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Sialic acid is a cellular receptor for coxsackievirus A24 variant, an emerging virus with pandemic potential
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.
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2008 (Engelska)Ingår i: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 82, nr 6, s. 3061-3068Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Binding to target cell receptors is a critical step in the virus life cycle. Coxsackievirus A24 variant (CVA24v) has pandemic potential and is a major cause of acute hemorrhagic conjunctivitis, but its cellular receptor has hitherto been unknown. Here we show that CVA24v fails to bind to and infect CHO cells defective in sialic acid expression. Binding of CVA24v to and infection of corneal epithelial cells are efficiently inhibited by treating cells with a sialic acid-cleaving enzyme or sialic acid-binding lectins and by treatment of the virus with soluble, multivalent sialic acid. Protease treatment of cells efficiently inhibited virus binding, suggesting that the receptor is a sialylated glycoprotein. Like enterovirus type 70 and influenza A virus, CVA24v can cause pandemics. Remarkably, all three viruses use the same receptor. Since several unrelated viruses with tropism for the eye use this receptor, sialic acid-based antiviral drugs that prevent virus entry may be useful for topical treatment of such infections.

Ort, förlag, år, upplaga, sidor
Baltimore: American Society for Microbiology , 2008. Vol. 82, nr 6, s. 3061-3068
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-21102DOI: 10.1128/JVI.02470-07PubMedID: 18184708OAI: oai:DiVA.org:umu-21102DiVA, id: diva2:210599
Tillgänglig från: 2009-04-02 Skapad: 2009-04-02 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Cellular receptors for viruses with ocular tropism
Öppna denna publikation i ny flik eller fönster >>Cellular receptors for viruses with ocular tropism
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Several viruses from different virus families are known to cause ocular infections, e.g. members of the Adenoviridae, Picornaviridae and the Herpesviridae families. These infections are spread by contact and in the case of adenoviruses (Ads) and picornaviruses they are also highly contagious. The ocular infections caused by Ads and picornaviruses are called epidemic keratoconjunctivitis (EKC) and acute hemorrhagic conjunctivitis (AHC), respectively. Historically, EKC is caused mainly by three types of Ads from species D: Ad8, Ad19 and Ad37. The infection is characterized by keratitis and conjunctivitis but also involves pain, edema, lacrimation and blurred vision. AHC is caused mainly by two types of picornaviruses: coxsackievirus A24v (CVA24v) and enterovirus 70 (EV70), and is characterized by pain, redness, excessive tearing, swelling and subconjunctival hemorrhages. In addition, blurred vision, keratitis, malaise, myalgia, fever, headache and upper respiratory tract symptoms can also be experienced. Both infections are problematic in many parts of the world, affecting millions of people every year. Despite the great need, the only treatment available today is supportive treatment; no antiviral drugs are available to combat these common viral infections.

Ad37 has previously been reported to use sialic acid (SA) as its cellular receptor. Since there is no antiviral treatment available against EKC we wanted to evaluate the inhibitory effect of SA-based antiviral compounds on Ad37 binding to and infection of ocular cells. We found that multivalent compounds consisting of SA linked to a globular carrier molecule, in this case human serum albumin, efficiently blocked Ad37 binding and infection at low concentrations. Further attempts were then made to improve the effect by chemically modifying SA monosaccharides. However, no enhanced inhibitory effect was accomplished and the conclusion was that the best inhibitors are based on unmodified SA. We next hypothesized that development of efficient SA-based binding inhibitors may require detailed knowledge about the structure of the SA-containing receptor. Using a battery of biological and biochemical experiments, including glycan array, binding and infection assays, X-ray crystallography and surface plasmon resonance (SPR); we identified a specific glycan involved in the binding and infection of Ad37. This glycan turned out to be a branched, di-SA-containing motif corresponding to the glycan motif of the ganglioside GD1a. However, the ganglioside itself did not function as a cellular receptor, as shown by a number of binding and infection assays. Instead, the receptor consisted of one or more glycoproteins that contain the GD1a glycan motif. This glycan docked with both its SAs into the trimeric Ad37 knob resulting in a very strong interaction as compared to most other protein-glycan interactions. Hopefully, this finding will aid development of more potent inhibitors of Ad37 binding and infection.

The receptor for CVA24v, one of the main causative agents of AHC, has been unknown until now. We showed that this ocular virus, like Ad37, is also able to use SA as a receptor on corneal cells but not on conjunctival cells. This suggested that CVA24v may use two different receptors. As for Ad37, the receptor used by CVA24v on corneal cells also appears to be one or more sialic acid-containing glycoproteins. We believe that these findings may be a starting point for design and development of candidate drugs for topical treatment of AHC.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå university, 2011. s. 123
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1414
Nyckelord
Adenovirus, picornavirus, receptors, antivirals
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Forskningsämne
molekylärbiologi; infektionssjukdomar; mikrobiologi
Identifikatorer
urn:nbn:se:umu:diva-42818 (URN)978-91-7459-182-8 (ISBN)
Disputation
2011-05-13, Major Groove, by 6L, Norrlands universitetssjukhus, Umeå, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2011-04-15 Skapad: 2011-04-13 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Nilsson, Emma CArnberg, Niklas

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