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Article

Insertion of Basic Amino Acids in the Hemagglutinin Cleavage Site of H4N2 Avian Influenza Virus (AIV)—Reduced Virus Fitness in Chickens is Restored by Reassortment with Highly Pathogenic H5N1 AIV

1
Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, 17493 Mecklenburg-Vorpommern, Germany
2
Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, 17493 Mecklenburg-Vorpommern, Germany
3
Department of Poultry Diseases, Faculty of Veterinary Medicine, Alexandria University, Alexandria 22758, Egypt
4
California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
5
Institute of Virology, Philipps University Marburg, 35043 Marburg, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(7), 2353; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072353
Received: 25 February 2020 / Revised: 25 March 2020 / Accepted: 27 March 2020 / Published: 28 March 2020
(This article belongs to the Special Issue Molecular Research in Emerging Viruses 2020)
Highly pathogenic (HP) avian influenza viruses (AIVs) are naturally restricted to H5 and H7 subtypes with a polybasic cleavage site (CS) in hemagglutinin (HA) and any AIV with an intravenous pathogenicity index (IVPI) ≥ 1.2. Although only a few non-H5/H7 viruses fulfill the criteria of HPAIV; it remains unclear why these viruses did not spread in domestic birds. In 2012, a unique H4N2 virus with a polybasic CS 322PEKRRTR/G329 was isolated from quails in California which, however, was avirulent in chickens. This is the only known non-H5/H7 virus with four basic amino acids in the HACS. Here, we investigated the virulence of this virus in chickens after expansion of the polybasic CS by substitution of T327R (322PEKRRRR/G329) or T327K (322PEKRRKR/G329) with or without reassortment with HPAIV H5N1 and H7N7. The impact of single mutations or reassortment on virus fitness in vitro and in vivo was studied. Efficient cell culture replication of T327R/K carrying H4N2 viruses increased by treatment with trypsin, particularly in MDCK cells, and reassortment with HPAIV H5N1. Replication, virus excretion and bird-to-bird transmission of H4N2 was remarkably compromised by the CS mutations, but restored after reassortment with HPAIV H5N1, although not with HPAIV H7N7. Viruses carrying the H4-HA with or without R327 or K327 mutations and the other seven gene segments from HPAIV H5N1 exhibited high virulence and efficient transmission in chickens. Together, increasing the number of basic amino acids in the H4N2 HACS was detrimental for viral fitness particularly in vivo but compensated by reassortment with HPAIV H5N1. This may explain the absence of non-H5/H7 HPAIV in poultry. View Full-Text
Keywords: highly pathogenic avian influenza virus; low pathogenic avian influenza virus; evolution; virulence determinants; non-H5/H7; cleavage site; chicken-to-chicken transmission; virulence; protease highly pathogenic avian influenza virus; low pathogenic avian influenza virus; evolution; virulence determinants; non-H5/H7; cleavage site; chicken-to-chicken transmission; virulence; protease
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MDPI and ACS Style

Gischke, M.; Ulrich, R.; I. Fatola, O.; Scheibner, D.; Salaheldin, A.H.; Crossley, B.; Böttcher-Friebertshäuser, E.; Veits, J.; Mettenleiter, T.C.; Abdelwhab, E.M. Insertion of Basic Amino Acids in the Hemagglutinin Cleavage Site of H4N2 Avian Influenza Virus (AIV)—Reduced Virus Fitness in Chickens is Restored by Reassortment with Highly Pathogenic H5N1 AIV. Int. J. Mol. Sci. 2020, 21, 2353. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072353

AMA Style

Gischke M, Ulrich R, I. Fatola O, Scheibner D, Salaheldin AH, Crossley B, Böttcher-Friebertshäuser E, Veits J, Mettenleiter TC, Abdelwhab EM. Insertion of Basic Amino Acids in the Hemagglutinin Cleavage Site of H4N2 Avian Influenza Virus (AIV)—Reduced Virus Fitness in Chickens is Restored by Reassortment with Highly Pathogenic H5N1 AIV. International Journal of Molecular Sciences. 2020; 21(7):2353. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072353

Chicago/Turabian Style

Gischke, Marcel, Reiner Ulrich, Olanrewaju I. Fatola, David Scheibner, Ahmed H. Salaheldin, Beate Crossley, Eva Böttcher-Friebertshäuser, Jutta Veits, Thomas C. Mettenleiter, and Elsayed M. Abdelwhab 2020. "Insertion of Basic Amino Acids in the Hemagglutinin Cleavage Site of H4N2 Avian Influenza Virus (AIV)—Reduced Virus Fitness in Chickens is Restored by Reassortment with Highly Pathogenic H5N1 AIV" International Journal of Molecular Sciences 21, no. 7: 2353. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072353

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