Molecular Determinants of Influenza Virus Pathogenesis in Mice

Abstract

Mice are widely used for studying influenza virus pathogenesis and immunology because of their low cost, the wide availability of mouse-specific reagents, and the large number of mouse strains available, including knockout and transgenic strains. However, mice do not fully recapitulate the signs of influenza infection of humans: transmission of influenza between mice is much less efficient than in humans, and influenza viruses often require adaptation before they are able to efficiently replicate in mice. In the process of mouse adaptation, influenza viruses acquire mutations that enhance their ability to attach to mouse cells, replicate within the cells, and suppress immunity, among other functions. Many such mouse-adaptive mutations have been identified, covering all 8 genomic segments of the virus. Identification and analysis of these mutations have provided insight into the molecular determinants of influenza virulence and pathogenesis, not only in mice but also in humans and other species. In particular, several mouse-adaptive mutations of avian influenza viruses have proved to be general mammalian-adaptive changes that are potential markers of pre-pandemic viruses. As well as evaluating influenza pathogenesis, mice have also been used as models for evaluation of novel vaccines and anti-viral therapies. Mice can be a useful animal model for studying influenza biology as long as differences between human and mice infections are taken into account.

A Hitchhiker's guide to humanized mice: new pathways to studying viral infections

“…epithelial cells) are also susceptible to influenza virus infection and wild‐type mice are commonly used as a model for influenza. Hence, it is difficult to define where the response originates in the humanized mice due to the cross reactivity with human and murine chemokines, cytokines and cell–cell interactions …”

“…Hence, it is difficult to define where the response originates in the humanized mice due to the cross reactivity with human and murine chemokines, cytokines and cell-cell interactions. 94…”

Influenza Viruses in Mice: Deep Sequencing Analysis of Serial Passage and Effects of Sialic Acid Structural Variation

“…While some IAV strains appear to infect and replicate to high levels in the lungs or other respiratory tissues of mice, many show relatively limited replication, most do not spread naturally from mouse to mouse, and many cause little disease unless they 85 are adapted by serial passage (19)(20)(21). The sequences of mouse-adapted IAVs often contain mutations in various genomic segments, including HA, NA, NS, as well as the polymerase gene segments (PB2, PB1, PA) (reviewed by 22). The considerable number of mouse adaptation studies of IAV vary in repetition, reproducibility, and specifics of the methodologies and experimental variables, all of which could impact virus evolution.…”

Identifying genetic determinants of complex phenotypes from whole genome sequence data

“…These phenotypes pertained either to their capacity to infect a human host (influenza), or their resistance to particular antibiotics (pseudomonas). Although these two biological systems are very different, both are expected to have a highly complex genetic basis: the molecular determinants of influenza virulence and pathogenesis can span its entire genome [21,22], and bacterial drug resistance can involve many distinct mechanisms [23]. We took advantage of an influenza database backed by experimental validations [24], and of a recent study of P. aeruginosa genomics [25], to train both algorithms.…”