Biological differences linked to severe COVID-19
Patients with COVID-19 can show several different antiviral immune response patterns, which may influence how the disease develops. This is shown in a new study from Karolinska Institutet, published in Genome Medicine, highlighting the importance of interactions between the immune system and metabolism.
Interferons are proteins that help the body fight viral infections by activating interferon-stimulated genes, also known as ISGs. In the present study, researchers at Karolinska Institutet investigated how this antiviral gene-response pattern varies among patients hospitalised with COVID-19. By analysing blood samples, they were able to group patients based on the expression of interferon-stimulated genes.
The findings show that the strength of this ISG response does not directly correspond to disease severity. Some patients with severe COVID-19 had low ISG expression, while others had high levels.
“A strong interferon-stimulated gene signature does not necessarily mean that the immune response is protective. Our results show that disease severity also depends on inflammation, metabolism, and how well innate immune cells function,” says Soham Gupta, associate professor at the Department of Laboratory Medicine, Karolinska Institutet.
Researchers also found that patients with high ISG expression often showed signs of inflammation and changes in innate immune cells, such as neutrophils and monocytes.
Interaction between immune response and metabolism
Among patients with both high ISG expression and severe disease, additional disturbances in metabolism were observed, particularly in lipid metabolism and energy pathways, which controls how the body breaks down and uses fat and energy.
Experiments further showed that their plasma could reduce the activation of certain immune cells, suggesting that the immune system may not function optimally despite signs of inflammation and a strong antiviral gene-response signature.
The study is based on analyses of blood and plasma samples from COVID-19 patients in Stockholm, comparisons with healthy and convalescent individuals, and advanced methods such as RNA sequencing, proteomics and metabolomics. The researchers also examined antibody reactivity against interferons, but this did not explain the differences between patient groups.
“This suggests that severe COVID-19 is not a single biological state, but may arise through several different mechanisms,” says Soham Gupta.
Next step
The findings may contribute to more personalised treatment approaches, where patients receive different therapies depending on how their immune response and metabolism are affected. The researchers now plan to investigate whether these immune-metabolic patterns are linked to long-term outcomes after infection.
The study was led by the Systems Virology Laboratory at the Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, in collaboration with researchers from Karolinska Institutet, Uppsala University, SciLifeLab and Södersjukhuset/Karolinska University Hospital Huddinge.
The research was funded by the Swedish Research Council, CIMED, Karolinska Institutet Foundations and Funds, the Göran Gustafsson Foundation and Region Stockholm. The authors declare no competing interests.
Publication
"Systemic multi-omics analysis reveals interferon response heterogeneity and links lipid metabolism to immune alterations in severe COVID-19", Ronaldo Lira-Junior, Anoop T. Ambikan, Axel Cederholm, Sefanit Rezene, Flora Mikaeloff, Sara Svensson Akusjärvi, Ahmet Yalcinkaya, Xi Chen, Maike Sperk, Maribel Aranda-Guillén, Hampus Nordqvist, Carl Johan Treutiger, Nils Landegren, Ujjwal Neogi, Soham Gupta. Genome Medicine, online 29 May 2026, doi: 10.1186/s13073-026-01677-z.