Structural and functional analysis of natural capsid variants reveals sialic-acid independent entry of BK polyomavirus

Sorin, M.; Di Maio, A.; Silva, L. M.; Ebert, D.; Delannoy, C.; Nguyen, N.-K.; Guerardel, Y.; Chai, W.; Halary, F.; Renaudin-Autain, K.; Liu, Y.; Bressollette-Bodin, C.; Stehle, T.; McILROY, D.

doi:10.1101/2022.07.13.499703

bioRxiv · 10.1101/2022.07.13.499703

Structural and functional analysis of natural capsid variants reveals sialic-acid independent entry of BK polyomavirus

Sorin, M.·Di Maio, A.·Silva, L. M.·Ebert, D.·Delannoy, C.·Nguyen, N.-K.·Guerardel, Y.·Chai, W.·Halary, F.·Renaudin-Autain, K.·Liu, Y.·Bressollette-Bodin, C.·Stehle, T.·McILROY, D.

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Abstract

BK Polyomavirus (BKPyV) is an opportunistic pathogen that causes nephropathy in kidney transplant recipients. The BKPyV major capsid protein, VP1, engages gangliosides, lipid-linked sialylated glycans at the cell surface, to gain entry into cells. Here, we characterise the influence of VP1 mutations observed in patients with persistent post-transplant BKPyV replication on ganglioside binding, VP1 protein structure, and the tropism of the virus in two renal cell lines: 293TT and immortalised renal tubular epithelial (RS) cells. Infectious entry of single mutants E73Q, E73A and the triple mutant A72V-E73Q-E82Q (VQQ) remained sialic acid-dependent. These three variants acquired binding to a-series gangliosides, including GD1a, although only E73Q was able to infect GD1a-supplemented LNCaP or GM95 cells. Crystal structures of the three mutants showed a clear shift of the BC2 loop in mutants E73A and VQQ that correlated with the inability of these VP1 variants to infect ganglioside complemented cells. On the other hand, the double mutant K69N-E82Q lost the ability to bind sialic acid, with the K69N mutation leading to a steric clash which precludes sialic acid binding. Nevertheless, this mutant retained significant infectivity in 293TT cells that was not dependent on heparan sulphate proteoglycans, implying that an unknown sialic acid-independent entry receptor for BKPyV exists.

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Sorin, M., Di Maio, A., Silva, L. M., Ebert, D., Delannoy, C., Nguyen, N.-K., Guerardel, Y., Chai, W., Halary, F., Renaudin-Autain, K., Liu, Y., Bressollette-Bodin, C., Stehle, T., McILROY, D.. 2022-07-14. Structural and functional analysis of natural capsid variants reveals sialic-acid independent entry of BK polyomavirus. https://doi.org/10.1101/2022.07.13.499703

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