Neuraminidase-associated plasminogen recruitment enables systemic spread of natural avian Influenza viruses H3N1
| Autor: | Dirk Höper, Anne Pohlmann, Bernd-Andreas Schwarz, Angele Breithaupt, Klaus-Peter Behr, Jacqueline King, Jacob Schön, Timm C. Harder, Christian Grund, Martin Beer, Jürgen Stech, Rokshana Parvin |
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| Rok vydání: | 2021 |
| Předmět: |
RNA viruses
Glycosylation Pathogenesis medicine.disease_cause Virus Replication Biochemistry Poultry Disease Outbreaks Influenza A virus Gamefowl Biology (General) Pathology and laboratory medicine 0303 health sciences Mutation biology Eukaryota Proteases Medical microbiology 3. Good health Enzymes Vertebrates Viruses Pathogens Research Article QH301-705.5 Plasmins Immunology Neuraminidase Microbiology Virus Birds 03 medical and health sciences Virology Genetics Viral neuraminidase medicine Animals Influenza viruses Molecular Biology Poultry Diseases 030304 developmental biology Medicine and health sciences 030306 microbiology Organisms Viral pathogens Biology and Life Sciences Proteins Plasminogen RC581-607 Influenza A virus subtype H5N1 Viral Replication Microbial pathogens Viral replication Fowl Influenza in Birds Amniotes biology.protein Enzymology Parasitology Immunologic diseases. Allergy Serine Proteases Chickens Zoology Orthomyxoviruses |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 17, Iss 4, p e1009490 (2021) |
| ISSN: | 1553-7374 |
| Popis: | Repeated outbreaks due to H3N1 low pathogenicity avian influenza viruses (LPAIV) in Belgium were associated with unusually high mortality in chicken in 2019. Those events caused considerable economic losses and prompted restriction measures normally implemented for eradicating high pathogenicity avian influenza viruses (HPAIV). Initial pathology investigations and infection studies suggested this virus to be able to replicate systemically, being very atypical for H3 LPAIV. Here, we investigate the pathogenesis of this H3N1 virus and propose a mechanism explaining its unusual systemic replication capability. By intravenous and intracerebral inoculation in chicken, we demonstrate systemic spread of this virus, extending to the central nervous system. Endoproteolytic viral hemagglutinin (HA) protein activation by either tissue-restricted serine peptidases or ubiquitous subtilisin-like proteases is the functional hallmark distinguishing (H5 or H7) LPAIV from HPAIV. However, luciferase reporter assays show that HA cleavage in case of the H3N1 strain in contrast to the HPAIV is not processed by intracellular proteases. Yet the H3N1 virus replicates efficiently in cell culture without trypsin, unlike LPAIVs. Moreover, this trypsin-independent virus replication is inhibited by 6-aminohexanoic acid, a plasmin inhibitor. Correspondingly, in silico analysis indicates that plasminogen is recruitable by the viral neuraminidase for proteolytic activation due to the loss of a strongly conserved N-glycosylation site at position 130. This mutation was shown responsible for plasminogen recruitment and neurovirulence of the mouse brain-passaged laboratory strain A/WSN/33 (H1N1). In conclusion, our findings provide good evidence in natural chicken strains for N1 neuraminidase-operated recruitment of plasminogen, enabling systemic replication leading to an unusual high pathogenicity phenotype. Such a gain of function in naturally occurring AIVs representing an established human influenza HA-subtype raises concerns over potential zoonotic threats. Author summary Avian influenza viruses (AIV) of subtype H3N1 caused outbreaks among gallinaceous poultry associated with an unusual high mortality in Belgium in 2019. Although those strains shared properties of a high pathogenicity (HP)-like phenotype in chicken experiments, still the viral hemagglutinin endoproteolytic cleavage site (HACS) matches that of canonical low pathogenicity (LP) AIV. Above all, the HACS motif is the molecular marker to distinguish low from high pathogenicity phenotypes in H5 and H7 AIV. Monobasic HACS motifs restrict the LPAIV to use tissue-specific host proteases and therefore confine their organ tropism to the respiratory and digestive tracts. By contrast, the polybasic HACS of HPAIV provides access to the ubiquitously expressed prohormone convertase furin, resulting in a grossly broadened organ tropism. Here, we show that the systemic spread of the Belgian H3N1 chicken viruses is independent from tissue-specific proteases and that their proteolytic HA activation is processed by plasminogen and associated to the loss of a conserved N-glycosylation site at position 130 of the neuraminidase. To date, this mechanism was only described for the mouse-adapted laboratory H1N1 strain WSN/33. Our data, however, provide evidence that this mechanism can also evolve in natural circulating AIV, as well as in human strains, suggesting a certain zoonotic potential. |
| Databáze: | OpenAIRE |
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