viruses Article H7N7 Avian Influenza Virus Mutation from Low to High Pathogenicity on a Layer Chicken Farm in the UK Alexander M. P. Byrne 1,† , Scott M. Reid 1, * ,† , Amanda H. Seekings 1 , Alejandro Núñez 2 , Ana B. Obeso Prieto 3 , Susan Ridout 4 , Caroline J. Warren 1 , Anita Puranik 1 , Vanessa Ceeraz 1 , Stephen Essen 1 , Marek J. Slomka 1 , Jill Banks 1 , Ian H. Brown 1 and Sharon M. Brookes 1   Citation: Byrne, A.M.P.; Reid, S.M.; Seekings, A.H.; Núñez, A.; Obeso Prieto, A.B.; Ridout, S.; Warren, C.J.; Puranik, A.; Ceeraz, V.; Essen, S.; et al. H7N7 Avian Influenza Virus Mutation from Low to High Pathogenicity on a Layer Chicken Farm in the UK. Viruses 2021, 13, 259. https://doi.org/10.3390/v13020259 Academic Editors: El-Sayed Mohammed Abdel-Whab and Angele Breithaupt Received: 30 December 2020 Accepted: 3 February 2021 Published: 8 February 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Virology, Animal and Plant Health Agency-Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK; Alexander.Byrne@APHA.gov.uk (A.M.P.B.); Amanda.Seekings@APHA.gov.uk (A.H.S.); Caroline.Warren@APHA.gov.uk (C.J.W.); A.Puranik@VMD.gov.uk (A.P.); Vanessa.Ceeraz@APHA.gov.uk (V.C.); Steve.Essen@APHA.gov.uk (S.E.); Marek.Slomka@APHA.gov.uk (M.J.S.); Jillybanks@btinternet.com (J.B.); Ian.Brown@APHA.gov.uk (I.H.B.); Sharon.Brookes@APHA.gov.uk (S.M.B.) 2 Pathology and Animal Sciences, Animal and Plant Health Agency-Weybridge, Woodham Lane, New Haw, Addlestone, Surrey KT15 3NB, UK; Alejandro.Nunez@APHA.gov.uk 3 Field Delivery, Animal and Plant Health Agency-Manchester, Manchester Airport, Manchester M90 5PZ, UK; Ana.Obeso@APHA.gov.uk 4 Field Delivery, Animal and Plant Health Agency-Crewe, Hornbeam House, Electra Way, Crewe, Cheshire CW1 6GJ, UK; Sue.Ridout@APHA.gov.uk * Correspondence: Scott.Reid@APHA.gov.uk † These authors contributed equally to this work. Abstract: Avian influenza virus (AIV) subtypes H5 and H7 are capable of mutating from low to high pathogenicity strains, causing high mortality in poultry with significant economic losses globally. During 2015, two outbreaks of H7N7 low pathogenicity AIV (LPAIV) in Germany, and one each in the United Kingdom (UK) and The Netherlands occurred, as well as single outbreaks of H7N7 high pathogenicity AIV (HPAIV) in Germany and the UK. Both HPAIV outbreaks were linked to precursor H7N7 LPAIV outbreaks on the same or adjacent premises. Herein, we describe the clinical, epidemiological, and virological investigations for the H7N7 UK HPAIV outbreak on a farm with layer chickens in mixed free-range and caged units. H7N7 HPAIV was identified and isolated from clinical samples, as well as H7N7 LPAIV, which could not be isolated. Using serological and molecular evidence, we postulate how the viruses spread throughout the premises, indicating potential points of incursion and possible locations for the mutation event. Serological and mortality data suggested that the LPAIV infection preceded the HPAIV infection and afforded some clinical protection against the HPAIV. These results document the identification of a LPAIV to HPAIV mutation in nature, providing insights into factors that drive its manifestation during outbreaks. Keywords: H7; avian influenza; outbreak; low pathogenicity; high pathogenicity; poultry 1. Introduction Avian Influenza (AI) caused by subtypes H5 and H7 is a notifiable avian disease (NAD) and a severe threat to the poultry industry globally, whilst the emergence of novel avian influenza virus (AIV) strains from wild bird reservoirs is a constant threat to animal and human health. From 1959 to 2017, the United Kingdom (UK) had 11 outbreaks of low pathogenicity AIV (LPAIV, subtypes H5 and H7) and 13 outbreaks of high pathogenicity AIV (HPAIV) [1–4]. Notably, these have included two LPAIV to HPAIV mutational events of the H7N7 subtype in layer chickens, occurring in 2008 [4] and 2015 [5]. During both events only the HPAIV was isolated from the premises; however, viral RNA containing hemagglutinin (HA) cleavage site (CS) motifs consistent with a LPAIV were found. Acquisition of HA CS alterations in LPAIV to become HPAIV occurs in part due to Viruses 2021, 13, 259. https://doi.org/10.3390/v13020259 https://www.mdpi.com/journal/viruses