In a Stockholm laboratory, researchers at Karolinska Institutet have upended a fundamental assumption about severe COVID-19: that a stronger antiviral immune response means better protection. Their new study, published in Genome Medicine, reveals instead that disease severity emerges from a complex interplay between antiviral genes, inflammation, metabolism, and how well immune cells actually function—a finding that could reshape how doctors treat the disease.
The team analyzed blood samples from hospitalized COVID-19 patients, focusing on interferon-stimulated genes, or ISGs, which are proteins that help the body fight viral infections. Researchers expected that patients with high ISG expression would fare better, but the data told a different story. Some patients with severe COVID-19 had low ISG expression, while others had high levels, yet both groups experienced similarly poor outcomes. "A strong interferon-stimulated gene signature does not necessarily mean that the immune response is protective," explains Soham Gupta, associate professor at the Department of Laboratory Medicine, Karolinska Institutet. "Our results show that disease severity also depends on inflammation, metabolism and how well innate immune cells function."
The breakthrough came when researchers looked beyond the immune response alone. Among patients with both high ISG expression and severe disease, they discovered additional disturbances in metabolism—particularly in lipid metabolism and energy pathways that control how the body breaks down and uses fat and energy. What's more, experiments showed that plasma from these severely ill patients could actually reduce the activation of certain immune cells, suggesting their immune system was functioning sub-optimally despite visible signs of inflammation and a powerful antiviral gene response.
Patients with high ISG expression also showed changes in innate immune cells, including neutrophils and monocytes, indicating that the inflammatory state itself may have been counterproductive. The team based these findings on analyses of blood and plasma samples from COVID-19 patients in Stockholm, compared against healthy and convalescent individuals, using advanced methods including RNA sequencing, proteomics, and metabolomics. Researchers even examined antibody reactivity against interferons but found this did not explain the differences between patient groups.
This research suggests that severe COVID-19 is not a single biological disease state, but rather a condition that can arise through several different biological mechanisms. That distinction matters enormously for treatment. Instead of a one-size-fits-all approach, clinicians could eventually match therapies to each patient's specific immune-metabolic profile. A patient whose severe illness stems from metabolic dysfunction might benefit from different interventions than one whose immune cells are inflamed but not activating properly.
The work represents a collaboration across Sweden's leading research institutions—Karolinska Institutet, Uppsala University, SciLifeLab, and Södersjukhuset/Karolinska University Hospital Huddinge. Gupta and his team now plan to investigate whether these immune-metabolic patterns are linked to long-term outcomes after infection, opening a pathway toward understanding and potentially preventing long COVID. In reframing what makes COVID-19 severe, they've given clinicians a map toward more precise, personalized treatment.