Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections
Abstract Both bacterial and viral infections can trigger an overwhelming host response, leading to immunopathology and organ dysfunction. Multiple studies have reported dysregulated myeloid cell states in patients with bacterial sepsis or severe SARS-CoV-2 infection. However, their relevance to vira...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08407-y |
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| author | Kimberly Kajihara Donghong Yan Gretchen L. Seim Hannah Little-Hooy Jing Kang Cynthia Chen Marco De Simone Tim Delemarre Spyros Darmanis Haridha Shivram Rebecca N. Bauer Carrie M. Rosenberger Sharookh B. Kapadia Min Xu Miguel Reyes |
| author_facet | Kimberly Kajihara Donghong Yan Gretchen L. Seim Hannah Little-Hooy Jing Kang Cynthia Chen Marco De Simone Tim Delemarre Spyros Darmanis Haridha Shivram Rebecca N. Bauer Carrie M. Rosenberger Sharookh B. Kapadia Min Xu Miguel Reyes |
| author_sort | Kimberly Kajihara |
| collection | DOAJ |
| description | Abstract Both bacterial and viral infections can trigger an overwhelming host response, leading to immunopathology and organ dysfunction. Multiple studies have reported dysregulated myeloid cell states in patients with bacterial sepsis or severe SARS-CoV-2 infection. However, their relevance to viral infections other than COVID-19, the factors driving their induction, and their role in tissue injury remain poorly understood. Here, we performed a multi-cohort analysis of single cell and bulk transcriptomic data from 1845 patients across 25 studies. Our meta-analysis revealed a conserved severity-associated gene signature pointing to emergency myelopoiesis (EM) and increased IL1R2 expression in monocytes and neutrophils from patients with bacterial sepsis, COVID-19, and influenza. Analysis of tocilizumab-treated COVID-19 patients showed that IL-6 signaling blockade partially reduces this signature and results in a compensatory increase in G-CSF. To validate the role of these cytokines in vivo, we used a mouse model of influenza infection that recapitulates severity-associated increases in IL1R2+ monocytes and IL1R2hi neutrophils, and demonstrate that combined IL-6 and G-CSF blockade inhibits their production. Our study demonstrates the cooperative role of G-CSF and IL-6 in driving the production of severity-associated IL1R2+ myeloid cells and highlights the link between myeloid dysregulation and tissue injury during severe infection. |
| format | Article |
| id | doaj-art-ec4a89f83ba54c4facfd2faf7d023fd9 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-ec4a89f83ba54c4facfd2faf7d023fd92025-08-20T04:02:55ZengNature PortfolioCommunications Biology2399-36422025-07-018111110.1038/s42003-025-08407-ySystemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infectionsKimberly Kajihara0Donghong Yan1Gretchen L. Seim2Hannah Little-Hooy3Jing Kang4Cynthia Chen5Marco De Simone6Tim Delemarre7Spyros Darmanis8Haridha Shivram9Rebecca N. Bauer10Carrie M. Rosenberger11Sharookh B. Kapadia12Min Xu13Miguel Reyes14Department of Infectious Diseases, GenentechDepartment of Translational Immunology, GenentechDepartment of Infectious Diseases, GenentechDepartment of Translational Immunology, GenentechDepartment of Translational Immunology, GenentechDepartment of Microchemistry, Proteomics, Lipidomics and Next-Generation Sequencing, GenentechDepartment of Microchemistry, Proteomics, Lipidomics and Next-Generation Sequencing, GenentechDepartment of Immunology and Regenerative Medicine, GenentechDepartment of Microchemistry, Proteomics, Lipidomics and Next-Generation Sequencing, GenentechDepartment of Translational Medicine, GenentechDepartment of Translational Medicine, GenentechDepartment of Immunology and Regenerative Medicine, GenentechDepartment of Infectious Diseases, GenentechDepartment of Translational Immunology, GenentechDepartment of Infectious Diseases, GenentechAbstract Both bacterial and viral infections can trigger an overwhelming host response, leading to immunopathology and organ dysfunction. Multiple studies have reported dysregulated myeloid cell states in patients with bacterial sepsis or severe SARS-CoV-2 infection. However, their relevance to viral infections other than COVID-19, the factors driving their induction, and their role in tissue injury remain poorly understood. Here, we performed a multi-cohort analysis of single cell and bulk transcriptomic data from 1845 patients across 25 studies. Our meta-analysis revealed a conserved severity-associated gene signature pointing to emergency myelopoiesis (EM) and increased IL1R2 expression in monocytes and neutrophils from patients with bacterial sepsis, COVID-19, and influenza. Analysis of tocilizumab-treated COVID-19 patients showed that IL-6 signaling blockade partially reduces this signature and results in a compensatory increase in G-CSF. To validate the role of these cytokines in vivo, we used a mouse model of influenza infection that recapitulates severity-associated increases in IL1R2+ monocytes and IL1R2hi neutrophils, and demonstrate that combined IL-6 and G-CSF blockade inhibits their production. Our study demonstrates the cooperative role of G-CSF and IL-6 in driving the production of severity-associated IL1R2+ myeloid cells and highlights the link between myeloid dysregulation and tissue injury during severe infection.https://doi.org/10.1038/s42003-025-08407-y |
| spellingShingle | Kimberly Kajihara Donghong Yan Gretchen L. Seim Hannah Little-Hooy Jing Kang Cynthia Chen Marco De Simone Tim Delemarre Spyros Darmanis Haridha Shivram Rebecca N. Bauer Carrie M. Rosenberger Sharookh B. Kapadia Min Xu Miguel Reyes Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections Communications Biology |
| title | Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections |
| title_full | Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections |
| title_fullStr | Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections |
| title_full_unstemmed | Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections |
| title_short | Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections |
| title_sort | systemic cytokines drive conserved severity associated myeloid responses across bacterial and viral infections |
| url | https://doi.org/10.1038/s42003-025-08407-y |
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