Abstract
Trichodysplasia spinulosa-associated Polyomavirus (TSPyV) was isolated from a patient suffering from trichodysplasia spinulosa, a skin disease that can appear in severely immunocompromised patients. While TSPyV is one of the five members of the polyomavirus family that are directly linked to a human disease, details about molecular recognition events, the viral entry pathway, and intracellular trafficking events during TSPyV infection remain unknown. Here we have used a structure-function approach to shed light on the first steps of TSPyV infection. We established by cell binding and pseudovirus infection studies that TSPyV interacts with sialic acids during attachment and/or entry. Subsequently, we solved high-resolution X-ray structures of the major capsid protein VP1 of TSPyV in complex with three different glycans, the branched GM1 glycan, and the linear trisaccharides α2,3- and α2,6-sialyllactose. The terminal sialic acid of all three glycans is engaged in a unique binding site on TSPyV VP1, which is positioned about 18 Å from established sialic acid binding sites of other polyomaviruses. Structure-based mutagenesis of sialic acid-binding residues leads to reduction in cell attachment and pseudovirus infection, demonstrating the physiological relevance of the TSPyV VP1-glycan interaction. Furthermore, treatments of cells with inhibitors of N-, O-linked glycosylation, and glycosphingolipid synthesis suggest that glycolipids play an important role during TSPyV infection. Our findings elucidate the first molecular recognition events of cellular infection with TSPyV and demonstrate that receptor recognition by polyomaviruses is highly variable not only in interactions with sialic acid itself, but also in the location of the binding site.
Highlights
Trichodysplasia spinulosa-associated Polyomavirus (TSPyV) was discovered in 2010 in facial skin samples from a patient with the skin disease trichodysplasia spinulosa (TS) [1]
We found that TSPyV engages sialic acid receptors but employs a novel binding site on the capsid that is shifted in comparison to other structurally characterized polyomaviruses
To determine if TSPyV interacts with sialic acids on cell surfaces, we first examined binding of unassembled TSPyV VP1 pentamers to cultured human cells by flow cytometry (Fig 1A and S1 Fig)
Summary
Trichodysplasia spinulosa-associated Polyomavirus (TSPyV) was discovered in 2010 in facial skin samples from a patient with the skin disease trichodysplasia spinulosa (TS) [1]. High viral loads have been detected only in TS patients, whereas samples from the skin, plucked eyebrows, serum/plasma, and urine of immunocompetent andcompromised individuals were mostly negative for TSPyV DNA [1,6,10]. The detection of TSPyV DNA in tonsillar samples from healthy individuals indicates that the virus infects lymphoid tissue establishing a persistent infection [10,14]. Viral shedding and spreading from this persistent site may be crucial for transmission and reactivation during immunosuppression [14]
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