[Source: PLoS Pathogens, full text: (LINK). Abstract, edited.]
Transmission of Equine Influenza Virus during an Outbreak Is Characterized by Frequent Mixed Infections and Loose Transmission Bottlenecks
Joseph Hughes 1, Richard C. Allen 2, Marc Baguelin 3, Katie Hampson 4, Gregory J. Baillie 5, Debra Elton 6, J. Richard Newton 7, Paul Kellam 8, James L. N. Wood 9, Edward C. Holmes 10, Pablo R. Murcia 11
Affiliations: 1 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; 2 Disease Dynamics Unit, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom; 3 Immunisation, Hepatitis and Blood Safety Department, Health Protection Agency, London, United Kingdom, Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; 4 Boyd Orr Centre for Population and Ecosystem Health, Institute for Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom; 5 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom; 6 Animal Health Trust, Centre for Preventive Medicine, Lanwades Park, Newmarket, United Kingdom; 7 Animal Health Trust, Centre for Preventive Medicine, Lanwades Park, Newmarket, United Kingdom; 8 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom; 9 Disease Dynamics Unit, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom; 10 Center for Infectious Disease Dynamics, Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America, Fogarty International Center, National Institute of Health, Bethesda, Maryland, United States of America; 11 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, Disease Dynamics Unit, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom
The ability of influenza A viruses (IAVs) to cross species barriers and evade host immunity is a major public health concern. Studies on the phylodynamics of IAVs across different scales – from the individual to the population – are essential for devising effective measures to predict, prevent or contain influenza emergence. Understanding how IAVs spread and evolve during outbreaks is critical for the management of epidemics. Reconstructing the transmission network during a single outbreak by sampling viral genetic data in time and space can generate insights about these processes. Here, we obtained intra-host viral sequence data from horses infected with equine influenza virus (EIV) to reconstruct the spread of EIV during a large outbreak. To this end, we analyzed within-host viral populations from sequences covering 90% of the infected yards. By combining gene sequence analyses with epidemiological data, we inferred a plausible transmission network, in turn enabling the comparison of transmission patterns during the course of the outbreak and revealing important epidemiological features that were not apparent using either approach alone. The EIV populations displayed high levels of genetic diversity, and in many cases we observed distinct viral populations containing a dominant variant and a number of related minor variants that were transmitted between infectious horses. In addition, we found evidence of frequent mixed infections and loose transmission bottlenecks in these naturally occurring populations. These frequent mixed infections likely influence the size of epidemics.
Influenza A viruses (IAVs) are major pathogens of humans and animals. Understanding how IAVs spread and evolve at different scales (individual, regional, global) in natural conditions is critical for preventing or managing influenza epidemics. A vast body of knowledge has been generated on the evolution of IAVs at the global scale. Additionally, recent experimental transmission studies have examined the diversity and transmission of influenza viruses within and between hosts. However, most studies on the spread of IAVs during epidemics have been based on consensus viral sequences, an approach that does not have enough discriminatory power to reveal exact transmission pathways. Here, we analyzed multiple within-host viral populations from different horses infected with equine influenza virus (EIV) during the course of an outbreak in a population within a confined area. This provided an opportunity to examine the genetic diversity of the viruses within single animals, the transmission of the viruses between each closely confined population within a yard, and the transmission between horses in different yards. We show that individual horses can be infected by viruses from more than one other horse, which has important implications for facilitating segment reassortment and the evolution of EIV. Additionally, by combining viral sequencing data and epidemiological data we show that the high levels of mixed infections can reveal the underlying epidemiological dynamics of the outbreak, and that epidemic size could be underestimated if only epidemiological data is considered. As sequencing technologies become cheaper and faster, these analyses could be undertaken almost in real-time and help control future outbreaks.
Citation: Hughes J, Allen RC, Baguelin M, Hampson K, Baillie GJ, et al. (2012) Transmission of Equine Influenza Virus during an Outbreak Is Characterized by Frequent Mixed Infections and Loose Transmission Bottlenecks. PLoS Pathog 8(12): e1003081. doi:10.1371/journal.ppat.1003081
Editor: Marco Vignuzzi, Pasteur Institute, France
Received: July 27, 2012; Accepted: October 25, 2012; Published: December 20, 2012
Copyright: © 2012 Hughes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Wellcome Trust and the Medical Research Council of the United Kingdom. PRM was supported by a Veterinary Postdoctoral Fellowship from the Wellcome Trust. JLNW is supported by the Alborada Trust and by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. ECH was supported by grant 2 R01 GM080533-06 from the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: Pablo.Murcia@Glasgow.ac.uk