Predicting 'Airborne' Influenza Viruses: (Trans-) Mission Impossible?
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Available online at www.sciencedirect.com Predicting ‘airborne’ influenza viruses: (trans-) mission impossible? EM Sorrell1, EJA Schrauwen1, M Linster1, M De Graaf2, S Herfst1 and RAM Fouchier1 Repeated transmission of animal influenza viruses to humans transmissible via small particle aerosols (typically <5 mm) has prompted investigation of the viral, host, and environmental or large respiratory droplets (typically >5 mm), shortened factors responsible for transmission via aerosols or respiratory hereafter as airborne transmissible. droplets. How do we determine — out of thousands of influenza virus isolates collected in animal surveillance studies Influenza A viruses are constantly undergoing genetic each year — which viruses have the potential to become and phenotypic changes during their circulation in avian ‘airborne’, and hence pose a pandemic threat? Here, using and mammalian species. Our knowledge of viral traits knowledge from pandemic, zoonotic and epidemic viruses, we necessary for host switching and virulence has increased postulate that the minimal requirements for efficient significantly over the last decade. However, what transmission of an animal influenza virus between humans are: exactly determines airborne transmission of influenza efficient virus attachment to (upper) respiratory tissues, viruses in humans has remained largely unknown. Only replication to high titers in these tissues, and release and when we fully understand the viral (genetic and phe- aerosolization of single virus particles. Investigating ‘airborne’ notypic), host, and environmental factors that drive transmission of influenza viruses is key to understand — and airborne transmission can we start to make predictions predict — influenza pandemics. about which influenza viruses may cause future influ- Addresses enza pandemics. 1 National Influenza Center and Department of Virology, Erasmus Medical Center, P.O. Box 2040, 3000CA Rotterdam, The Netherlands 2 Department of Zoology, University of Cambridge, Downing Street, Past pandemics Cambridge CB2 3EJ, United Kingdom Four major pandemics have been recognized for which Corresponding author: Fouchier, viral genome sequence data is available. While it was RAM ([email protected]) initially proposed that the 1918 H1N1 Spanish influenza pandemic was caused by a wholly avian virus that adapted to humans [1], recent evidence suggests that some of its Current Opinion in Virology 2011, 1:635–642 genes were derived from mammalian viruses circulating This review comes from a themed issue on as early as 1911 [2 ]. The 1957 H2N2 Asian influenza Emerging viruses pandemic resulted from the reassortment of avian HA, Edited by JS Malik Peiris and Colin Parrish NA, and PB1 virus genes with the then circulating sea- sonal human H1N1 influenza virus [3]. The H3N2 Hong Available online 3rd September 2011 Kong influenza pandemic of 1968 was also a product of 1879-6257/$ – see front matter reassortment between avian and human virus genes; HA # 2011 Elsevier B.V. All rights reserved. and PB1 genes of the H2N2 virus were replaced by those DOI 10.1016/j.coviro.2011.07.003 of an avian H3 virus [3]. In 2009, an H1N1 influenza virus of swine origin caused the first pandemic of the 21st century [4]. The gene constellation of this virus showed clear evidence of multiple reassortment events that had Introduction presumably occurred in pigs over a period of years [5] The virus or virus subtype that will cause the next (Figure 1). The role of swine as a mixing vessel for the influenza pandemic is a highly debated topic in the field. generation of reassortant influenza A viruses with pan- Some believe that only influenza virus subtypes H1, H2, demic potential is generally accepted, yet still under- and H3 can cause pandemics in humans, and therefore — estimated (reviewed in [6]). However, it should be noted beyond isolated cases of zoonotic infections — we should that reassortment can conceivably take place in avian or not worry about virus subtypes such as H5N1, H7N7 or human hosts; for pandemics before 2009, there is no H9N2 for human health. Many believe that swine viruses, evidence that reassortment events occurred in pigs. rather than avian viruses, are more likely to cause the next Regardless of the identity of the mixing vessel it is pandemic. However, beyond the fact that there will be important to emphasize that most, if not all, recent future pandemics, there is little known in terms of the influenza pandemics were caused by reassortant viruses. viral origin, subtype, and virulence of the next pandemic. The expansion in surveillance efforts in pigs in response One other assumption can be made: the virus will be to the 2009 pandemic will most likely reveal many more www.sciencedirect.com Current Opinion in Virology 2011, 1:635–642 636 Emerging viruses Figure 1 mammalian avian seasonal human avianseasonal human avian seasonal human avianclassical swine avian H?N? H?N? H1N1 H2N2 H2N2 H3N? H3N2 H1N1 H1N1 H1N1 (PB2, PA, NP,MA, NS) (PB1, NA, HA) (PB2, PA, NP, NA, MA, NS) (PB1, HA) (PB1) (PB2, PA) (HA, NP, NS) reassortant eurasian swine H1N? H1N1 (PB2, PB1, PA, HA, NA, NS) (NA, MA) reassortant reassortant reassortant H1N1? H2N2 H3N2 reassortant H1N1 pandemic human pandemic human pandemic human pandemic human H1N1 H2N2 H3N2 H1N1 before or in 1918: before or in 1957: before or in 1968: before or in 2009: Spanish influenza Asian influenza Hong Kong influenza swine origin H1N1 pandemic H2N2 pandemic H3N2 pandemic H1N1 pandemic Current Opinion in Virology Reassortment and adaptation events of pandemic influenza A viruses. For the 1918 H1N1 ‘Spanish influenza’ pandemic, evidence for two mutually exclusive scenarios has been presented: the gradual adaptation of avian genes to the human host and a reassortment event between avian and mammalian viruses. After 1918, the H1N1 virus caused seasonal epidemics until 1957, when the H2N2 influenza A virus emerged upon reassortment between the seasonal H1N1 and an avian H2N2 virus, introducing the avian HA, NA, and PB1 genes. This H2N2 virus circulated in humans until 1968, when reassortment of the H2N2 with an avian H3 virus resulted in exchange of the H3 HA and PB1 genes to yield a new pandemic virus of subtype H3N2. The 2009 H1N1 pandemic contained the NA and M genes of the Eurasian swine lineage, and the other genes of a ‘triple reassortant’ swine influenza virus that earlier acquired its genes upon reassortment between human, avian, and (classical) swine viruses. Grey colour in virus particles indicates uncertainty of viral gene segment origin or lack of data. Dotted arrows indicate uncertain scenarios and solid arrows indicate events that are supported by scientific evidence. Dashed arrows represent pandemic viruses circulating in following influenza seasons. reassortant viruses that may or may not have the potential Viral determinants of transmission to infect and spread in humans. But how, out of thousands Retrospective analysis of pandemic H1 (1918), H2 and of animal influenza viruses from surveillance studies, can H3 viruses has revealed that only one to two mutations in we select the ones we should prepare for as potential the HA receptor binding site are required to confer causes of new pandemics? binding preference for virus receptors on cells of the Current Opinion in Virology 2011, 1:635–642 www.sciencedirect.com Predicting ‘airborne’ influenza viruses Sorrell et al. 637 upper respiratory tract (URT) of humans, a2,6-linked thought to be the mechanism behind the increase in sialic acids (SAs) [7]. Partially borrowing from this knowl- replication efficiency [20]. edge, several mutations in the HA protein, including Q222L, G224S, E186D, K189R, S223N and N182K PA and NP genes have also been associated with viral host (H5 numbering), have been shown to change and/or restriction but the key amino acids have yet to be ident- increase receptor binding of avian H9N2 and H5N1 ified. Even fewer experiments have looked at the roles of viruses to human URT tissues [8–12] with changes like NA, M and NS proteins in determining host range and Q226L (H3 numbering) improving replication and trans- transmission. It is likely that virus tropism, efficiency in mission of H9 viruses [13]. However, to date, none of the replication, amount of virus shed, and the duration of ‘designer’ H5N1 viruses carrying these mutations have shedding are important factors for transmission efficiency. resulted in airborne transmission [11,14]. Efficient H5 A longer duration of virus shedding at high titer may be transmission may thus require more subtle differences in hypothesized to increase the chance for the virus to reach receptor preference than simple a2,3 (the receptor for susceptible host(s) and therefore increase transmission avian viruses) versus a2,6 SA linkage specificity. events [21]. Previous research has also pointed to key changes in the Airborne transmission; size does matter polymerase proteins that increase virus replication effi- Human-to-human transmission of influenza viruses can ciency at 33 8C, the accepted temperature for efficient occur through contact, direct or indirect, and/or respirat- replication in the mammalian URT [15 ,16]. These ory droplets (large droplets and aerosols). Opinions differ changes at positions 627, 701 and 591 of PB2 have also on the importance of each mode of transmission been shown to support transmission of multiple subtypes (reviewed in [22,23]). The role of each has been well in mammalian models [17,18,19 ]. A decrease in associ- studied in mammalian models, focusing on the ferret