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Inborn resistance of mice to myxoviruses: macrophages express phenotype in vitro
Abstract:
A strain of avian influenza A virus was adapted to grow in mouse peritoneal macrophages in vitro. The adapted strain, called M-TUR, induced a marked cytopathic effect in macrophages from susceptible mice. Mice homozygous (A2G) or heterozygous (F1 hybrids between A2G and several susceptible strains) for the gene Mx, shown previously to induce a high level of resistance towards lethal challenge by a number of myxoviruses in vivo, yielded peritoneal macrophages which were not affected by M-TUR. Peritoneal macrophages could be classified as resistant or susceptible to M-TUR without sacrificing the cell donor. Backcrosses were arranged between (A2G X A/J)F1 and A/J mice. 64 backcross animals could be tested individually both for resistance of their macrophages in vitro after challenge with M-TUR, and for resistance of the whole animal in vivo after challenge with NWS (a neurotropic variant of human influenza A virus). Macrophages from 36 backcross mice were classified as susceptible, and all of these mice died after challenge. Macrophages from 28 mice were classified as resistant, and 26 mice survived challenge. We conclude that resistance of macrophages and resistance of the whole animal are two facets of the same phenomenon.
Insights
Mouse macrophages resistant to avian influenza virus M-TUR indicate whole-animal resistance. This finding links macrophage susceptibility to influenza virus infection with overall animal survival, offering a new method for resistance assessment.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Avian influenza A virus can be adapted to infect mouse peritoneal macrophages.
- The adapted strain, M-TUR, causes cytopathic effects in macrophages from susceptible mice.
- The Mx gene confers resistance to myxoviruses in vivo.
Purpose of the Study:
- To investigate the correlation between macrophage resistance to M-TUR in vitro and whole-animal resistance in vivo.
- To determine if macrophage susceptibility to M-TUR can predict overall animal resistance to influenza virus challenge.
Main Methods:
- Adapting avian influenza A virus to grow in mouse peritoneal macrophages (M-TUR).
- Assessing M-TUR's cytopathic effect on macrophages from mice with varying Mx gene status (homozygous resistant A2G, heterozygous, and susceptible).
- Correlating in vitro macrophage resistance/susceptibility to M-TUR with in vivo survival rates after challenge with NWS influenza A virus in backcross mice.
Main Results:
- Macrophages from mice with the Mx gene (A2G or heterozygous) were resistant to M-TUR.
- In backcross mice, macrophage resistance to M-TUR in vitro strongly correlated with survival after in vivo NWS challenge.
- 36/64 backcross mice with susceptible macrophages died, while 28/64 with resistant macrophages survived.
Conclusions:
- Macrophage resistance to M-TUR is a reliable indicator of whole-animal resistance to influenza virus.
- The Mx gene's role in conferring resistance is demonstrated at the macrophage level.
- This study establishes a link between cellular and organismal resistance to influenza, providing a potential in vitro screening method.