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

Ananthakrishnan Ganesan¹, Andrew R Moore², Hong Zheng¹, Jiaying Toh¹, Michael Freedman³, Andrew T Magis⁴, James R Heath⁵, Purvesh Khatri⁶

Affiliations

¹ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA; Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, USA.
² Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA; Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA, USA.
³ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA; Division of Pediatric Critical Care, Stanford University, Stanford, CA, USA.
⁴ Institute of Systems Biology, Seattle, WA, USA.
⁵ Institute of Systems Biology, Seattle, WA, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
⁶ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA; Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, USA. Electronic address: pkhatri@stanford.edu.

PMID: 40532705
DOI: 10.1016/j.immuni.2025.05.020

Free article

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

Ananthakrishnan Ganesan et al. Immunity. 2025.

Free article

. 2025 Aug 12;58(8):2104-2119.e5.

doi: 10.1016/j.immuni.2025.05.020. Epub 2025 Jun 17.

Authors

Ananthakrishnan Ganesan¹, Andrew R Moore², Hong Zheng¹, Jiaying Toh¹, Michael Freedman³, Andrew T Magis⁴, James R Heath⁵, Purvesh Khatri⁶

Affiliations

¹ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA; Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, USA.
² Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA; Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA, USA.
³ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA; Division of Pediatric Critical Care, Stanford University, Stanford, CA, USA.
⁴ Institute of Systems Biology, Seattle, WA, USA.
⁵ Institute of Systems Biology, Seattle, WA, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
⁶ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA; Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, CA, USA. Electronic address: pkhatri@stanford.edu.

PMID: 40532705
DOI: 10.1016/j.immuni.2025.05.020

Abstract

Older age, being male, obesity, smoking, and comorbidities (e.g., diabetes, asthma) are associated with an 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 was associated with each of these risk factors prior to infection. Furthermore, this conserved immune signature was modifiable using immunomodulatory drugs and lifestyle changes. The SoM score predicted the individuals with sepsis who would be harmed by hydrocortisone treatment and individuals with asthma who would 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 the baseline immune state and response to chronic, subacute, and acute illnesses.

Keywords: all-cause mortality; conserved immune dysregulation; impact of lifestyle changes; multi-cohort analysis; multi-omics; risk factors for severe infections; sepsis; treatment response prediction.

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Conflict of interest statement

Declaration of interests P.K. is a co-founder of, consultant to, and a scientific advisor to Inflammatix, Inc. This work has been disclosed through Stanford’s Office of Technology and Licensing.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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