Human Desmoglein-2 and Human CD46 Mediate Human Adenovirus Type 55 Infection, but Human Desmoglein-2 Plays the Major Roles

Abstract

Human adenovirus type 55 (HAdV55) represents an emerging respiratory pathogen and causes severe pneumonia with high fatality in humans. The cellular receptors, which are essential for understanding the infection and pathogenesis of HAdV55, remain unclear. Here, we found that HAdV55 binding and infection were sharply reduced by disrupting the interaction of viral fiber protein with human desmoglein-2 (hDSG2) but only slightly reduced by disrupting the interaction of viral fiber protein with human CD46 (hCD46). Loss-of-function studies using soluble receptors, blocking antibodies, RNA interference, and gene knockout demonstrated that hDSG2 predominantly mediated HAdV55 infection. Non-permissive rodent cells became susceptible to HAdV55 infection when hDSG2 or hCD46 was expressed, but hDSG2 mediated more efficient HAd55 infection than hCD46. We generated two transgenic mouse lines that constitutively express either hDSG2 or hCD46. Although non-transgenic mice were resistant to HAdV55 infection, infection of HAd55 was significantly increased in hDSG2+/+ mice but was much less increased in hCD46+/+ mice. Our findings demonstrate that both hDSG2 and hCD46 are able to mediate HAdV55 infection but hDSG2 plays the major roles. The hDSG2 transgenic mouse can be used as a rodent model for evaluation of HAdV55 vaccine and therapeutics. IMPORTANCE Human adenovirus type 55 (HAdV55) has recently emerged as a highly virulent respiratory pathogen and has been linked to severe and even fatal pneumonia in immuno-competent adults. However, the cellular receptors mediating the entry of HAdV55 into host cells remain unclear, which hinders the establishment of HAdV55-infected animal models and the development of antiviral approaches. In this study, we demonstrated that human desmoglein-2 (hDSG2) plays the major roles during HAdV55 infection. Human CD46 (hCD46) could also mediate the infection of HAdV55, but the efficiency was much lower than hDSG2. We generated two transgenic mouse lines that express either hDSG2 or hCD46, both of which enabled HAd55 infection in otherwise non-transgenic mice. hDSG2 transgenic mice enabled more efficient HAdV55 infection than hCD46 transgenic mice. Our study adds to our understanding of HAdV55 infection and provides an animal model for evaluating HAdV55 vaccines and therapeutics.

A Human In Vitro Model to Study Adenoviral Receptors and Virus Cell Interactions

“…FACS analysis revealed that A549 cells express CD46 at high levels and CAR at lower levels ( Figure 1 ). Other surface molecules important for cell entry of adenoviruses are DSG2, CD80 and CD86 [ 46 , 47 ]. For DSG2, we detected a positive signal for 98.6% of the analyzed cells, and for CD80 and CD86, no expression was detected on A549 cells ( Supplementary Table S1 ).…”

“…A recent study described a DSG-2 and CD46 single and double knockout cell line based on A549 cells, which was used to investigate the receptor usage of human adenovirus type 55 [ 47 ]. This study revealed that this virus type mainly uses DSG-2 as an entry receptor and underlines the value of our generated cell lines.…”

Infectivity of human group B adenovirus to cells from different species

“…Accord to the phylogenetic evolution analysis, the amino acid sequences of human and monkey CD46 were most similar. Studies have mentioned that transferring human CD46 to animal cells or making human CD46 transgenic animals can increase the infectivity of group B adenoviruses [20]. While Lei et al reported different results and they showed that expression of human CD46 failed to allow productive infection by a group B oncolytic adenovirus in murine cancer cells [21].…”

Chinese tree shrew: a permissive model for in vitro and in vivo replication of human adenovirus species B

“…Although this tree shrew model maybe imperfect and there are several questions related to this model, such as whether the virus transmitted from inoculated tree shrew caused pathogenesis in lung, bronchia or other tissues of naïve tree shrew, or whether this virus could be transmitted to other tree shrews, which will be answered in our future work. Recently, Feng Y et al reported that although both human desmoglein-2 and human CD46 mediate HAdV-55 infection, but human desmoglein-2 plays a major role [ 51 ]. Amino acid sequence alignment showed 81.24% similarity between desmoglein-2 of Homo sapiens and Chinese tree shrew (Tupaia chinensis), which is higher than that between Homo sapiens and Sus scrofa (78.41%), and Mus musculus (76.18%), but lower than between Homo sapiens and Gorilla gorilla gorilla (97.5%), and Macaca mulatta (96.26%).…”