| dc.description.abstract |
Polyomaviruses are non-enveloped, double-stranded DNA viruses infecting animals, including mammals, birds, and fish. In immunocompromised individuals, certain polyomaviruses can inflict severe disease. In most cases, however, infection with a polyomavirus is asymptomatic and remains latent. Polyomavirus particles comprise a capsid containing the genomic DNA, and that capsid is an icosahedral construct of several capsid proteins. The capsid is scaffolded by the major capsid protein VP1, a pentameric protein that protects the genome and enables polyomaviruses to recognize and eventually infect their target cells. Most known natural cellular receptors of polyomaviruses are carbohydrate structures (glycans) that carry a terminal sialic acid. The sialic acid, a nine-carbon comprising monosaccharide, is recognized by VP1 through peripheral protrusions from its core domain. These carbohydrate receptor-engaging protein loops are highly diverse between polyomavirus species and vary in sequence and length. This diversity, often called plasticity, constitutes the platform to recognize the different structural contexts of sialic acids, such as their chemical modifications or their linkage to the next monosaccharide. The individual interactions between a VP1 and its sialic acid receptors are usually weak with millimolar dissociation constants. However, 360 binding sites on the entire capsid can act in concert during cellular attachment, compensating for this deficiency. Polyomavirus receptors beyond the scope of sialylated glycans are known, including glycosaminoglycans and membrane proteins, but detailed structural information about the respective interactions remains elusive.\\
In this thesis, I show for the first time that several polyomaviruses can interact with non-sialylated, neutral carbohydrates. Therein, I characterize a binding site for the Forssman antigen (FA) glycan in the sheep polyomavirus (ShPyV) VP1. My functional assays reveal that ShPyV VP1 efficiently binds to FA-positive blood cells, surpassing established FA-binding proteins in specificity and affinity. These findings complement our understanding of receptor engagement by polyomaviruses and include the first report of a virus specifically interacting with FA. As an aberrant glycosylation linked to human cancer, the Forssman antigen is a potential biomedical marker. ShPyV VP1 may facilitate its detection in the future. |
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