The ferret has been widely used to study both the pathogenicity and the transmissibility of respiratory viral infections, but little is known about how host-associated microbial communities alter disease susceptibility owing to the lack of a validated model. Here, we compared the safety of injectable versus oral broad-spectrum antibiotics and their efficacy in reducing culturable bacteria from the upper respiratory tract of ferrets before an influenza A virus challenge. Both injectable and oral antibiotic treatment led to drastic reductions in cultivable bacteria from nasal wash specimens when assessed after 7 days of ongoing treatment. Even when extended to 14 days, there were few adverse events noted and no clinically significant bloodwork changes. During challenge with either a high-dose or low-dose A(H1N1)pdm09 influenza A virus inoculum, all animals became productively infected and had generally similar viral titers and clinical measurements, regardless of antibiotic pretreatment. Collectively, these results support that both antibiotic regimens evaluated in laboratory ferrets can be utilized to further characterize host-microbial interactions in the context of respiratory viral infections and other pathogens, including a needle-free approach that may be suitable for studies of high-consequence pathogens in containment laboratory facilities.

Ferrets represent an invaluable model for the study of influenza virus pathogenicity and transmissibility due to the ability of this species to recapitulate clinical symptoms of influenza infection present in humans. Ferrets are also employed for the study of bacterial pathogens that naturally infect humans at different anatomical sites, including the respiratory and gastrointestinal tracts. While viral and bacterial infection studies in isolation using animal models are important for furthering our understanding of pathogen biology and for the development of improved therapeutics, it is also critical to extend our knowledge to pathogen coinfections in vivo, to more closely examine interkingdom dynamics that may contribute to overall disease outcomes. Despite the increasing use of ferrets for studies with influenza virus, few reports have investigated influenza and bacterial coinfection challenges in ferrets. In this review, we discuss how ferrets have been employed to study a diverse range of both influenza viruses and bacterial species and summarize key studies that have utilized the ferret model for primary influenza virus challenge followed by secondary bacterial infection. These co-pathogenesis studies have provided critical insight into the dynamic interplay between these pathogens, underscoring the utility of ferrets as a model system for investigating influenza virus-bacteria interactions.

Competition assays were conducted in vitro and in vivo to examine how the Delta (B.1.617.2) variant displaced the prototype Washington/1/2020 (WA/1) strain. While WA/1 virus exhibited a moderately increased proportion compared to that in the inoculum following co-infection in human respiratory cells, Delta variant possessed a substantial in vivo fitness advantage as this virus becoming predominant in both inoculated and contact animals. This work identifies critical traits of the Delta variant that likely played a role in it becoming a dominant variant and highlights the necessities of employing multiple model systems to assess the fitness of newly emerged SARS-CoV-2 variants.