Molecular analysis of acute pyelonephritis—excessive innate and attenuated adaptive immunity
This study investigated the molecular basis of disease severity in acute pyelonephritis (APN), a common and potentially life-threatening bacterial infection. Two cohorts of infants with febrile urinary tract infection were included. Renal involvement was defined by DMSA scans and molecular disease determinants by gene expression analysis and proteomic screens, at diagnosis and after 6 mo. Innate immune hyper-activation, systemically and locally in the urinary tract, was defined as a cytokine storm. Neutrophil degranulation and renal toxicity genes were strongly regulated, with overexpression in the APN group (first DMSA+). Adaptive immune attenuation in the APN group further supported the notion of an immune imbalance. DNA exome genotyping identified APN and febrile urinary tract infection as genetically distinct and scarring associated genes, but the activation of renal toxicity genes during acute infection was unrelated to the development of renal scarring. The results define APN as a hyper-inflammatory disorder with the characteristics of a cytokine storm combined with adaptive immune attenuation. The findings are consistent with innate immune dysfunctions and neutrophil disorders identified as determinants of APN susceptibility in genetic models.
Authors
- Gabriela Godaly (ORCID: https://orcid.org/0000-0002-3467-1350)
- Bernett Teck Kwong Lee (ORCID: https://orcid.org/0000-0002-2709-1972)
- Shahram Ahmadi (ORCID: https://orcid.org/0000-0001-5069-7131)
- Yong Hong Ng (ORCID: https://orcid.org/0000-0001-8884-1805)
- Therese Rosenblad (ORCID: https://orcid.org/0000-0001-8088-0287)
- Per Brandström (ORCID: https://orcid.org/0000-0001-8269-4488)
- John E. Connolly (ORCID: https://orcid.org/0000-0002-9680-3216)
- Inès Ambite (ORCID: https://orcid.org/0000-0003-1470-671X)
- Indra Ganesan (ORCID: https://orcid.org/0000-0003-3065-4948)
- Trần Thị Hiền (ORCID: https://orcid.org/0009-0004-0065-4490)
- Catharina Svanborg (ORCID: https://orcid.org/0000-0001-8145-0553)
- Farhan Haq (ORCID: https://orcid.org/0000-0001-9190-4360)
- Swaine L. Chen (ORCID: https://orcid.org/0000-0002-0107-2861)
- Petter Storm (ORCID: https://orcid.org/0000-0002-7655-3731)
- Magnus Lindén (ORCID: https://orcid.org/0000-0002-5592-1267)
- Sing Ming Chao
- Richard A. Hopkins
Institutions
- Agency for Science, Technology and Research (SG)
- National University of Singapore (SG)
- Lund University (SE)
- Singapore Immunology Network (SG)
- Drottning Silvias barn- och ungdomssjukhus (SE)
- KK Women's and Children's Hospital (SG)
- Hallands sjukhus Halmstad (SE)
- Genome Institute of Singapore (SG)
- University of Gothenburg (SE)
Publication Details
- Journal
- Life Science Alliance
- Published
- 2024-12-20
- DOI
- https://doi.org/10.26508/lsa.202402926
- Citations
- 4
- Primary Topic
- Pediatric Urology and Nephrology Studies
- Type
- article
- Field-Weighted Citation Impact
- 4.44
Funders
- European Commission
- Agency for Science, Technology and Research
- Cancerfonden
- Fondation pour la Recherche Médicale
- Vetenskapsrådet
- Kungliga Fysiografiska Sällskapet i Lund
- Horizon 2020 Framework Programme
- Medical Research Council
- European Research Council
- National Medical Research Council
- Biomedical Research Council