Role of sialic acid-containing molecules and the α4β1 integrin receptor in the early steps of polyomavirus infection

Abstract

Murine polyomavirus (MPyV) infection occurs through recognition of sialic acid (SA) residues present on the host cell membrane, but the nature of the molecules involved and the exact role of this interaction in virus cell entry still need to be clarified. In this work, mutations at residues R 77 or H 298 of the MPyV VP1 protein were shown to lead to a complete loss of virus infectivity, which, however, could be restored by lipofection of virus particles into the cytoplasm of the host cells. Using virus-like particles (VLPs), it was demonstrated that the non-infectivity of these mutants was due to impaired cell entry caused by total abrogation of SA-dependent cell binding. This indicates that SA residues are essential primary cell receptors for MPyV. As the a4b1 integrin has been identified recently as a cell receptor for MPyV, the relationship, if any, was investigated between SA-containing and a4b1 integrin receptors. The ability of mutants R 77 Q and H 298 Q and wt VLPs to bind to cells overexpressing the a4b1 integrin was studied in SA-positive (BALB/c 3T3 cells and Pro-5 cells) and SA-deficient (Pro5-derived Lec-2 cells) backgrounds. Overexpression of a4b1 integrin did not restore binding of mutant VLPs in any of these cell lines or, indeed, that of wt VLPs in a SA-deficient background. Moreover, evidence is provided that overexpression of the sialylated a4b1 integrin enhances wt VLP cell binding, suggesting that, in addition to its function at a post-attachment level, a4b1 integrin acts also as one of the SA-containing receptors for initial cell binding.

Host cell virus entry mechanisms enhance anti-JCV-antibody switch in natalizumab-treated multiple sclerosis patients

“…Together with transferrin receptor, these two highly expressed molecules contribute to increased viral insertion into host cells of future JCV switchers (Caruso et al 2003;Komagome et al 2002). We would like to note that in a previous report by Harrer et al that examined gene expression effects of natalizumab treatment, in contrast to our findings, VLA-4 was found to be down-regulated (Harrer et al 2011).…”

The role of sialic acid in human polyomavirus infections

“…SV40 uses MHC class I molecules to enter cells but, unlike other polyomaviruses, it has not been shown to require sialic acid [13,103]. MPyV uses α4β1 integrin to enter cells but also requires sialic acid [17,18]. It is well documented that mPyV requires α2-3-linked sialic acid to bind functionally to cells, although it is also clear that the virus can bind α2-6-linked sialic acid which acts as a pseudoreceptor [31].…”

“…SV40 uses MHC class I molecules as cell surface receptors [14]. MPyV uses α4β1 integrin as a cellular receptor although initial attachment is mediated by sialic acid [15][16][17][18][19]. JCV uses the serotonergic receptor 5HT 2A to infect cells, but infection is also dependent on α2-6-linked sialic acid [20,21].…”

Bionanoparticles and their Biomedical Applications

“…Many viruses of Polyomaviridae family generate intact VLPs, solely constructed of the major coat protein, VP1, without the two minor coat proteins (VP2 and VP3) [138]. VP1, when expressed in insect cells [139][140][141][142], yeast [143] and E. coli [144,145], self-assembles as protein cages, and naturally targets a cell surface glycoprotein with a terminal a2,3-linked N-acetyl neuraminic acid [138,146], and is internalized by the cells via a 4 b 1 integrin receptors [147,148]. Human JC polyomavirus, which in its native form infects human oligodendrocytes in the brain [149], was engineered as VLPs to deliver therapeutic genes to human fetal glial cells [150].…”