Human adenovirus type 55 (HAdV-B55) is a re-emergent acute respiratory disease pathogen that causes adult community-acquired pneumonia (CAP).Previous studies have shown that the receptor of HAdV-B 14,which genome is highly similar with HAdV-B55,is human Desmoglein 2 (DSG2).However,whether the receptor of HAdV-B55 is DSG2 is undetermined because there are three amino acid mutations in thefiber gene between HAdV-B 14 and HAdV-B55.Here,firstly we found the 3T3 cells,a mouse embryo fibroblast rodent cell line which does not express human DSG2,were able to be infected by HAdV-B55 after transfected with pcDNA3.1-DSG2,while normal 3T3 cells were still unsusceptible to HAdV-B55 infection.Next,A549 cells with hDSG2 knock-down by siRNA were hard to be infected by HAdV-B3/-B 14/-B55,while the control siRNA group was still able to be infected by all these types of HAdVs.Finally,immunofluorescence confocal microscopy indicated visually that Cy3-conjugated HAdV-B55 viruses entered A549 cells by binding to DSG2 protein.Therefore,DSG2 is a major receptor of HAdV-B55 causing adult CAP.Our finding is important for better understanding of interactions between adenoviruses and host cells and may shed light on the development of new drugs that can interfere with these processes as well as for the development of potent prophylactic vaccines.