Genetic analysis of cuproptosis subtypes and immunological features in severe influenza

The mechanisms regulating cuproptosis in severe influenza are still unknown. We aimed to identify the molecular subtypes of cuproptosis and immunological characteristics associated with severe influenza in patients requiring invasive mechanical ventilation (IMV). The expression of cuproptosis modulatory factors and immunological characteristics of these patients were analyzed using the public datasets (GSE101702, GSE21802, and GSE111368) from the Gene Expression Omnibus (GEO). Seven cuproptotic-associated genes (ATP7B, ATP7A, FDX1, LIAS, DLD, MTF1, DBT) related to active immune responses were identified in patients suffering from severe and non-severe influenza and two cuproptosis-associated molecular subtypes were discovered in severe influenza patients. Singe-set gene set expression analysis (SsGSEA) indicated that compared with subtype 2, subtype 1 was characterized by reduced adaptive cellular immune responses and increased neutrophil activation. Gene set variation assessment revealed that cluster-specific differentially expressed genes (DEGs) in subtype 1 were involved in autophagy, apoptosis, oxidative phosphorylation, and T cell, immune, and inflammatory responses, amongst others. The random forest (RF) model revealed the most differentiating efficiency with relatively small residual and root mean square error and an increased area under the curve value (AUC = 0.857). Lastly, a five-gene-based RF model (CD247, GADD45A, KIF1B, LIN7A, HLA_DPA1) was established, which showed satisfactory efficiency in the test datasets GSE111368 (AUC = 0.819). Nomogram calibration and decision curve analysis demonstrated its accuracy for the prediction of severe influenza. This study suggests that cuproptosis might be associated with the immunopathology of severe influenza. Additionally, an efficient model for the prediction of cuproptosis subtypes was developed which will contribute to the prevention and treatment of severe influenza patients needing IMV.