The GD1a glycan is a cellular receptor for adenoviruses causing epidemic keratoconjunctivitis

Abstract

Adenovirus type 37 (Ad37) is a leading cause of epidemic keratoconjunctivitis (EKC), a severe and highly contagious ocular disease. Whereas most other adenoviruses infect cells by engaging CD46 or the coxsackie and adenovirus receptor (CAR), Ad37 binds previously unknown sialic acid-containing cell surface molecules. By glycan array screening, we show here that the receptor-recognizing knob domain of the Ad37 fiber protein specifically binds a branched hexasaccharide that is present in the GD1a ganglioside and that features two terminal sialic acids. Soluble GD1a glycan and GD1a-binding antibodies efficiently prevented Ad37 virions from binding and infecting corneal cells. Unexpectedly, the receptor is constituted by one or more glycoproteins containing the GD1a glycan motif rather than the ganglioside itself, as shown by binding, infection and flow cytometry experiments. Molecular modeling, nuclear magnetic resonance and X-ray crystallography reveal that the two terminal sialic acids dock into two of three previously established sialic acid-binding sites in the trimeric Ad37 knob. Surface plasmon resonance analysis shows that the knob-GD1a glycan interaction has high affinity. Our findings therefore form a basis for the design and development of sialic acid-containing antiviral drugs for topical treatment of EKC.

A unique secreted adenovirus E3 protein binds to the leukocyte common antigen CD45 and modulates leukocyte functions

“…For coprecipitation with purified sec49K, 600 ng of purified sec49K was added, followed by incubation for 1 h at 4°C before immunoprecipitation. Immunoprecipitation was performed with antibodies directed against the C terminus (lanes [1][2][3][4][5][6][7][8][9] or N terminus (lanes 10-13). Arrows indicate full-length E3/49K (49K) and E3/49K-derived species, and arrowheads indicate the three protein species specifically binding to E3/49K in Jurkat cell lysates.…”

“…Interestingly, some Ads of species D, including Ad8, Ad37, Ad19a [recently renamed Ad64 (2)], and the more recently sequenced Ad53, Ad54, and Ad56 (2,4,5), cause a distinct disease, epidemic keratoconjunctivitis (EKC) (6). Surprisingly, this specific pathogenesis in the eye contrasts with the rather ubiquitous receptor profile of EKC-causing Ads (7,8), and thus is likely linked to selective events occurring postattachment, such as differential triggering of innate and adaptive immune responses (3,9,10). Thus, differential immunomodulatory functions encoded in early transcription unit 3 (E3) may play an important role in disease (9,11).…”

The complete genome sequence of human adenovirus 84, a highly recombinant new Human mastadenovirus D type with a unique fiber gene

“…Sialic acid is used mainly by ocular adenoviruses, and most respiratory adenoviruses use other receptors such as CD46, DSG2 and/or CAR (Arnberg, 2012). These results might indicate that specific types of sialic acid-binding adenoviruses (Nilsson et al, 2011) may also cause respiratory infections. Cases of HAdV-D respiratory infection are only reported from neonate patients.…”

“…A bioinformatic analysis was performed to assess this fiber's potential receptor-binding capabilities. Desmoglein 2-(DSG2), CD46-, sialic acid-and coxsackie and adenovirus receptor-(CAR) binding was analysed by comparing the HAdV-84 fiber sequence to those of HAdV-3 (NCBI Protein: YP_002213796) (Wang et al, 2013), HAdV-11 (AAN62521) (Persson et al, 2007), HAdV-19 (1UXB_A) and HAdV-37 (ABK59080) (Burmeister et al, 2004;Nilsson et al, 2011;Seiradake et al, 2006), respectively. Alignments with the above mentioned fiber knobs' aa sequences were conducted using the MAFFT G-INS-I method.…”

More symptoms with sialic receptor‐positive adenovirus in epidemic keratoconjunctivitis

“…We believe we found two cases of HAdV-53 in our cohort; however, this was a surprise and the methodology was not validated for this at the time of analysis. The presence of SA-binding HAdV capsid protein (fibre) may also be a possible target for treatment (Nilsson et al 2011). The virus load per se did not seem to correlate with the symptoms at the inclusion; however, the presence of SA + HAdV seems to be related to more …”