tetano
Editor, Senior Moderator
EBioMedicine
. 2024 Sep 30:108:105361.
doi: 10.1016/j.ebiom.2024.105361. Online ahead of print. Influence of Th1 versus Th2 immune bias on viral, pathological, and immunological dynamics in SARS-CoV-2 variant-infected human ACE2 knock-in mice
Shailendra Kumar Verma[SUP] 1 [/SUP], Fernanda Ana-Sosa-Batiz[SUP] 1 [/SUP], Julia Timis[SUP] 1 [/SUP], Norazizah Shafee[SUP] 2 [/SUP], Erin Maule[SUP] 1 [/SUP], Paolla Beatriz Almeida Pinto[SUP] 1 [/SUP], Chris Conner[SUP] 2 [/SUP], Kristen M Valentine[SUP] 1 [/SUP], Dale O Cowley[SUP] 3 [/SUP], Robyn Miller[SUP] 1 [/SUP], Annie Elong Ngono[SUP] 1 [/SUP], Linda Tran[SUP] 1 [/SUP], Krithik Varghese[SUP] 1 [/SUP], Rúbens Prince Dos Santos Alves[SUP] 1 [/SUP], Kathryn M Hastie[SUP] 1 [/SUP], Erica Ollmann Saphire[SUP] 1 [/SUP], David R Webb[SUP] 2 [/SUP], Kurt Jarnagin[SUP] 2 [/SUP], Kenneth Kim[SUP] 4 [/SUP], Sujan Shresta[SUP] 5 [/SUP]
Affiliations
Background: Mouse models that recapitulate key features of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are important tools for understanding complex interactions between host genetics, immune responses, and SARS-CoV-2 pathogenesis. Little is known about how predominantly cellular (Th1 type) versus humoral (Th2 type) immune responses influence SARS-CoV-2 dynamics, including infectivity and disease course.
Methods: We generated knock-in (KI) mice expressing human ACE2 (hACE2) and/or human TMPRSS2 (hTMPRSS2) on Th1-biased (C57BL/6; B6) and Th2-biased (BALB/c) genetic backgrounds. Mice were infected intranasally with SARS-CoV-2 Delta (B.1.617.2) or Omicron BA.1 (B.1.1.529) variants, followed by assessment of disease course, respiratory tract infection, lung histopathology, and humoral and cellular immune responses.
Findings: In both B6 and BALB/c mice, hACE2 expression was required for infection of the lungs with Delta, but not Omicron BA.1. Disease severity was greater in Omicron BA.1-infected hTMPRSS2-KI and double-KI BALB/c mice compared with B6 mice, and in Delta-infected double-KI B6 and BALB/c mice compared with hACE2-KI mice. hACE2-KI B6 mice developed more severe lung pathology and more robust SARS-CoV-2-specific splenic CD8 T cell responses compared with hACE2-KI BALB/c mice. There were no notable differences between the two genetic backgrounds in plasma cell, germinal center B cell, or antibody responses to SARS-CoV-2.
Interpretation: SARS-CoV-2 Delta and Omicron BA.1 infection, disease course, and CD8 T cell response are influenced by the host genetic background. These humanized mice hold promise as important tools for investigating the mechanisms underlying the heterogeneity of SARS-CoV-2-induced pathogenesis and immune response.
Funding: This work was funded by NIH U19 AI142790-02S1, the GHR Foundation, the Arvin Gottleib Foundation, and the Overton family (to SS and EOS); Prebys Foundation (to SS); NIH R44 AI157900 (to KJ); and by an American Association of Immunologists Career Reentry Fellowship (FASB).
Keywords: B cells; BALB/c; C57BL/6; CD4 T cells; CD8 T cells; Delta; Mouse model; Omicron BA.1; hACE2; hTMPRSS2.
. 2024 Sep 30:108:105361.
doi: 10.1016/j.ebiom.2024.105361. Online ahead of print. Influence of Th1 versus Th2 immune bias on viral, pathological, and immunological dynamics in SARS-CoV-2 variant-infected human ACE2 knock-in mice
Shailendra Kumar Verma[SUP] 1 [/SUP], Fernanda Ana-Sosa-Batiz[SUP] 1 [/SUP], Julia Timis[SUP] 1 [/SUP], Norazizah Shafee[SUP] 2 [/SUP], Erin Maule[SUP] 1 [/SUP], Paolla Beatriz Almeida Pinto[SUP] 1 [/SUP], Chris Conner[SUP] 2 [/SUP], Kristen M Valentine[SUP] 1 [/SUP], Dale O Cowley[SUP] 3 [/SUP], Robyn Miller[SUP] 1 [/SUP], Annie Elong Ngono[SUP] 1 [/SUP], Linda Tran[SUP] 1 [/SUP], Krithik Varghese[SUP] 1 [/SUP], Rúbens Prince Dos Santos Alves[SUP] 1 [/SUP], Kathryn M Hastie[SUP] 1 [/SUP], Erica Ollmann Saphire[SUP] 1 [/SUP], David R Webb[SUP] 2 [/SUP], Kurt Jarnagin[SUP] 2 [/SUP], Kenneth Kim[SUP] 4 [/SUP], Sujan Shresta[SUP] 5 [/SUP]
Affiliations
- PMID: 39353281
- DOI: 10.1016/j.ebiom.2024.105361
Background: Mouse models that recapitulate key features of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are important tools for understanding complex interactions between host genetics, immune responses, and SARS-CoV-2 pathogenesis. Little is known about how predominantly cellular (Th1 type) versus humoral (Th2 type) immune responses influence SARS-CoV-2 dynamics, including infectivity and disease course.
Methods: We generated knock-in (KI) mice expressing human ACE2 (hACE2) and/or human TMPRSS2 (hTMPRSS2) on Th1-biased (C57BL/6; B6) and Th2-biased (BALB/c) genetic backgrounds. Mice were infected intranasally with SARS-CoV-2 Delta (B.1.617.2) or Omicron BA.1 (B.1.1.529) variants, followed by assessment of disease course, respiratory tract infection, lung histopathology, and humoral and cellular immune responses.
Findings: In both B6 and BALB/c mice, hACE2 expression was required for infection of the lungs with Delta, but not Omicron BA.1. Disease severity was greater in Omicron BA.1-infected hTMPRSS2-KI and double-KI BALB/c mice compared with B6 mice, and in Delta-infected double-KI B6 and BALB/c mice compared with hACE2-KI mice. hACE2-KI B6 mice developed more severe lung pathology and more robust SARS-CoV-2-specific splenic CD8 T cell responses compared with hACE2-KI BALB/c mice. There were no notable differences between the two genetic backgrounds in plasma cell, germinal center B cell, or antibody responses to SARS-CoV-2.
Interpretation: SARS-CoV-2 Delta and Omicron BA.1 infection, disease course, and CD8 T cell response are influenced by the host genetic background. These humanized mice hold promise as important tools for investigating the mechanisms underlying the heterogeneity of SARS-CoV-2-induced pathogenesis and immune response.
Funding: This work was funded by NIH U19 AI142790-02S1, the GHR Foundation, the Arvin Gottleib Foundation, and the Overton family (to SS and EOS); Prebys Foundation (to SS); NIH R44 AI157900 (to KJ); and by an American Association of Immunologists Career Reentry Fellowship (FASB).
Keywords: B cells; BALB/c; C57BL/6; CD4 T cells; CD8 T cells; Delta; Mouse model; Omicron BA.1; hACE2; hTMPRSS2.