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Capsid protein functions of enteric human adenoviruses
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. (Niklas Arnberg)ORCID iD: 0000-0002-4873-8528
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2018. , p. 70
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1953
Keywords [en]
Adenovirus, gastroenteritis, capsid proteins, receptor, integrins, heparan sulfate, sialic acid
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-146908ISBN: 978-91-7601-860-6 (print)OAI: oai:DiVA.org:umu-146908DiVA, id: diva2:1201000
Public defence
2018-05-18, Biomedicinhuset E04, Building 6A, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2018-04-27 Created: 2018-04-24 Last updated: 2018-06-09Bibliographically approved
List of papers
1. Enteric species F human adenoviruses use laminin-binding integrins as co-receptors for infection of HT-29 cells
Open this publication in new window or tab >>Enteric species F human adenoviruses use laminin-binding integrins as co-receptors for infection of HT-29 cells
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(English)Manuscript (preprint) (Other academic)
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-146978 (URN)
Available from: 2018-04-24 Created: 2018-04-24 Last updated: 2018-06-09
2. Low pH primes short fibers of enteric human adenoviruses to use heparan sulfate as a cellular receptor
Open this publication in new window or tab >>Low pH primes short fibers of enteric human adenoviruses to use heparan sulfate as a cellular receptor
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(English)Manuscript (preprint) (Other academic)
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-146979 (URN)
Available from: 2018-04-24 Created: 2018-04-24 Last updated: 2018-06-09
3. Human Adenovirus 52 Uses Sialic Acid-containing Glycoproteins and the Coxsackie and Adenovirus Receptor for Binding to Target Cells
Open this publication in new window or tab >>Human Adenovirus 52 Uses Sialic Acid-containing Glycoproteins and the Coxsackie and Adenovirus Receptor for Binding to Target Cells
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2015 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, no 2, article id e1004657Article in journal (Refereed) Published
Abstract [en]

Most adenoviruses attach to host cells by means of the protruding fiber protein that binds to host cells via the coxsackievirus and adenovirus receptor (CAR) protein. Human adenovirus type 52 (HAdV-52) is one of only three gastroenteritis-causing HAdVs that are equipped with two different fiber proteins, one long and one short. Here we show, by means of virion-cell binding and infection experiments, that HAdV-52 can also attach to host cells via CAR, but most of the binding depends on sialylated glycoproteins. Glycan microarray, flow cytometry, surface plasmon resonance and ELISA analyses reveal that the terminal knob domain of the long fiber (52LFK) binds to CAR, and the knob domain of the short fiber (52SFK) binds to sialylated glycoproteins. X-ray crystallographic analysis of 52SFK in complex with 2-O-methylated sialic acid combined with functional studies of knob mutants revealed a new sialic acid binding site compared to other, known adenovirus: glycan interactions. Our findings shed light on adenovirus biology and may help to improve targeting of adenovirus-based vectors for gene therapy.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-103565 (URN)10.1371/journal.ppat.1004657 (DOI)000352083400038 ()25674795 (PubMedID)
Available from: 2015-05-25 Created: 2015-05-21 Last updated: 2018-06-07Bibliographically approved
4. Interaction of Human Enterochromaffin Cells with Human Enteric Adenovirus 41 Leads to Serotonin Release and Subsequent Activation of Enteric Glia Cells
Open this publication in new window or tab >>Interaction of Human Enterochromaffin Cells with Human Enteric Adenovirus 41 Leads to Serotonin Release and Subsequent Activation of Enteric Glia Cells
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2018 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, no 7, article id e00026-18Article in journal (Refereed) Published
Abstract [en]

Human adenovirus 41 (HAdV-41) causes acute gastroenteritis in young children. The main characteristics of HAdV-41 infection are diarrhea and vomiting. Nevertheless, the precise mechanism of HAdV-41-induced diarrhea is unknown, as a suitable small-animal model has not been described. In this study, we used the human midgut carcinoid cell line GOT1 to investigate the effect of HAdV-41 infection and the individual HAdV-41 capsid proteins on serotonin release by enterochromaffin cells and on enteric glia cell (EGC) activation. We first determined that HAdV-41 could infect the enterochromaffin cells. Immunofluorescence staining revealed that the cells expressed HAdV-41-specific coxsackievirus and adenovirus receptor (CAR); flow cytometry analysis supported these findings. HAdV-41 infection of the enterochromaffin cells induced serotonin secretion dose dependently. In contrast, control infection with HAdV-5 did not induce serotonin secretion in the cells. Confocal microscopy studies of enterochromaffin cells infected with HAdV-41 revealed decreased serotonin immunofluorescence compared to that in uninfected cells. Incubation of the enterochromaffin cells with purified HAdV-41 short fiber knob and hexon proteins increased the serotonin levels in the harvested cell supernatant significantly. HAdV-41 infection could also activate EGCs, as shown in the significantly altered expression of glia fibrillary acidic protein (GFAP) in EGCs incubated with HAdV-41. The EGCs were also activated by serotonin alone, as shown in the significantly increased GFAP staining intensity. Likewise, EGCs were activated by the cell supernatant of HAdV-41-infected enterochromaffin cells.

Keywords
gastroenteritis, enteric adenovirus, EC cells, serotonin, enteric glia cells
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-146907 (URN)10.1128/JVI.00026-18 (DOI)000428409800002 ()29367250 (PubMedID)
Funder
Swedish Research Council, 320301
Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-06-27Bibliographically approved

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