The prion-family protein Doppel exerts a protective role during influenza virus infection

The cellular form of the prion protein (PrPC), known for its involvement as a misfolded isoform in transmissible spongiform encephalopathies, has recently been identified to exert a protective effect against viral infections. In this study, we explored the role of 2 other prion family members, Shadoo and Doppel, in protection against influenza A virus infection in mice. Lung expression levels of these genes revealed marked differences, with high expression of PrPC, low expression of Doppel, while Shadoo remained undetectable. Mice genetically knocked out for the genes encoding PrPC, Prnp-/- or Doppel, Prnd-/-, showed increased susceptibility to the virus, resulting in elevated morbidity compared with wild-type mice and mice knocked out for Shadoo, Sprn-/-. Unlike previous results observed in Prnp-/- mice, the absence of Doppel does not show enhancing effect on virus replication levels. Histological analysis of lung tissue from Prnd-/- mice revealed no difference in lesion size and severity compared with wild-type mice. However, transcriptomic analysis on day 7 postinfection revealed distinct signatures in Prnd-/- mice, highlighting the role of specific genes associated with polymorphonuclear neutrophil cells. Bronchoalveolar lavages confirmed a substantial neutrophil influx and increased inflammatory markers in the lungs of Prnd-/- mice. Neutrophil depletion experiments demonstrated a direct link between excessive neutrophil influx and increased susceptibility, mitigating pathology and partially restoring a wild-type phenotype in Prnd-/- mice. These findings underscore the complex role of Doppel in modulating the host immune response to influenza virus infection, particularly in regulating neutrophil recruitment and its implications on disease outcomes.