Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology

Chauhan, N. R.; Kundu, S.; Bal, R.; Chattopadhyay, D.; Mehto, S.; Sahu, R.; Yadav, R.; Krishna, S.; Jena, K. K.; Satapathy, S.; Murmu, K. C.; Singh, B.; Das, S. K.; Jena, S.; Harshan, K. H.; Syed, G. H.; Prasad, P.; Chauhan, S.

doi:10.1101/2022.12.17.520843

bioRxiv · 10.1101/2022.12.17.520843

Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology

Chauhan, N. R.·Kundu, S.·Bal, R.·Chattopadhyay, D.·Mehto, S.·Sahu, R.·Yadav, R.·Krishna, S.·Jena, K. K.·Satapathy, S.·Murmu, K. C.·Singh, B.·Das, S. K.·Jena, S.·Harshan, K. H.·Syed, G. H.·Prasad, P.·Chauhan, S.

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Abstract

Type 1 interferon (IFN-I) response is the first line of host defense against invading viruses. In the absence of definite mouse models, the role of IFN-I in SARS-CoV-2 infections remained to be perplexing. Here, we developed two mouse models, one with constitutively high IFN-I response (hACE2; Irgm1-/-) and the other with dampened IFN-I response (hACE2; Ifnar1-/-) to comprehend the role of IFN-I response during SARS-CoV-2 invasion. We found that hACE2; Irgm1-/- mice were resistant to lethal SARS-CoV-2 infection with substantially reduced cytokine storm and immunopathology. In striking contrast, a severe SARS-CoV-2 infection along with immune cells infiltration, inflammatory response, and enhanced pathology was observed in the lungs of hACE2; Ifnar1-/- mice. Additionally, hACE2; Ifnar1-/- mice were highly susceptible to SARS-CoV-2 neuroinvasion in the brain accompanied by immune cell infiltration, microglia/astrocytes activation, cytokine response, and demyelination of neurons. The hACE2; Irgm1-/- Ifnar1-/- double knockout mice or hACE2; Irgm1-/- mice treated with STING or RIPK2 pharmacological inhibitors displayed loss of the protective phenotypes observed in hACE2; Irgm1-/- mice suggesting that heightened IFN-I response accounts for the observed immunity. Taken together, we explicitly demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/520843v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@a3aad4org.highwire.dtl.DTLVardef@12452fcorg.highwire.dtl.DTLVardef@1c43dc0org.highwire.dtl.DTLVardef@b2167d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Chauhan, N. R., Kundu, S., Bal, R., Chattopadhyay, D., Mehto, S., Sahu, R., Yadav, R., Krishna, S., Jena, K. K., Satapathy, S., Murmu, K. C., Singh, B., Das, S. K., Jena, S., Harshan, K. H., Syed, G. H., Prasad, P., Chauhan, S.. 2022-12-19. Transgenic Mouse Models Establish a Protective Role of Type 1 IFN Response in SARS-CoV-2 infection-related Immunopathology. https://doi.org/10.1101/2022.12.17.520843

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