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Avian Influenza Virus: Deciphering receptor interactions and their role in interspecies transmission
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Zoonosis Science Center)ORCID iD: 0000-0001-7633-403X
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

Influenza A virus (IAV) annually infects approximately 5–15 % of the human population, causing ~500,000 deaths globally. Novel IAVs have emerged and spread pandemically in the human population, but have over time established endemic circulation with reduced pathogenicity causing seasonal influenza. The natural reservoir of IAVs is wild waterfowl. The past pandemics have been associated with host switch and have partly or entirely originated from birds, or adapted via passage through pigs (postulated IAV mixing vessel). Understanding IAV interspecies transmission mechanisms is essential for pandemic preparedness. Enzootic circulation of avian IAV (AIV) is concentrated to a few waterfowl species, while other bird species seldom are infected. A species barrier preventing IAV interspecies transmission has been suggested. To investigate IAV host range and mixing vessels, histochemistry studies were conducted with tissues from avian species, pigs, and humans. Virus adaptation to new hosts was studied by challenging tufted ducks and chickens with mallard-derived AIVs, together with AIV receptor tropism and glycoproteomic analysis of receptor distribution. Finally, receptor and tissue tropism in ducks was studied systematically for AIV (H1–16). More abundant AIV attachment to human than pig tissues was observed, questioning the pig mixing vessel theory. Attachment patterns of AIVs to bird tissues was generally broad with abundant attachment to trachea. However, among ducks, pronounced attachment was observed to colon of Anas spp., suggesting that intestinal infection might be restricted to Anas spp., whereas other species may be susceptible to respiratory infection. Tufted ducks and chickens could not be infected by intraesophageal inoculation further supporting this hypothesis. Glycan array analysis revealed 3’SLN, 3’STF, and their fucosylated and sulfated analogues as main AIV receptors. Moreover, AIV Neu5Acα2,6 recognition was widespread. Avian respiratory and intestinal tracts glycoproteomic analysis revealed that avian and mammalian receptor structures are much more similar than earlier thought. Furthermore, observed AIV subtype titer variation in challenged tufted ducks and chickens did not correlate with virus receptor tropism. In summary, this thesis suggests that IAV receptor recognition, in particular α2,3 vs. α2,6 sialylated receptor structures, is less important for the IAV interspecies barrier than previously thought.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 72
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1609
Keywords [en]
birds, glycobiology, glycovirology, host range, mixing vessel, virus attachment
National Category
Microbiology in the medical area
Research subject
Medical Virology
Identifiers
URN: urn:nbn:se:uu:diva-395407ISBN: 978-91-513-0797-8 (print)OAI: oai:DiVA.org:uu-395407DiVA, id: diva2:1365237
Public defence
2019-12-14, Trippelrummet, Navet, SciLifeLab, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-11-21 Created: 2019-10-24 Last updated: 2019-11-21
List of papers
1. Characterization of avian influenza virus attachment patterns to human and pig tissues
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12215Article in journal (Refereed) Published
Abstract [en]

Wild birds of Anseriformes and Charadriiformes are natural reservoirs of influenza A viruses (IAVs). Occasionally, IAVs transmit and adapt to mammalian hosts, and are maintained as epidemic strains in their new hosts. Viral adaptions to mammalian hosts include altered receptor preference of host epithelial sialylated oligosaccharides from terminal alpha 2,3-linked sialic acid (SA) towards alpha 2,6-linked SA. However, alpha 2,3-linked SA has been found in human respiratory tract epithelium, and human infections by avian IAVs (AIVs) have been reported. To further explore the attachment properties of AIVs, four AIVs of different subtypes were investigated on human and pig tissues using virus histochemistry. Additionally, glycan array analysis was performed for further characterization of IAVs' receptor structure tropism. Generally, AIV attachment was more abundant to human tissues than to pig tissues. The attachment pattern was very strong to human conjunctiva and upper respiratory tract, but variable to the lower respiratory tract. AIVs mainly attached to alpha 2,3-linked SA, but also to combinations of alpha 2,3-and alpha 2,6-linked SA. The low attachment of these AIV isolates to pig tissues, but high attachment to human tissues, addresses the question whether AIVs in general require passage through pigs to obtain adaptions towards mammalian receptor structures.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Microbiology
Identifiers
urn:nbn:se:uu:diva-362683 (URN)10.1038/s41598-018-29578-1 (DOI)000441625500038 ()30111851 (PubMedID)
Funder
Swedish Research Council, 2015-03877Swedish Research Council, 2016-02596Knut and Alice Wallenberg Foundation
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2019-10-24Bibliographically approved
2. Attachment Patterns of Human and Avian Influenza Viruses to Trachea and Colon of 26 Bird Species: Support for the Community Concept
Open this publication in new window or tab >>Attachment Patterns of Human and Avian Influenza Viruses to Trachea and Colon of 26 Bird Species: Support for the Community Concept
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2019 (English)In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 10, article id 815Article in journal (Refereed) Published
Abstract [en]

Avian influenza A viruses (AIVs) have a broad host range, but are most intimately associated with waterfowl (Anseriformes) and, in the case of the H13 and H16 subtypes, gulls (Charadriiformes). Host associations are multifactorial, but a key factor is the ability of the virus to bind host cell receptors and thereby initiate infection. The current study aims at investigating the tissue attachment pattern of a panel of AIVs, comprising H3N2, H6N1, H12N5, and H16N3, to avian trachea and colon tissue samples obtained from host species of different orders. Virus attachment was not restricted to the bird species or order from which the virus was isolated. Instead, extensive virus attachment was observed to several distantly related avian species. In general, more virus attachment and receptor expression were observed in trachea than in colon samples. Additionally, a human seasonal H3N2 virus was studied. Unlike the studied AIVs, this virus mainly attached to tracheae from Charadriiformes and a very limited set of avian cola. In conclusion, the reported results highlight the importance of AIV attachment to trachea in many avian species. Finally, the importance of chickens and mallards in AIVs dynamics was illustrated by the abundant AIV attachment observed.

Keywords
virus histochemistry, lectin staining, pattern of virus attachment, avian influenza, birds
National Category
Microbiology
Identifiers
urn:nbn:se:uu:diva-382841 (URN)10.3389/fmicb.2019.00815 (DOI)000464963200002 ()31057520 (PubMedID)
Funder
Swedish Research Council, 2015-03877Swedish Research Council, 2016-02596Knut and Alice Wallenberg Foundation
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2019-05-22 Created: 2019-05-22 Last updated: 2019-10-24Bibliographically approved
3. Assessing the interspecies transmission mechanisms of influenza A viruses
Open this publication in new window or tab >>Assessing the interspecies transmission mechanisms of influenza A viruses
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(English)Manuscript (preprint) (Other academic)
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-395403 (URN)
Available from: 2019-10-18 Created: 2019-10-18 Last updated: 2019-10-24
4. Host range of influenza A virus H1 to H16 in dabbling vs. diving ducks based on tissue and receptor binding studies
Open this publication in new window or tab >>Host range of influenza A virus H1 to H16 in dabbling vs. diving ducks based on tissue and receptor binding studies
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(English)Manuscript (preprint) (Other academic)
National Category
Microbiology
Identifiers
urn:nbn:se:uu:diva-395405 (URN)
Available from: 2019-10-18 Created: 2019-10-18 Last updated: 2019-10-24

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