, the virus behind the COVID-19 pandemic, prompts the immune system to attack healthy cells, leading to dangerous inflammation. But how does the virus enable this attack? Johns Hopkins University researchers have taken one step toward answering that question—and suggested a potential solution in drugs that are already in clinical testing.

The Johns Hopkins team focused on two proteins, factor H and factor D, which are known as “complement” proteins, because they help the immune system clear pathogens from the body. The researchers discovered that COVID-19’s spike protein causes factor D to overstimulate the immune response, which in turn prevents factor H from mediating that response. Blocking factor D prevents that chain of events, they reported in the journal Blood.

Previous studies had shown that COVID-19 “activates a cascading series of biological reactions—what we call the alternative pathway of complement,” said senior author Robert Brodsky, M.D., director of the hematology division at the Johns Hopkins University School of Medicine, in a statement. “The goal of our study was to discover how the virus activates this pathway and to find a way to inhibit it before the damage happens.”

The researchers zeroed in on a process that occurs when the spike protein binds to healthy cells: The spikes attach to a sugar molecule called heparan, which is prevalent on cells in the lungs, blood vessels and organ muscles. They discovered that during that process, SARS-CoV-2 blocks factor H from binding to cells, leaving them vulnerable to the dangerous immune attack.

Because factor D is upstream in the complement pathway, the researchers figured that blocking it might stop that immune response. They tested a small-molecule factor D inhibitor, ACH-145951, in cells and found that SARS-CoV-2’s spike protein was unable to activate the alternative complement pathway, they reported.

Factor D inhibitors are being developed by the likes of Alexion to address complement alternative pathway-mediated diseases. And Alexion launched a phase 3 trial of a different complement-directed drug, Ultomiris, in severe COVID-19 patients in April. Ultomiris works by inhibiting “terminal” complements and is approved by the FDA to treat rare blood disorders.

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Also this week, a team of researchers at Imperial College London reported their discovery that another protein, Foxp3, plays a role in mediating the inflammatory immune response to COVID-19. They explained the findings in the journal Frontiers in Immunology.

They studied tissue samples from the lungs of six severely ill patients, three moderately sick patients and three healthy people in China. The researchers discovered that the lungs of the sickest COVID-19 patients were filled with “hyperactive” T cells, suggesting a failure of the braking mechanism in the immune system that prevents dangerous immune reactions, they said in a statement. Foxp3 usually initiates that braking system but was lacking in the samples from those patients.

The Imperial College team is now planning future studies aimed at better understanding Foxp3’s role in COVID-19 and finding ways to restore the immune system’s braking mechanism.