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Citation: Murcia PR, Hughes J, Battista P, Lloyd L, Baillie GJ, et al. (2012) Evolution of an Eurasian Avian-like Influenza Virus in Na?ve and Vaccinated Pigs. PLoS Pathog 8(5): e1002730. doi:10.1371/journal.ppat.1002730
Pablo R. Murcia1,2, Joseph Hughes2, Patrizia Battista1, Lucy Lloyd3, Gregory J. Baillie4, Ricardo H. Ramirez-Gonzalez5, Doug Ormond4, Karen Oliver4, Debra Elton3, Jennifer A. Mumford1, Mario Caccamo5, Paul Kellam4, Bryan T. Grenfell6,7, Edward C. Holmes7,8, James L. N. Wood1*
1 Cambridge Infectious Diseases Consortium, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom, 2 Medical Research Council-University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom, 3 Animal Health Trust, Centre for Preventive Medicine, Lanwades Park, Newmarket, United Kingdom, 4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom, 5 The Genome Analysis Centre, Norwich Research Park, Norwich, United Kingdom, 6 Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America, 7 Center for Infectious Disease Dynamics, Department of Biology, The Pennsylvania State University, Pennsylvania, United States of America, 8 Fogarty International Center, National Institute of Health, Bethesda, Maryland, United States of America
Abstract Top
Influenza viruses are characterized by an ability to cross species boundaries and evade host immunity, sometimes with devastating consequences. The 2009 pandemic of H1N1 influenza A virus highlights the importance of pigs in influenza emergence, particularly as intermediate hosts by which avian viruses adapt to mammals before emerging in humans. Although segment reassortment has commonly been associated with influenza emergence, an expanded host-range is also likely to be associated with the accumulation of specific beneficial point mutations. To better understand the mechanisms that shape the genetic diversity of avian-like viruses in pigs, we studied the evolutionary dynamics of an Eurasian Avian-like swine influenza virus (EA-SIV) in na?ve and vaccinated pigs linked by natural transmission. We analyzed multiple clones of the hemagglutinin 1 (HA1) gene derived from consecutive daily viral populations. Strikingly, we observed both transient and fixed changes in the consensus sequence along the transmission chain. Hence, the mutational spectrum of intra-host EA-SIV populations is highly dynamic and allele fixation can occur with extreme rapidity. In addition, mutations that could potentially alter host-range and antigenicity were transmitted between animals and mixed infections were commonplace, even in vaccinated pigs. Finally, we repeatedly detected distinct stop codons in virus samples from co-housed pigs, suggesting that they persisted within hosts and were transmitted among them. This implies that mutations that reduce viral fitness in one host, but which could lead to fitness benefits in a novel host, can circulate at low frequencies.
Author Summary Top
The latest human influenza pandemic highlights the ability of influenza viruses to jump species barriers and emerge in new hosts, as well as the role of pigs in generating viruses with pandemic potential. The mutational power of influenza virus, caused by intrinsically error-prone viral polymerases, has been directly linked to viral emergence, as adaptive mutations present in the reservoir host are likely to be key to the evolution of sustained transmission in new hosts. Hence, studying how mutations are generated, maintained and transmitted in and among pigs is critical to understanding how novel viruses could emerge. Here we characterized the evolution and mutational spectra of influenza virus populations within na?ve and vaccinated pigs linked by natural transmission, by analyzing multiple viral sequences obtained at different times post-infection. We show that the genetic make-up of influenza viruses in pigs is highly dynamic: the frequency of particular mutations, including those that could potentially alter host specificity or result in vaccine escape, fluctuated markedly, including one rapid fixation event. We also show that co-infections are common and multiple viruses ? even defective ones ? were transmitted between pigs despite being vaccinated. Our results provide empirical evidence of the complex dynamics of influenza viral populations in pigs and provide insight on the evolutionary basis of RNA viral emergence.
http://www.plospathogens.org/articl.../NewArticles+(Ambra+-+Pathogens+New+Articles)
Pablo R. Murcia1,2, Joseph Hughes2, Patrizia Battista1, Lucy Lloyd3, Gregory J. Baillie4, Ricardo H. Ramirez-Gonzalez5, Doug Ormond4, Karen Oliver4, Debra Elton3, Jennifer A. Mumford1, Mario Caccamo5, Paul Kellam4, Bryan T. Grenfell6,7, Edward C. Holmes7,8, James L. N. Wood1*
1 Cambridge Infectious Diseases Consortium, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom, 2 Medical Research Council-University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom, 3 Animal Health Trust, Centre for Preventive Medicine, Lanwades Park, Newmarket, United Kingdom, 4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom, 5 The Genome Analysis Centre, Norwich Research Park, Norwich, United Kingdom, 6 Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America, 7 Center for Infectious Disease Dynamics, Department of Biology, The Pennsylvania State University, Pennsylvania, United States of America, 8 Fogarty International Center, National Institute of Health, Bethesda, Maryland, United States of America
Abstract Top
Influenza viruses are characterized by an ability to cross species boundaries and evade host immunity, sometimes with devastating consequences. The 2009 pandemic of H1N1 influenza A virus highlights the importance of pigs in influenza emergence, particularly as intermediate hosts by which avian viruses adapt to mammals before emerging in humans. Although segment reassortment has commonly been associated with influenza emergence, an expanded host-range is also likely to be associated with the accumulation of specific beneficial point mutations. To better understand the mechanisms that shape the genetic diversity of avian-like viruses in pigs, we studied the evolutionary dynamics of an Eurasian Avian-like swine influenza virus (EA-SIV) in na?ve and vaccinated pigs linked by natural transmission. We analyzed multiple clones of the hemagglutinin 1 (HA1) gene derived from consecutive daily viral populations. Strikingly, we observed both transient and fixed changes in the consensus sequence along the transmission chain. Hence, the mutational spectrum of intra-host EA-SIV populations is highly dynamic and allele fixation can occur with extreme rapidity. In addition, mutations that could potentially alter host-range and antigenicity were transmitted between animals and mixed infections were commonplace, even in vaccinated pigs. Finally, we repeatedly detected distinct stop codons in virus samples from co-housed pigs, suggesting that they persisted within hosts and were transmitted among them. This implies that mutations that reduce viral fitness in one host, but which could lead to fitness benefits in a novel host, can circulate at low frequencies.
Author Summary Top
The latest human influenza pandemic highlights the ability of influenza viruses to jump species barriers and emerge in new hosts, as well as the role of pigs in generating viruses with pandemic potential. The mutational power of influenza virus, caused by intrinsically error-prone viral polymerases, has been directly linked to viral emergence, as adaptive mutations present in the reservoir host are likely to be key to the evolution of sustained transmission in new hosts. Hence, studying how mutations are generated, maintained and transmitted in and among pigs is critical to understanding how novel viruses could emerge. Here we characterized the evolution and mutational spectra of influenza virus populations within na?ve and vaccinated pigs linked by natural transmission, by analyzing multiple viral sequences obtained at different times post-infection. We show that the genetic make-up of influenza viruses in pigs is highly dynamic: the frequency of particular mutations, including those that could potentially alter host specificity or result in vaccine escape, fluctuated markedly, including one rapid fixation event. We also show that co-infections are common and multiple viruses ? even defective ones ? were transmitted between pigs despite being vaccinated. Our results provide empirical evidence of the complex dynamics of influenza viral populations in pigs and provide insight on the evolutionary basis of RNA viral emergence.
http://www.plospathogens.org/articl.../NewArticles+(Ambra+-+Pathogens+New+Articles)