Since its first detection in December 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has rapidly spread worldwide, resulting in over 79.2 million documented cases in one year. Lack of pre-existing immunity against this newly emerging virus has pushed the urgent development of anti-viral therapeutics and vaccines to reduce the spread of the virus and alleviate disease. Appropriate animal models recapitulating the pathogenesis of and host responses to SARS-CoV-2 infection in humans have and will continue to accelerate this development process. Several animal models including mice, hamsters, ferrets, and non-human primates have been evaluated and actively applied in preclinical studies. However, since each animal model has unique features, it is necessary to weigh the strengths and weaknesses of each according to the goals of the study. Here, we summarize the key features, strengths and weaknesses of animal models for SARS-CoV-2, focusing on their application in anti-viral therapeutic and vaccine development.

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22implicated the PA gene segment as a major driver of this phenotype and quantification of viral 33RNA synthesis indicated that both replication and transcription were affected. These findings 34 indicate that multiple distinct mechanisms underlie IAV reliance on multiple infection and 35 underscore the importance of virus-virus interactions in IAV infection, evolution and emergence. 36Importantly, multiple infection with identical viral genomes can also alter infection 58 outcomes. Such cooperation was documented for VSV and HIV, where rates of transcription and 59 replication were enhanced with increasing multiplicity of infection (MOI) 23,24 . Similarly, faster 60 kinetics of virus production were seen at high MOI for poliovirus and IAV 19,25 . In these instances, 61 it is thought that increased copy number of infecting viral genomes provides a kinetic benefit 62 important in the race to establish infection before innate antiviral responses take hold. Indeed, it 63 has been suggested that multiple infection may be particularly relevant for facilitating viral growth 64 under adverse conditions, such as antiviral drug treatment 3,26 . 65For IAV, an important adverse condition to consider is that of a novel host environment. 66IAVs occupy a broad host range, including multiple species of wild waterfowl, poultry, swine, 67 humans and other mammals 27,28 . Host barriers to infection typically confine a given lineage to 68 circulation in one species or a small number of related species 29,30 . Spillovers occur occasionally, 69 however, and can seed novel lineages. When a novel IAV lineage is established in humans, the 70 result is a pandemic of major public health consequence 31,32 . The likelihood of successful cross-71 species transfer of IAV is determined largely by the presence, absence, and compatibility of host 72 factors on which the virus relies to complete its life cycle, and on the viruses' ability to overcome 73 antiviral defenses in the novel host [33][34][35] . 74Our objective herein was to assess the degree to which IAV relies on the delivery of 75 multiple viral genomes to a cell to ensure production of progeny. In particular, we sought to 76 determine whether this phenotype varies with host species. We therefore examined the 77 multiplicity dependence of one human and a panel of avian-origin viruses in multiple host systems. 78Results from all virus/cell combinations tested confirm prior reports that cells multiply-infected with 79 IAV produce more viral progeny than singly-infected cells. Importantly, however, the extent to 80 which viral progeny production is concentrated within the multiply-infected fraction of a cell 81 population varies greatly with virus-host context. Two poultry-adapted H9N2 viruses (A/guinea 82 fowl/HK/WF10/99 (GFHK99) and A/quail/HK/A28945/88 (QaHK88)) exhibit an acute dependence 83 on multiple infection in mammalian systems that is greatly diminished in natural host systems. 84This strong dependence on multiple infection is not seen for the human strain, influenza 85 ...

The polymerase of avian influenza A virus (AIV) is a heterotrimer composed of PB2, PB1, and PA. PB2 plays a role in overcoming the host barrier; however, the genetic prerequisites for avian PB2 to acquire mammalian pathogenic mutations have not been well elucidated. Previously, we identified a prototypic avian PB2 that conferred non-replicative and non-pathogenic traits to a PR8-derived recombinant virus when it was used to infect mice. Here, we demonstrated that key amino acid mutations (I66M, I109V, and I133V, collectively referred to as MVV) of this prototypic avian PB2 increase the replication efficiency of recombinant PR8 virus carrying the mutated PB2 in both avian and mammalian hosts. The MVV mutations caused no weight loss in mice, but they did allow replication in infected lungs, and the viruses acquired fatal mammalian pathogenic mutations such as Q591R/K, E627K, or D701N in the infected lungs. The MVV mutations are located at the interfaces of the trimer and are predicted to increase the strength of this structure. Thus, gaining MVV mutations might be the first step for AIV to acquire mammalian pathogenicity. These results provide new insights into the evolution of AIV in birds and mammals.

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