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Interfer-on time: lessons from genetically diverse mouse models of SARS-CoV-2 infection

Genes & Immunity (2023)Cite this article

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Robertson SJ, Bedard O, McNally KL, et al. Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19. Nat Commun. 2023;14:4481 (2023). https://doi.org/10.1038/s41467-023-40076-5.

Infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) results in mild to moderate respiratory symptoms in most individuals, while others suffer severe, and sometimes life-threatening, multi-organ disease. Although many environmental, viral, and host factors contribute to this variability, dynamics of innate immune signaling are hypothesized to be an important determinant of disease outcome [1]. If all goes well, an innate immune response, defined by expression of type I (IFN-I or IFNα/β) and type III interferons (IFN-III or IFN-λ), should occur within hours of initial infection and induce the expression of interferon-stimulated genes (ISGs) that function to limit virus replication and coordinate inflammation. Upon SARS-CoV-2 infection, most individuals mount an effective IFN response that promotes virus clearance and adaptive immunity. However, a delayed IFN response relative to peak virus burden that contributes to dysregulated inflammation has been observed in patients that progress to severe COVID-19, the disease caused by SARS-CoV-2 [2]. Human clinical data has revealed important innate immune correlates of disease and have further shown that failure of innate immunity is multifactorial including polymorphisms in genes required for pathogen sensing pathways or production of autoantibodies directed towards IFN-I [1]. The complex dynamics of IFNs in SARS-CoV-2 infection are important to understand, particularly as the use of IFNs in the treatment of COVID-19 is pursued. The most widely used mouse model for infection, C57BL/6 mice expressing the human ACE2 receptor as a transgene (K18-hACE2), has been instrumental in the development of vaccines and therapeutics [1]. However, efforts to delineate the paradoxical roles of IFNs in virus control and inflammation using this model have been only moderately revealing.

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Acknowledgements

This work was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

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  1. Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT, USA

    Shelly J. Robertson & Sonja M. Best

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SJR and SMB contributed equally to writing and editing this commentary.

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Correspondence to Sonja M. Best.

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Robertson, S.J., Best, S.M. Interfer-on time: lessons from genetically diverse mouse models of SARS-CoV-2 infection. Genes Immun (2023). https://doi.org/10.1038/s41435-023-00250-7

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