Abstract
Species B human adenoviruses (Ads) are increasingly associated with outbreaks of acute respiratory disease in U.S. military personnel and civil population. The initial interaction of Ads with cellular attachment receptors on host cells is via Ad fiber knob protein. Our previous studies showed that one species B Ad receptor is the complement receptor CD46 that is used by serotypes 11, 16, 21, 35, and 50 but not by serotypes 3, 7, and 14. In this study, we attempted to identify yet-unknown species B cellular receptors. For this purpose we used recombinant Ad3 and Ad35 fiber knobs in high-throughput receptor screening methods including mass spectrometry analysis and glycan arrays. Surprisingly, we found that the main interacting surface molecules of Ad3 fiber knob are cellular heparan sulfate proteoglycans (HSPGs). We subsequently found that HSPGs acted as low-affinity co-receptors for Ad3 but did not represent the main receptor of this serotype. Our study also revealed a new CD46-independent infection pathway of Ad35. This Ad35 infection mechanism is mediated by cellular HSPGs. The interaction of Ad35 with HSPGs is not via fiber knob, whereas Ad3 interacts with HSPGs via fiber knob. Both Ad3 and Ad35 interacted specifically with the sulfated regions within HSPGs that have also been implicated in binding physiologic ligands. In conclusion, our findings show that Ad3 and Ad35 directly utilize HSPGs as co-receptors for infection. Our data suggest that adenoviruses evolved to simulate the presence of physiologic HSPG ligands in order to increase infection.
Highlights
Human adenoviruses (Ads) have been classified into six species (A to F) currently containing 51 serotypes
Screening assays indicated that (i) CD46 is a ligand of the Ad35 but not the Ad3 knob and (ii) cellular heparan sulfate proteoglycans (HSPGs) are ligands of the Ad3 but not the Ad35 knob
We subsequently confirmed that the Ad3 but not the Ad35 knob interacted with HSPGs on cells in a cationindependent, sulfation-dependent and low-affinity manner
Summary
Human adenoviruses (Ads) have been classified into six species (A to F) currently containing 51 serotypes. Most Ad serotypes utilize the coxsackie-adenovirus-receptor, CAR, as a primary attachment receptor [1]. Species B Ads form two genetic clusters, B1 (Ad3, Ad7, Ad16, Ad21, and Ad50) and B2 (Ad11p, Ad14, Ad34, and Ad35) [2] This classification of species B partially correlates with tissue tropism but does not indicate receptor usage. Our previous study showed that receptor X is identical for Ad3, 7, 11p and 14 [3] This novel receptor-usage based grouping system is supported by studies from others and us that found CD46-usage for Ad serotype 11p, 16, 21, 35 and 50 but not for serotype 3 and 7 [4,5,6,7]. Marttila et al confirmed that CD46 blockade on human cells did not affect Ad3 and Ad7 infection, only partially inhibited Ad11p infection and completely abolished infection by serotype 16, 21, 35 and 50 [4]
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