Ferreting Out Influenza Virus Pathogenicity and Transmissibility: Past and Future Risk Assessments in the Ferret Model

Belser, Jessica A.; Pulit-Penaloza, Joanna A.; Maines, Taronna R.

doi:10.1101/cshperspect.a038323

Cited by 26 publications

(29 citation statements)

References 120 publications

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“…Ferrets display human-like clinical symptoms after viral infection 52 . Weight and temperature were monitored after inoculation for 14 days ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Male sex and age biases viral burden, viral shedding, and type 1 and 2 interferon responses during SARS-CoV-2 infection in ferrets

Francis

Richardson

McNeil

et al. 2021

Preprint

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SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) hospitalizations and deaths disportionally affect males and the elderly. Here we investigated the impact of male sex and age by infecting adult male, aged male, and adult female ferrets with SARS-CoV-2. Aged male ferrets had a decrease in temperature which was accompanied by prolonged viral replication with increased pathology in the upper respiratory tract after infection. Transcriptome analysis of the nasal turbinates and lungs indicated that female ferrets had significant increases in interferon response genes (OASL, MX1, ISG15, etc.) on day 2 post infection which was delayed in aged males. In addition, genes associated with taste and smell such as RTP1, CHGA, and CHGA1 at later time points were upregulated in males but not in females. These results provide insight into COVID-19 and suggests that older males may play a role in viral transmission due to decreased antiviral responses.

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“…Ferrets display human-like clinical symptoms after viral infection 52 . Weight and temperature were monitored after inoculation for 14 days ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Male sex and age biases viral burden, viral shedding, and type 1 and 2 interferon responses during SARS-CoV-2 infection in ferrets

Francis

Richardson

McNeil

et al. 2021

Preprint

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“…However, the possible side effects linked to changes in the ability of a new MDV A/AA/6/60 LAIV to modulate host innate immune responses, such as low immunogenicity, should be evaluated in other animal models of influenza infection. For instance, the implication in virus transmission should be tested in ferrets or guinea pigs, both well-stablished animal models of influenza virus infection and transmission [43][44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Increasing the Safety Profile of the Master Donor Live Attenuated Influenza Vaccine

et al. 2020

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Seasonal influenza epidemics remain one of the largest public health burdens nowadays. The best and most effective strategy to date in preventing influenza infection is a worldwide vaccination campaign. Currently, two vaccines are available to the public for the treatment of influenza infection, the chemically Inactivated Influenza Vaccine (IIV) and the Live Attenuated Influenza Vaccine (LAIV). However, the LAIV is not recommended for parts of the population, such as children under the age of two, immunocompromised individuals, the elderly, and pregnant adults. In order to improve the safety of the LAIV and make it available to more of the population, we sought to further attenuate the LAIV. In this study, we demonstrate that the influenza A virus (IAV) master donor virus (MDV) A/Ann Arbor/6/60 H2N2 LAIV can inhibit host gene expression using both the PA-X and NS1 proteins. Furthermore, we show that by removing PA-X, we can limit the replication of the MDV LAIV in a mouse model, while maintaining full protective efficacy. This work demonstrates a broadly applicable strategy of tuning the amount of host antiviral responses induced by the IAV MDV for the development of newer and safer LAIVs. Moreover, our results also demonstrate, for the first time, the feasibility of genetically manipulating the backbone of the IAV MDV to improve the efficacy of the current IAV LAIV.

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“…Airborne transmission of IAV have been widely studied since the 2009 pandemic (Belser et al, 2020), yet there are relatively few studies on the role of coinfection in IAV transmission, partially due to limitations of mouse models to examine airborne transmission of IAV (Bouvier, 2015). Ferrets are the preferred animal model for IAV airborne transmission and have been used extensively by many groups to study transmission of H1N1pdm09 (Belser, Maines, Katz, & Tumpey, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Ferrets are the gold standard animal model for IAV pathogenesis and transmission due to their susceptibility to human IAV strains, release of virus into the air within a range of aerosol sizes that can infect a susceptible host, similarity in lung physiology, infection kinetics and clinical symptoms when compared to humans (Belser, Eckert, Tumpey, & Maines, 2016;Belser, Pulit-Penaloza, & Maines, 2020;Lakdawala et al, 2015Lakdawala et al, , 2011Lakdawala et al, , 2013. In addition, ferrets first infected with IAV have been shown to be susceptible to Spn colonization and promote Spn airborne transmission (McCullers et al, 2010;Peltola, Boyd, McAuley, Rehg, & McCullers, 2006;Peltola, Rehg, & McCullers, 2004;Rowe, Karlsson, et al, 2019).…”

Section: Introduction (826 Words)mentioning

confidence: 99%

Coinfection ofStreptococcus pneumoniaereduces airborne transmission of influenza virus

et al. 2020

Preprint

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Secondary bacterial infection, especially with Streptococcus pneumoniae (Spn), is a common complication in fatal and ICU cases of influenza virus infection. During the H1N1 pandemic of 2009 (H1N1pdm09), there was higher mortality in healthy young adults due to secondary bacterial pneumonia, with Spn being the most frequent bacterial species. Previous studies in mice and ferrets have suggested a synergistic relationship between Spn and influenza viruses. In this study, we used the ferret model to study whether airborne transmission of H1N1pdm09 was influenced by coinfection with two Spn serotypes: type 2 (D39) and type 19F (BHN97). We found that coinfected animals experienced more severe clinical symptoms as well as increased bacterial colonization of the upper respiratory tract. In contrast, we observed that coinfection resulted in reduced airborne transmission of influenza virus. Only 1/3 animals coinfected with D39 transmitted H1N1pdm09 virus to a naïve recipient compared to 3/3 transmission efficiency in animals infected with influenza virus alone. A similar trend was seen in coinfection with BHN97, suggesting that coinfection with Spn reduces influenza virus airborne transmission. The decrease in transmission does not appear to be caused by decreased stability of H1N1pdm09 in expelled droplets in the presence of Spn. Rather, coinfection resulted in decreased viral shedding in the ferret upper respiratory tract. Thus, we conclude that coinfection enhances colonization and airborne transmission of Spn but decreases replication and transmission of H1N1pdm09. Our data points to an asymmetrical relationship between these two pathogens rather than a synergistic one.SignificanceAirborne transmission of respiratory viruses is influenced by many host and environmental parameters. The complex interplay between bacterial and viral coinfections on transmission of respiratory viruses has been understudied. We demonstrate that coinfection with Streptococcus pneumoniae reduces airborne transmission of influenza A viruses by decreasing viral titers in the upper respiratory tract. Instead of implicating a synergistic relationship between bacteria and virus, our work demonstrates an asymmetric relationship where bacteria benefit from the virus but where the fitness of influenza A viruses is negatively impacted by coinfection. The implications of exploring how microbial communities can influence the fitness of pathogenic organisms is a novel avenue for transmission control of pandemic respiratory viruses.

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Ferreting Out Influenza Virus Pathogenicity and Transmissibility: Past and Future Risk Assessments in the Ferret Model

Cited by 26 publications

References 120 publications

Male sex and age biases viral burden, viral shedding, and type 1 and 2 interferon responses during SARS-CoV-2 infection in ferrets

Male sex and age biases viral burden, viral shedding, and type 1 and 2 interferon responses during SARS-CoV-2 infection in ferrets

Increasing the Safety Profile of the Master Donor Live Attenuated Influenza Vaccine

Coinfection ofStreptococcus pneumoniaereduces airborne transmission of influenza virus

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