Pdcd1^-/- Mice Exhibit High Susceptibility to Respiratory Syncytial Virus Infection

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract illness in infants, yet no highly effective treatment exists. The widely used BALB/c mouse model is only semipermissive to RSV and does not fully recapitulate the severe disease seen in humans, highlighting the need for improved preclinical models.

WT and Pdcd1^-/- mice were challenged intranasally (i.n.) with a low dose of RSV (10⁶ PFU). Disease severity was assessed by weight loss, lung function, viral load, and histopathology. Immune responses were characterized via flow cytometry, immunohistochemistry, and cytokine/chemokine measurement.

Compared to WT mice, Pdcd1^-/- mice developed significantly more severe illness, evidenced by exacerbated weight loss, lung dysfunction, histopathology, and elevated viral replication. The acute phase was marked by robust neutrophil lung infiltration, elevated chemokines (CXCL1 and CXCL2), and heightened myeloperoxidase (Mpo) activity. Pdcd1 knockout skewed the adaptive immune response, promoting a Th2-biased CD4⁺ T cell infiltration while impairing CD8⁺ T cell cytotoxicity, as indicated by reduced perforin and granzyme B expression. Critically, Pdcd1^-/- mice exhibited a profound defect in antiviral cytokine production, with significantly lower levels of both IFN-γ and IFN-α in lungs and serum postinfection.

Pdcd1 knockout renders mice highly susceptible to RSV, manifesting as enhanced viral replication, severe immunopathology featuring Th2 bias and neutrophil-driven inflammation, and a blunted antiviral interferon response. This phenotype more closely mirrors key aspects of severe human RSV infection, establishing the Pdcd1^-/- mouse as a sensitive animal model for evaluating novel therapeutics.