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Revealing Interspecies Transmission Barriers of Avian Influenza a Viruses 3 4 Mahmoud M bioRxiv preprint doi: https://doi.org/10.1101/2020.11.17.386755; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Title: 2 Revealing interspecies transmission barriers of avian influenza A viruses 3 4 Mahmoud M. Naguib1, Per Eriksson1, Elinor Jax 2,3, Jonas Nilsson4,5, Carina Sihlbom6, 5 Cecilia Lindskog7, Caroline Bröjer8, Britt-Marie Olsson6, Michelle Wille1#, Jonas 6 Waldenström9, Göran Larson4,5, Robert H. S. Kraus2,3, Åke Lundkvist1, Björn Olsen10, 7 Josef D. Järhult10*, Patrik Ellström10* 8 9 1Zoonosis Science Center, Department of Medical Biochemistry and Microbiology, 10 Uppsala University, Uppsala SE-75237, Sweden 11 2Department of Migration, Max Planck Institute of Animal Behavior, Radolfzell 78315, 12 Germany 13 3Department of Biology, University of Konstanz, Konstanz 78457, Germany 14 4Department of Laboratory Medicine, University of Gothenburg, SE-413 45, Gothenburg, 15 Sweden 16 5Laboratory of Clinical Chemistry, Sahlgrenska University Hospital, SE-413 45, 17 Gothenburg, Sweden 18 6Proteomics Core Facility, University of Gothenburg, Sahlgrenska Academy, SE-405 30, 19 Gothenburg, Sweden 20 7Department of Immunology, Genetics and Pathology, Science for Life Laboratory, 21 Uppsala University, SE-75185, Uppsala, Sweden 22 8 Department of Pathology and Wildlife Diseases, National Veterinary Institute (SVA) , SE- 23 75189 Uppsala, Sweden 24 9Centre for Ecology and Evolution in Microbial Model Systems, Linnaeus University, SE- 25 391 82 Kalmar, Sweden 26 10Zoonosis Science Center, Department of Medical Sciences, Uppsala University, 27 Uppsala SE-75185, Sweden 28 # Present address: Marie Bashir Institute for Infectious Diseases and Biosecurity, School 29 of Life and Environmental Sciences and School of Medical Sciences, The University of 30 Sydney, Sydney, Australia. 31 32 * JJ and PEl contributed equally to this publication 33 34 Corresponding Author 35 Patrik Ellstrom: [email protected] 36 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.17.386755; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 37 Abstract 38 39 Influenza A virus (IAV) pandemics result from interspecies transmission events within the 40 avian reservoir and further to mammals including humans. Investigating molecular virus– 41 host interactions dictating this process and the adaptations to the new hosts that follow is 42 vital to understand zoonotic IAV spread. Receptor incompatibility has been suggested to 43 limit zoonotic IAV transmission from the wild bird reservoir. Other barriers to interspecies 44 transmission, particularly within the avian system, largely remain elusive. Through 45 assessment of infection dynamics of mallard origin IAV in two different avian hosts, 46 coupled with studies of receptor expression and host response we aimed to reveal the 47 host-pathogen interactions in a cross-species transmission event. We found that shedding 48 patterns and innate immune responses were highly dependent on viral genotypes, host 49 species and inoculation routes, but less dependent on receptor expression. Further, in 50 contrary to the prevailing dogma we demonstrate that birds can produce a wide range of 51 different sialylated structures also found in mammals, e.g. extended N- and O-linked 52 Neu5Acα2,6 terminated glycans. Overall, receptor incompatibility is not the sole 53 transmission barrier for IAV between birds and to humans, but other host-pathogen factors 54 deserve dedicated studies to achieve proper pandemic preparedness. 55 56 57 58 59 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.17.386755; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 60 Zonotic viruses have the capacity to cause severe pandemics 1. The three latest influenza 61 A virus (IAV) pandemics (H2N2 1957, H3N2 1968, and H1N1 2009) 2-4 have contained 62 genetic material originating from avian influenza viruses. These events have most likely 63 involved spread from wild to domestic bird species and to pigs. Key barriers for 64 interspecies transmission are molecular interactions between host and virus, including 65 recognition of host receptors by virus surface proteins, adaptation to changes in pH and 66 temperature, as well as avoiding the host´s innate and adaptive immune response to 67 infection 5,6. 68 69 One of the biological traits required for interspecies transmissions of IAV is a change in 70 receptor binding specificity. Avian viruses preferentially bind to α2,3-linked sialic acid 71 (SA)-containing receptors, whereas human IAVs prefer α2,6-linked SA-containing 72 receptors 7-11. Originally it was believed that α2,3-linked SA was exclusive to bird tissues, 73 whereas α2,6-linked SA was exclusive to humans 12-14. Furthermore, species specific 74 differences in the sialylated glycan structures serving as receptors for IAVs have been 75 proposed as barriers for transmission between bird species 12,13,15. More recent 76 characterization of the human airway epithelium has revealed that α2,3-linked SA can 77 indeed be found 16,17, and primary screenings with lectins have indicated the presence of 78 α2,6-linked SA in avian tissues as well 18-23. The most important target organs for IAV 79 replication are poorly defined in most bird species. For mallards (Anas platyrhynchos), the 80 central reservoir for IAVs, viruses replicate in the surface epithelium of the intestinal tract 81 and transmission occurs via the fecal–oral route24. In contrast, the respiratory tract is 82 known to be important for replication in chickens and indirect evidence suggest that this 83 is the case also in an array of wild bird species, including tufted ducks (Aythya fuligula) 84 23,25-27, particularly in the case of infection with highly pathogenic avian influenza virus 85 (HPAIV). 86 87 Considering the barriers that dictate cross species transmission events, we hypothesized 88 that the repertoire of expressed sialylated glycan receptors for IAV differs between birds 89 and mammals, and that differences in the glycan structure were to be found even between 90 distantly related bird species. Furthermore, we hypothesized that the outcome of 91 experimental transmission of low pathogenic avian influenza viruses (LPAIVs) between 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.17.386755; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 92 bird species would differ depending on infection route and site of infection, receptor 93 repertoire, host response and virus subtype. Moreover, successful introduction of an 94 LPAIV into a new host species would likely be accompanied by adaptive viral genetic 95 changes. To test these hypotheses, we undertook two main approaches. First, we 96 comprehensively assessed infection potential and host response to infection of a broad 97 array of mallard-origin LPAIVs in two different avian hosts: chicken - a key link to zoonotic 98 transmission, and tufted duck - a representative of the wild reservoir. To evaluate the 99 outcomes of these experiments we assessed virus shedding and monitored the host 100 response as well as SNPs in viruses after infection. Second, we characterized and 101 compared the IAV glycan receptor repertoire displayed on cell surfaces of presumed 102 target organs of mallards, chickens and tufted ducks using glycoproteomics. 103 104 Results 105 106 The outcomes of experimental AIV infection differ between virus subtypes, host species 107 and routes of infection. 108 To interrogate how outcomes of AIV infection can differ depending on host species and 109 route of infection, chickens and tufted ducks were infected with eight different subtypes of 110 mallard-origin LPAIVs (Table S1) using two different routes of virus inoculation: 111 oculonasal or intraesophageal. All birds tested negative for AIV antibodies prior to the 112 infection experiments. All chickens and tufted ducks inoculated intraesophaegally were 113 negative in both oropharyngeal and cloacal swab samples by RT-qPCR for all viruses with 114 only two exceptions: one out of four tufted ducks inoculated with H8N4 showed positive 115 AIV RNA (2.54 10-log EID50 equivalent) at 1 day post infection (d.p.i.) and one out of four 116 tufted ducks inoculated with H11N9 (0.79 10-log EID50 equivalent) at 2 d.p.i. (data not 117 shown). 118 In contrast, oculonasal inoculation yielded positive oropharyngeal samples for all viruses 119 in both host species at 1 d.p.i (Figure 1a). In oculonasaly inoculated chickens, virus 120 shedding was detected on all days in all four chickens inoculated with H3N8, H4N6, and 121 H6N2 viruses. In chickens inoculated with H10N1 and H15N5, shedding remained until 3 122 d.p.i. in a subset of birds whereas the H8N4 virus was detected only at 1 d.p.i. Surprisingly, 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.17.386755; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
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