Higher affinities of fibers with cell receptors increase the infection capacity and virulence of human adenovirus type 7 and type 55 compared to type 3

Human adenovirus (HAdV) type 7 and type 55 infections cause more severe pneumonia than type 3 infections. However, the underlying mechanisms remain unclear. This study provided evidence linking the receptor-binding protein, fiber, to the stronger virulence of HAdV-55 and HAdV-7. Wild-type HAdV-7 and HAdV-55 produced larger plaques and grew more efficiently, resulting in a higher viral yield than HAdV-3. The recombinant knobs of HAdV-55 and HAdV-7 had higher binding affinities with desmoglein 2 (DSG2) than the HAdV-3 knob. Fiber-chimeric rAdV3E-K7 and rAdV3E-K55 were generated by replacing the knob of recombinant HAdV-3 (rAd3E) with knobs from HAdV-7 and HAdV-55, respectively. Full-length fiber-replaced rAd5-F3, rAd5-F7, and rAd5-F55 were generated from replication-defective HAdV-5. The replication and infectivity of these adenoviruses were compared using passage and primary cell and DSG2-humanized mouse models. Both rAdV3E-K7 and rAdV3E-K55 produced larger plaques and adsorbed more efficiently than rAd3E in A549 cells and primary human bronchial epithelial cells. Additionally, rAd5-F7 and rAd5-F55 showed stronger infectivity than rAd5-F3. Finally, rAdV3E-K7 and rAdV3E-K55 infections contributed to slightly more but not significant severe pneumonia than rAd3E in the humanized mouse model. In summary, higher binding affinities of fibers with DSG2 lead to higher infection efficiency of HAdV-7 and HAdV-55 compared to HAdV-3. This study provides new insights into the mechanisms of differential pathogenicity between HAdV types. It may have implications for the surveillance of highly pathogenic adenovirus strains and the development of novel adenovirus vectors and vaccines.IMPORTANCEHAdV-3, -7, and -55 are the predominant types causing acute respiratory disease outbreaks and can lead to severe and fatal pneumonia in children and adults. In recent years, emerging or re-emerging strains of HAdV-7 and HAdV-55 have caused multiple outbreaks globally in both civilian and military populations, drawing increased attention. Clinical studies have reported that HAdV-7 and HAdV-55 cause more severe pneumonia than HAdV-3. This study aimed to investigate the mechanisms explaining the higher severity of HAdV-7 and HAdV-55 infection compared to HAdV-3 infection. Our findings provided evidence linking the receptor-binding protein fiber to stronger infectivity of the strains mentioned above by comparing several fiber-chimeric or fiber-replaced adenoviruses. Our study improves our understanding of adenovirus infection and highlights potential implications, including in novel vector and vaccine development. HAdV-3, -7, and -55 are the predominant types causing acute respiratory disease outbreaks and can lead to severe and fatal pneumonia in children and adults. In recent years, emerging or re-emerging strains of HAdV-7 and HAdV-55 have caused multiple outbreaks globally in both civilian and military populations, drawing increased attention. Clinical studies have reported that HAdV-7 and HAdV-55 cause more severe pneumonia than HAdV-3. This study aimed to investigate the mechanisms explaining the higher severity of HAdV-7 and HAdV-55 infection compared to HAdV-3 infection. Our findings provided evidence linking the receptor-binding protein fiber to stronger infectivity of the strains mentioned above by comparing several fiber-chimeric or fiber-replaced adenoviruses. Our study improves our understanding of adenovirus infection and highlights potential implications, including in novel vector and vaccine development.