Potential effects of genetic variations in fusion protein on the virulence of human respiratory syncytial virus

Introduction: The fusion glycoprotein (F protein) of human respiratory syncytial virus (HRSV) critically determines viral infectivity and host immune recognition. This study evaluated the effects of F protein genetic variations from the globally dominant HRSV genotypes ON1 and BA9 on viral replication dynamics and pathogenicity. Methods: Using a reverse genetics system, two recombinant HRSV strains, rLong-BJ1903-AF and rLong-SY2103-BF, were generated by replacing the F gene in the isogenic Long-bacterial artificial chromosome (BAC) backbone with F genes derived from the clinical isolates BJ19-03 (ON1 genotype) and SY21-03 (BA9 genotype), respectively. Their phenotypes were assessed in cellular and animal models. Among them, rLong-SY2103-BF displayed greater pathogenicity than rLong-BJ1903-AF, as shown by slower body weight recovery, higher lung viral loads, elevated proinflammatory cytokine levels, and marked pulmonary pathological alterations. Discussion: These findings indicate that both recombinant viruses exhibit reduced replication capacity and less severe pathogenic phenotypes compared with the Long-BAC parental strain in this F-gene replacement system, providing a foundation for antiviral and immunological strategies targeting HRSV.