Predicting 'airborne' influenza viruses: (trans-) mission impossible?

Abstract

Repeated transmission of animal influenza viruses to humans has prompted investigation of the viral, host, and environmental factors responsible for transmission via aerosols or respiratory droplets. How do we determine-out of thousands of influenza virus isolates collected in animal surveillance studies each year-which viruses have the potential to become 'airborne', and hence pose a pandemic threat? Here, using knowledge from pandemic, zoonotic and epidemic viruses, we postulate that the minimal requirements for efficient transmission of an animal influenza virus between humans are: efficient virus attachment to (upper) respiratory tissues, replication to high titers in these tissues, and release and aerosolization of single virus particles. Investigating 'airborne' transmission of influenza viruses is key to understand-and predict-influenza pandemics.

Figure 1. 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.

Figure 2. Proposed minimal requirements for influenza viruses to become airborne

Figures represent theoretical virus subtypes with non-transmissible (virus 1) and transmissible (virus 2) phenotypes, unpublished data. Virus attachment to ferret URT is visualized with FITC-labelled viruses. (A) Shows no attachment of virus 1 to URT whereas (B) shows red staining indicative for attachment of virus 2 to the ferret URT. Virus yield in the URT of ferrets (intranasal infection) is shown for virus 1 (C) and virus 2 (D), with grey bars representing virus shedding from nose swabs and black bars from throat swabs. Electron microscopy of viruses budding from human 293T cells. (E) Shows viral aggregates released in clusters of spherical particles of virus 1 while (F) shows single virus 2 particles being released from the infected cell as both spherical and filamentous virions.