Transgenic mouse models support a protective role of type I IFN response in SARS-CoV-2 infection-related lung immunopathology and neuroinvasion

Nishant Ranjan Chauhan; Soumya Kundu; Ramyasingh Bal; Diya Chattopadhyay; Rinku Sahu; Subhash Mehto; Rina Yadav; Sivaram Krishna; Kautilya Kumar Jena; Sameekshya Satapathy; Anusha Pv; Krushna C. Murmu; Bharati Singh; Srinivas Patnaik; Sarita Jena; Krishnan H. Harshan; Gulam Hussain Syed; Mohammed M. Idris; Punit Prasad; Santosh Chauhan

doi:10.1016/j.celrep.2023.113275

Transgenic mouse models support a protective role of type I IFN response in SARS-CoV-2 infection-related lung immunopathology and neuroinvasion

Nishant Ranjan Chauhan, Soumya Kundu, Ramyasingh Bal, Diya Chattopadhyay, Rinku Sahu, Subhash Mehto, Rina Yadav, Sivaram Krishna, Kautilya Kumar Jena, Sameekshya Satapathy, Anusha Pv, Krushna C. Murmu, Bharati Singh, Srinivas Patnaik, Sarita Jena, Krishnan H. Harshan, Gulam Hussain Syed, Mohammed M. Idris, Punit Prasad, Santosh Chauhan

Research output: Contribution to journal › Article › peer-review

Abstract

Type I 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 infection remains perplexing. Here, we develop 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. We report that hACE2; Irgm1^−/− mice are resistant to lethal SARS-CoV-2 infection. In contrast, a severe SARS-CoV-2 infection along with immune cell infiltration, cytokine storm, and enhanced pathology is observed in the lungs and brain of hACE2; Ifnar1^−/− mice. The hACE2; Irgm1^−/−Ifnar1^−/− double-knockout mice display loss of the protective phenotype observed in hACE2; Irgm1^−/− mice, suggesting that heightened IFN-I response accounts for the observed immunity. Taking the results together, we demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target against SARS-CoV-2.

Original language	English (US)
Article number	113275
Journal	Cell Reports
Volume	42
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2023.113275
State	Published - Nov 28 2023
Externally published	Yes

Keywords

CP: Immunology
CP: Microbiology
Delta
IRGM
Ifnar1
Irgm1
Omicron
SARS-CoV-2
hACE2- K18 mice
interferon response

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2023.113275

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Chauhan, N. R., Kundu, S., Bal, R., Chattopadhyay, D., Sahu, R., Mehto, S., Yadav, R., Krishna, S., Jena, K. K., Satapathy, S., Pv, A., Murmu, K. C., Singh, B., Patnaik, S., Jena, S., Harshan, K. H., Syed, G. H., Idris, M. M., Prasad, P., & Chauhan, S. (2023). Transgenic mouse models support a protective role of type I IFN response in SARS-CoV-2 infection-related lung immunopathology and neuroinvasion. Cell Reports, 42(11), Article 113275. https://doi.org/10.1016/j.celrep.2023.113275

Chauhan, NR, Kundu, S, Bal, R, Chattopadhyay, D, Sahu, R, Mehto, S, Yadav, R, Krishna, S, Jena, KK, Satapathy, S, Pv, A, Murmu, KC, Singh, B, Patnaik, S, Jena, S, Harshan, KH, Syed, GH, Idris, MM, Prasad, P & Chauhan, S 2023, 'Transgenic mouse models support a protective role of type I IFN response in SARS-CoV-2 infection-related lung immunopathology and neuroinvasion', Cell Reports, vol. 42, no. 11, 113275. https://doi.org/10.1016/j.celrep.2023.113275

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title = "Transgenic mouse models support a protective role of type I IFN response in SARS-CoV-2 infection-related lung immunopathology and neuroinvasion",

abstract = "Type I 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 infection remains perplexing. Here, we develop 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. We report that hACE2; Irgm1−/− mice are resistant to lethal SARS-CoV-2 infection. In contrast, a severe SARS-CoV-2 infection along with immune cell infiltration, cytokine storm, and enhanced pathology is observed in the lungs and brain of hACE2; Ifnar1−/− mice. The hACE2; Irgm1−/−Ifnar1−/− double-knockout mice display loss of the protective phenotype observed in hACE2; Irgm1−/− mice, suggesting that heightened IFN-I response accounts for the observed immunity. Taking the results together, we demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target against SARS-CoV-2.",

keywords = "CP: Immunology, CP: Microbiology, Delta, IRGM, Ifnar1, Irgm1, Omicron, SARS-CoV-2, hACE2- K18 mice, interferon response",

author = "Chauhan, {Nishant Ranjan} and Soumya Kundu and Ramyasingh Bal and Diya Chattopadhyay and Rinku Sahu and Subhash Mehto and Rina Yadav and Sivaram Krishna and Jena, {Kautilya Kumar} and Sameekshya Satapathy and Anusha Pv and Murmu, {Krushna C.} and Bharati Singh and Srinivas Patnaik and Sarita Jena and Harshan, {Krishnan H.} and Syed, {Gulam Hussain} and Idris, {Mohammed M.} and Punit Prasad and Santosh Chauhan",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = nov,

day = "28",

doi = "10.1016/j.celrep.2023.113275",

language = "English (US)",

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T1 - Transgenic mouse models support a protective role of type I IFN response in SARS-CoV-2 infection-related lung immunopathology and neuroinvasion

AU - Chauhan, Nishant Ranjan

AU - Kundu, Soumya

AU - Bal, Ramyasingh

AU - Chattopadhyay, Diya

AU - Sahu, Rinku

AU - Mehto, Subhash

AU - Yadav, Rina

AU - Krishna, Sivaram

AU - Jena, Kautilya Kumar

AU - Satapathy, Sameekshya

AU - Pv, Anusha

AU - Murmu, Krushna C.

AU - Singh, Bharati

AU - Patnaik, Srinivas

AU - Jena, Sarita

AU - Harshan, Krishnan H.

AU - Syed, Gulam Hussain

AU - Idris, Mohammed M.

AU - Prasad, Punit

AU - Chauhan, Santosh

PY - 2023/11/28

Y1 - 2023/11/28

N2 - Type I 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 infection remains perplexing. Here, we develop 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. We report that hACE2; Irgm1−/− mice are resistant to lethal SARS-CoV-2 infection. In contrast, a severe SARS-CoV-2 infection along with immune cell infiltration, cytokine storm, and enhanced pathology is observed in the lungs and brain of hACE2; Ifnar1−/− mice. The hACE2; Irgm1−/−Ifnar1−/− double-knockout mice display loss of the protective phenotype observed in hACE2; Irgm1−/− mice, suggesting that heightened IFN-I response accounts for the observed immunity. Taking the results together, we demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target against SARS-CoV-2.

AB - Type I 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 infection remains perplexing. Here, we develop 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. We report that hACE2; Irgm1−/− mice are resistant to lethal SARS-CoV-2 infection. In contrast, a severe SARS-CoV-2 infection along with immune cell infiltration, cytokine storm, and enhanced pathology is observed in the lungs and brain of hACE2; Ifnar1−/− mice. The hACE2; Irgm1−/−Ifnar1−/− double-knockout mice display loss of the protective phenotype observed in hACE2; Irgm1−/− mice, suggesting that heightened IFN-I response accounts for the observed immunity. Taking the results together, we demonstrate that IFN-I protects from lethal SARS-CoV-2 infection, and Irgm1 (IRGM) could be an excellent therapeutic target against SARS-CoV-2.

KW - CP: Immunology

KW - CP: Microbiology

KW - Delta

KW - IRGM

KW - Ifnar1

KW - Irgm1

KW - Omicron

KW - SARS-CoV-2

KW - hACE2- K18 mice

KW - interferon response

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DO - 10.1016/j.celrep.2023.113275

M3 - Article

C2 - 37874678

AN - SCOPUS:85174674582

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 113275

ER -

Transgenic mouse models support a protective role of type I IFN response in SARS-CoV-2 infection-related lung immunopathology and neuroinvasion

Abstract

Keywords

ASJC Scopus subject areas

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