Direct Correlation between Sialic Acid Binding and Infection of Cells by Two Human Polyomaviruses (JC Virus and BK Virus)

Dugan, Aisling S.; Gasparovic, Megan L.; Atwood, Walter J.

doi:10.1128/jvi.02123-07

Cited by 56 publications

(46 citation statements)

References 32 publications

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“…Gangliosides are used by Sendai virus, bovine adeno-associated virus (BAAV), and human parainfluenza virus types 1 and 2 (21, 60, 66), but bovine parvovirus (BPV), influenza A virus, BK virus, JC virus, EV70, human norovirus, rotavirus, and adeno-associated virus serotypes 4 and 5 (AAV4 and AAV5) use sialic acid-containing glycoproteins as receptors (8,16,18,19,33,42,53,59,74). In many of these cases, the underlying glycan-carrying molecule is poorly understood, and this is also the case for AHC-causing CVA24v.…”

Section: Discussionmentioning

confidence: 99%

Coxsackievirus A24 Variant Uses Sialic Acid-Containing O -Linked Glycoconjugates as Cellular Receptors on Human Ocular Cells

Mistry¹,

Inoue²,

Jamshidi³

et al. 2011

J Virol

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Coxsackievirus A24 variant (CVA24v) is a main causative agent of acute hemorrhagic conjunctivitis (AHC), which is a highly contagious eye infection. Previously it has been suggested that CVA24v uses sialic acidcontaining glycoconjugates as attachment receptors on corneal cells, but the nature of these receptors is poorly described. Here, we set out to characterize and identify the cellular components serving as receptors for CVA24v. Binding and infection experiments using corneal cells treated with deglycosylating enzymes or metabolic inhibitors of de novo glycosylation suggested that the receptor(s) used by CVA24v are constituted by sialylated O-linked glycans that are linked to one or more cell surface proteins but not to lipids. CVA24v bound better to mouse L929 cells overexpressing human P-selectin glycoprotein ligand-1 (PSGL-1) than to mocktransfected cells, suggesting that PSGL-1 is a candidate receptor for CVA24v. Finally, binding competition experiments using a library of mono-and oligosaccharides mimicking known PSGL-1 glycans suggested that CVA24v binds to Neu5Ac␣2,3Gal disaccharides (Neu5Ac is N-acetylneuraminic acid). These results provide further insights into the early steps of the CVA24v life cycle.

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Section: Discussionmentioning

confidence: 99%

Coxsackievirus A24 Variant Uses Sialic Acid-Containing O -Linked Glycoconjugates as Cellular Receptors on Human Ocular Cells

Mistry¹,

Inoue²,

Jamshidi³

et al. 2011

J Virol

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“…3C) (43)(44)(45)(46). Incubation of Vero cells with HD5 at 4°C for 1 h did not block AF488-BKV attachment to the cells.…”

Section: ␣-Defensins Inhibit Bk Virusmentioning

confidence: 99%

Human α-Defensins Inhibit BK Virus Infection by Aggregating Virions and Blocking Binding to Host Cells

Dugan

Maginnis

Jordan

et al. 2008

Journal of Biological Chemistry

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BK virus (BKV) is a polyomavirus that establishes a lifelong persistence in most humans and is a major impediment to success of kidney grafts. The function of the innate immune system in BKV infection and pathology has not been investigated. Here we examine the role of antimicrobial defensins in BKV infection of Vero cells. Our data show that ␣-defensin human neutrophil protein 1 (HNP1) and human ␣-defensin 5 (HD5) inhibit BKV infection by targeting an early event in the viral lifecycle. HD5 treatment of BKV reduced viral attachment to cells, whereas cellular treatment with HD5 did not. Colocalization studies indicated that HD5 interacts directly with BKV. Ultrastructural analysis revealed HD5-induced aggregation of virions. HD5 also inhibited infection of cells by other related polyomaviruses. This is the first study to demonstrate polyomavirus sensitivity to defensins. We also show a novel mechanism whereby HD5 binds to BKV leading to aggregation of virion particles preventing normal virus binding to the cell surface and uptake into cells.BK virus is a member of the polyomaviridae family. Polyomaviruses are small (40 -50 nm in diameter), non-enveloped, double-stranded DNA viruses that cause tumors in some species outside of their natural host range (1). BKV infects ϳ80 -90% of the human population and establishes a lifelong persistence within epithelial cells of the urinary tract (2, 3). Although BKV infection remains asymptomatic throughout the lifetime of most humans, immunocompromised individuals are susceptible to BKV-induced disease. Reactivation of BKV has been linked to hemorrhagic cystitis in bone marrow transplant recipients and is the etiological agent of polyomavirus-induced nephropathy (PVN), 2 a complication found in 5% of kidney transplant recipients (4, 5). In PVN, BKV induces interstitial nephritis resulting in graft destruction and leads to transplant failure in ϳ50% of diagnosed cases (6, 7). BKV reactivation causes a serious viral infection after renal transplantation and is a significant obstacle to the success of kidney grafts.The factors that contribute to BKV-induced disease are largely unknown. As only a subset of kidney transplant recipients develop PVN, this raises the question of what unique factors are present in these situations for pathogenesis to ensue? The factors that contribute to PVN likely comprise multiple conditions that involve the virus, the host, and the graft. Some risk factors for the development of PVN include male gender, older age, and higher number of HLA mismatches (7, 8). Epidemiological studies suggest that the most significant cofactor leading to PVN is the degree of immunosuppression. The rise in PVN diagnoses is directly correlated to the increased use of the more potent anti-rejection drugs, tacromilus and mycophenolate mofetil (9, 10). Currently, a reduction of immunosuppressive therapy is effectively used to decrease viral replication in PVN patients suggesting that a functional immune system is critical in controlling BKV replication and pathology (11). ...

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“…However, binding was reduced when cells were pretreated with neuraminidase, indicating that JCPyV bound to the appropriate sialic acid receptor (Fig. 5C) (55,56). To confirm the impact of SMN knockdown on infection, the same experiments were undertaken using commercially available fibroblasts from an unaffected carrier and a type I SMA patient.…”

Section: Significancementioning

confidence: 99%

Decreased function of survival motor neuron protein impairs endocytic pathways

Dimitriadi

Derdowski

Kalloo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.endocytic trafficking | survival motor neuron | spinal muscular atrophy | C. elegans | infection S pinal muscular atrophy (SMA) is one of the most severe neuromuscular diseases of childhood, with an incidence of 1 in 10,000 live births and a high carrier frequency of roughly 1 in 40 Caucasians (1-3). SMA is caused by reduced levels of the ubiquitously expressed survival of motor neuron (SMN) protein and results in degeneration of α-spinal cord motor neurons, muscle weakness, and/or death. Two human genes encode the SMN protein, SMN1 and SMN2. SMA alleles arise at relatively high frequency due to small intrachromosomal de novo rearrangements including the SMN1 locus (4). Patients often carry homozygous SMN1 deletions, although missense and nonsense alleles exist (5). Multiple copies of SMN2 rarely compensate for loss of SMN1 due to a C > T nucleotide change in SMN2 exon 7 that perturbs pre-mRNA splicing and results in a truncated protein of diminished function and stability (SMNΔ7) (5-9).SMN has numerous roles and interacts with various proteins, yet it remains unclear which interactions are most pertinent to SMA pathogenesis. As a component of the Gemin complex, SMN is required for biogenesis of small nuclear ribonucleoprotein (snRNP) particles critical for pre-mRNA splicing (10-12). Furthermore, SMN is needed for stress granule formation (13,14), is found in RNP granules moving through neuronal processes, and is part of RNP complexes implicated in synaptic local translation (15)(16)(17)(18)(19)(20). Additional roles for SMN, in transcription (21), in the PTEN-mediated protein synthesis pathway (22), in translational control (23), and in cell proliferation/differentiation (24), have been described. Importantly, no consensus has been reached regarding the cellular and molecular pathways wh...

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Direct Correlation between Sialic Acid Binding and Infection of Cells by Two Human Polyomaviruses (JC Virus and BK Virus)

Cited by 56 publications

References 32 publications

Coxsackievirus A24 Variant Uses Sialic Acid-Containing O -Linked Glycoconjugates as Cellular Receptors on Human Ocular Cells

Coxsackievirus A24 Variant Uses Sialic Acid-Containing O -Linked Glycoconjugates as Cellular Receptors on Human Ocular Cells

Human α-Defensins Inhibit BK Virus Infection by Aggregating Virions and Blocking Binding to Host Cells

Decreased function of survival motor neuron protein impairs endocytic pathways

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