A conserved immune dysregulation is associated with infection severity, risk factors prior to infection, and treatment response

Ganesan, A.; Moore, A. R.; Zheng, H.; Toh, J.; Freedman, M.; Magis, A. T.; Heath, J. R.; Khatri, P.

doi:10.1101/2025.04.18.649544

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bioRxiv · 10.1101/2025.04.18.649544

A conserved immune dysregulation is associated with infection severity, risk factors prior to infection, and treatment response

Ganesan, A.·Moore, A. R.·Zheng, H.·Toh, J.·Freedman, M.·Magis, A. T.·Heath, J. R.·Khatri, P.

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Abstract

Older age, being male, obesity, smoking, and comorbidities (e.g., diabetes, asthma) are associated with the increased risk for severe infections. We hypothesized that there is a conserved common immune dysregulation across these risk factors. We integrated single cell and bulk transcriptomic data and proteomic data from 12,026 blood samples across 68 cohorts to test this hypothesis. We found that our previously described 42-gene Severe-or-Mild (SoM) signature, is associated with each of these risk factors prior to infection. Furthermore, we found this conserved immune signature is modifiable using immunomodulatory drugs and lifestyle changes. The SoM score predicted patients with sepsis that would be harmed from hydrocortisone treatment, and patients with asthma that will not respond to monoclonal antibody treatment. Finally, the SoM score was associated with all-cause mortality. The SoM signature has the potential to redefine the immunologic framing of baseline immune state and response to chronic, subacute, and acute illnesses.

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Ganesan, A., Moore, A. R., Zheng, H., Toh, J., Freedman, M., Magis, A. T., Heath, J. R., Khatri, P.. 2025-04-22. A conserved immune dysregulation is associated with infection severity, risk factors prior to infection, and treatment response. https://doi.org/10.1101/2025.04.18.649544

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