Influence of Th1 versus Th2 immune bias on viral, pathological, and immunological dynamics in SARS-CoV-2 variant-infected human ACE2 knock-in miceResearch in context
Shailendra Kumar Verma,
Fernanda Ana-Sosa-Batiz,
Julia Timis,
Norazizah Shafee,
Erin Maule,
Paolla Beatriz Almeida Pinto,
Chris Conner,
Kristen M. Valentine,
Dale O. Cowley,
Robyn Miller,
Annie Elong Ngono,
Linda Tran,
Krithik Varghese,
Rúbens Prince Dos Santos Alves,
Kathryn M. Hastie,
Erica Ollmann Saphire,
David R. Webb,
Kurt Jarnagin,
Kenneth Kim,
Sujan Shresta
Affiliations
Shailendra Kumar Verma
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Fernanda Ana-Sosa-Batiz
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Julia Timis
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Norazizah Shafee
Synbal Inc., 1759 Yorktown Rd., San Mateo, CA, 94402, USA
Erin Maule
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Paolla Beatriz Almeida Pinto
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Chris Conner
Synbal Inc., 1759 Yorktown Rd., San Mateo, CA, 94402, USA
Kristen M. Valentine
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Dale O. Cowley
TransViragen Inc., 109 Mason Farm Road, Chapel Hill, NC, 27599, USA
Robyn Miller
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Annie Elong Ngono
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Linda Tran
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Krithik Varghese
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Rúbens Prince Dos Santos Alves
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Kathryn M. Hastie
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
Erica Ollmann Saphire
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
David R. Webb
Synbal Inc., 1759 Yorktown Rd., San Mateo, CA, 94402, USA
Kurt Jarnagin
Synbal Inc., 1759 Yorktown Rd., San Mateo, CA, 94402, USA
Kenneth Kim
Histopathology Core Facility, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA; Corresponding author.
Sujan Shresta
Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA; Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, UC San Diego School of Medicine, La Jolla, CA, 92037, USA; Corresponding author.
Summary: 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).
