An Infant Mouse Model of Influenza Virus Transmission Demonstrates the Role of Virus-Specific Shedding, Humoral Immunity, and Sialidase Expression by Colonizing Streptococcus pneumoniae.

Mila Brum Ortigoza,Alexandria J Hammond,Simone B Blaser,Jeffrey N Weiser,M Ammar Zafar,Keith P Klugman

doi:10.1128/mbio.02359-18

Abstract

The pandemic potential of influenza A viruses (IAV) depends on the infectivity of the host, transmissibility of the virus, and susceptibility of the recipient. While virus traits supporting IAV transmission have been studied in detail using ferret and guinea pig models, there is limited understanding of host traits determining transmissibility and susceptibility because current animal models of transmission are not sufficiently tractable. Although mice remain the primary model to study IAV immunity and pathogenesis, the efficiency of IAV transmission in adult mice has been inconsistent. Here we describe an infant mouse model that supports efficient transmission of IAV. We demonstrate that transmission in this model requires young age, close contact, shedding of virus particles from the upper respiratory tract (URT) of infected pups, the use of a transmissible virus strain, and a susceptible recipient. We characterize shedding as a marker of infectiousness that predicts the efficiency of transmission among different influenza virus strains. We also demonstrate that transmissibility and susceptibility to IAV can be inhibited by humoral immunity via maternal-infant transfer of IAV-specific immunoglobulins and modifications to the URT milieu, via sialidase activity of colonizing Streptococcus pneumoniae Due to its simplicity and efficiency, this model can be used to dissect the host's contribution to IAV transmission and explore new methods to limit contagion.IMPORTANCE This study provides insight into the role of the virus strain, age, immunity, and URT flora on IAV shedding and transmission efficiency. Using the infant mouse model, we found that (i) differences in viral shedding of various IAV strains are dependent on specific hemagglutinin (HA) and/or neuraminidase (NA) proteins, (ii) host age plays a key role in the efficiency of IAV transmission, (iii) levels of IAV-specific immunoglobulins are necessary to limit infectiousness, transmission, and susceptibility to IAV, and (iv) expression of sialidases by colonizing S. pneumoniae antagonizes transmission by limiting the acquisition of IAV in recipient hosts. Our findings highlight the need for strategies that limit IAV shedding and the importance of understanding the function of the URT bacterial composition in IAV transmission. This work reinforces the significance of a tractable animal model to study both viral and host traits affecting IAV contagion and its potential for optimizing vaccines and therapeutics that target disease spread.

Highlights

The pandemic potential of influenza A viruses (IAV) depends on the infectivity of the host, transmissibility of the virus, and susceptibility of the recipient
Despite the availability of vaccines that have been efficacious at preventing hospitalizations, morbidity, and mortality, evidence that the inactivated influenza virus (IIV) vaccine blocks virus acquisition, shedding, or transmission has been limited in animal models [3,4,5,6,7]
Since the 1930s, the mouse model has been essential in understanding IAV immunity and pathogenesis, and early studies described its usefulness in evaluating IAV transmission [20, 21]

Summary

Introduction

The pandemic potential of influenza A viruses (IAV) depends on the infectivity of the host, transmissibility of the virus, and susceptibility of the recipient. NI treatment of index cases alone shows limited effectiveness at reducing viral shedding or transmission, possibly due to its short therapeutic window [10, 11, 14, 15] These limitations of our current options to prevent disease spread highlight a critical aspect of the influenza A virus (IAV) ecology that needs further study: contagion. Scientific progress to date has emphasized viral genetics, viral tropism, and environmental impacts on transmission [16,17,18,19] While these factors contribute to knowledge about IAV contagion, host characteristics that could affect transmissibility, including the highly variable composition of the upper respiratory tract (URT) flora, remain largely unexplored. In this study, we sought to reevaluate the mouse as a tool to study the biology of IAV contagion, the contribution of host factors

Methods

Results

Conclusion