The best kind of negative data

Comparison of traditional intranasal and aerosol inhalation inoculation of mice with influenza A viruses

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Intranasal inoculation (diluting virus in liquid, placing it on the nares of the animal, and allowing the animal to inhale the liquid suspension) represents the traditional way to inoculate small mammalian models with respiratory viruses. It is a consistently reliable method to achieve a uniform infection among animals (all good things, if you are a laboratorian). However, there is one drawback to this approach: it does not reflect how humans are exposed to respiratory viruses in the real world. While there are many potential routes of human exposure to respiratory viruses like influenza, inhalation of virus-containing aerosols appears to be a prominent one. In efforts to more closely mirror a “natural” human infection, several aerosol inhalation inoculation models have been developed in recent years, demonstrating that in addition to traditional intranasal inoculation, mammalian species can become infected via aerosolized influenza virus.

If the animals become infected by either intranasal or aerosol inhalation, why is having a more “human-like exposure” mammalian model important? The answer lies in how the data collected from these models is used in the prevention and control of influenza viruses in humans. If an influenza virus causes mammals like mice or ferrets to become very sick, this contributes to our risk assessment of the virus. If an influenza virus transmits readily between ferrets or guinea pigs, this indicates that this trait may also be enhanced in humans. Therefore, if animals inoculated by the intranasal route are over- or under-estimating these properties compared with more “naturally” inoculated animals, the way we interpret this data may be called into question. The goal of our study was to determine if the way we inoculate a ubiquitous model in influenza, the mouse, influences the conclusions drawn by mammalian pathotyping studies of emerging viruses which contribute to the overall risk assessment of influenza viruses.

As a scientist, you hope for experiments that provide clear-cut, statistically significant differences between Condition A and Condition B. But, sometimes all you get is “negative data” where there isn’t much of a difference at all. In our case, our finding that viruses delivered to mice by either the traditional intranasal route or the aerosol inhalation route exhibit generally similar infectivity, replication, and disease severity is the best kind of negative data: it means that our tried-and-true model of inoculating mice is likely just as efficacious in determining the virulence of an emerging influenza virus as an aerosol inhalation model, which requires expensive equipment and specialized expertise to operate and analyze. Ongoing studies examining the contribution of inoculation route and dose in other mammalian species, particularly the ferret, will continue to shed light on the role these properties contribute to our understanding of influenza virus virulence, and ultimately improve our ability to assess the risk of emerging influenza viruses to humans.

Belser Table 1

Table 1: Generally comparable infectivity and lethality in mice inoculated by the traditional intranasal route or aerosol inhalation route, using three influenza viruses of pandemic concern.

Introducing the Author

Belser Photo

Jessica Belser, CDC

About the research

Comparison of traditional intranasal and aerosol inhalation inoculation of mice with influenza A viruses
Virology, Volume 481, July 2015, Pages 107–112
Jessica A. Belser, Kortney M. Gustin, Jacqueline M. Katz, Taronna R. Maines, Terrence M. Tumpey

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