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Enteric species F human adenoviruses use laminin-binding integrins as co-receptors for infection of Ht-29 cells
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). (Niklas Arnberg)ORCID-id: 0000-0002-4873-8528
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
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2018 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, nr 1, artikel-id 10019Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The enteric species F human adenovirus types 40 and 41 (HAdV-40 and -41) are the third most common cause of infantile gastroenteritis in the world. Knowledge about HAdV-40 and -41 cellular infection is assumed to be fundamentally different from that of other HAdVs since HAdV-40 and -41 penton bases lack the αV-integrin-interacting RGD motif. This motif is used by other HAdVs mainly for internalization and endosomal escape. We hypothesised that the penton bases of HAdV-40 and -41 interact with integrins independently of the RGD motif. HAdV-41 transduction of a library of rodent cells expressing specific human integrin subunits pointed to the use of laminin-binding α2-, α3- and α6-containing integrins as well as other integrins as candidate co-receptors. Specific laminins prevented internalisation and infection, and recombinant, soluble HAdV-41 penton base proteins prevented infection of human intestinal HT-29 cells. Surface plasmon resonance analysis demonstrated that HAdV-40 and -41 penton base proteins bind to α6-containing integrins with an affinity similar to that of previously characterised penton base:integrin interactions. With these results, we propose that laminin-binding integrins are co-receptors for HAdV-40 and -41.

Ort, förlag, år, upplaga, sidor
Springer Nature , 2018. Vol. 8, nr 1, artikel-id 10019
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-146978DOI: 10.1038/s41598-018-28255-7ISI: 000437097000036PubMedID: 29968781Scopus ID: 2-s2.0-85049507353OAI: oai:DiVA.org:umu-146978DiVA, id: diva2:1200828
Anmärkning

Originally included in thesis in manuscript form.

Tillgänglig från: 2018-04-24 Skapad: 2018-04-24 Senast uppdaterad: 2018-08-29Bibliografiskt granskad
Ingår i avhandling
1. Capsid protein functions of enteric human adenoviruses
Öppna denna publikation i ny flik eller fönster >>Capsid protein functions of enteric human adenoviruses
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Human adenoviruses (HAdVs) cause respiratory illnesses, epidemic conjunctivitis and infantile gastroenteritis. HAdV types 40 and 41 cause enteric infections in infants worldwide. HAdVs use various receptors for attachment onto different host cells. Coxsackievirus and adenovirus receptor, CD46, sialic acid, coagulation factors IX and X, lactoferrin and heparan sulfate are some receptors and molecules which the hexon and fiber proteins (components of the capsid) bind for direct or indirect cellular attachment. The penton base protein (another component of the capsid) is responsible for the internalization of the virus into the host cell. An arginine-glycine-aspartic acid amino acid motif is present in most but not all adenovirus penton base proteins and mediates interaction with αv integrins, resulting in internalization.

The enteric HAdVs are unique since they do not have this arginine-glycine-aspartic acid motif on their penton base. Using a library of hamster cells expressing specific human integrins, along with recombinant soluble penton base from HAdV type 41 and commercially available soluble laminins, we identified laminin-binding integrins as co-receptors for entry and infection of human intestinal HT-29 cells by the enteric HAdVs.

HAdV types 40, 41 and 52 are the only three HAdVs that have two different fiber proteins, one long and one short. By performing cell binding and infection experiments, we have found that the receptor for the short fiber of HAdV-52 is sialic acid-containing glycans and the long fiber receptor is CAR although most of the binding was dependent on sialic acid-containing glycans. We also observed that the short fiber of HAdV type 40 interacts with soluble heparin or cell surface heparan sulfate. Further investigation pointed out that the specific sulfate groups on heparin/heparan sulfate (sulfated glycosaminoglycans) are important for this binding. Also, we identified that the interaction and utilization of these glycosaminoglycans as receptors is dependent on exposure to low pH. We also studied the potential mechanism behind the symptoms caused by these enteric HAdVs in enteroendocrine cells called enterochromaffin cells. We could show that the short fiber and the hexon of HAdV type 41 stimulated release of serotonin from the enterochromaffin cells, which can be a cause of vomiting and diarrhea.

These studies have given us insight into the role of enteric HAdV capsid proteins as ligands to hitherto unidentified receptors and co-receptors. We also show that these molecules play important functions in the virus’ infectious cycle and probably also in their disease mechanism of host cells.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2018. s. 70
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1953
Nyckelord
Adenovirus, gastroenteritis, capsid proteins, receptor, integrins, heparan sulfate, sialic acid
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-146908 (URN)978-91-7601-860-6 (ISBN)
Disputation
2018-05-18, Biomedicinhuset E04, Building 6A, NUS, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-04-27 Skapad: 2018-04-24 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

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