Influenza A virus replicates productively in primary human kidney cells and induces factors and mechanisms related to regulated cell death and renal pathology observed in virus-infected patients

Front Cell Infect Microbiol. 2024 Mar 25:14:1363407. doi: 10.3389/fcimb.2024.1363407. eCollection 2024.


Introduction: Influenza A virus (IAV) infection can cause the often-lethal acute respiratory distress syndrome (ARDS) of the lung. Concomitantly, acute kidney injury (AKI) is frequently noticed during IAV infection, correlating with an increased mortality. The aim of this study was to elucidate the interaction of IAV with human kidney cells and, thereby, to assess the mechanisms underlying IAV-mediated AKI.

Methods: To investigate IAV effects on nephron cells we performed infectivity assays with human IAV, as well as with human isolates of either low or highly pathogenic avian IAV. Also, transcriptome and proteome analysis of IAV-infected primary human distal tubular kidney cells (DTC) was performed. Furthermore, the DTC transcriptome was compared to existing transcriptomic data from IAV-infected lung and trachea cells.

Results: We demonstrate productive replication of all tested IAV strains on primary and immortalized nephron cells. Comparison of our transcriptome and proteome analysis of H1N1-type IAV-infected human primary distal tubular cells (DTC) with existing data from H1N1-type IAV-infected lung and primary trachea cells revealed enrichment of specific factors responsible for regulated cell death in primary DTC, which could be targeted by specific inhibitors.

Discussion: IAV not only infects, but also productively replicates on different human nephron cells. Importantly, multi-omics analysis revealed regulated cell death as potential contributing factor for the clinically observed kidney pathology in influenza.

Keywords: acute kidney injury; distal tubular cells; influenza A virus; proteomics; regulated cell death; transcriptomics.

MeSH terms

  • Acute Kidney Injury*
  • Humans
  • Influenza A Virus, H1N1 Subtype*
  • Influenza A Virus, H3N2 Subtype / physiology
  • Influenza A virus*
  • Influenza, Human*
  • Kidney / pathology
  • Orthomyxoviridae Infections* / pathology
  • Proteome / metabolism
  • Regulated Cell Death*
  • Virus Replication / physiology


  • Proteome

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The research was funded in part by the University Hospital Frankfurt am Main, a postdoctoral fellowship of the Justus-Liebig University, Giessen, Germany (Just’Us to AM), and the NRC internal project (TT110801 to AM). Furthermore, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) funded collaborative research center SFB1021 (TP C01 to StP) and the German Ministry for Education and Research (BMBF) funded German Center for Infection Research, partner site Giessen, Germany (DZIF, TTU 01.806 to SP and JZ). The research was also funded by the Alexander von Humboldt Foundation with a Georg Forster Research Fellowship (MS). StP is a member of the German FluResearchNet, a nationwide research network on zoonotic influenza. Research on influenza in the LM-S laboratory is partially supported by the R01AI145332 and R01AI141607 grants from the National Institute of Health (NIH); by the Center for Research on Influenza Pathogenesis and Transmission (CRIPT), one of the National Institute of Allergy and Infectious Diseases (NIAID)-funded Centers of Excellence for Influenza Research and Response (CEIRR; contract No. 75N93021C00014); and by the American Lung Association. The funders had no role in study design, data collection/analysis, decision to publish, or preparation of the manuscript.