TY - JOUR
T1 - Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model
AU - Johns Hopkins COVID-19 Hamster Study Group
AU - Dhakal, Santosh
AU - Ruiz-Bedoya, Camilo A.
AU - Zhou, Ruifeng
AU - Creisher, Patrick S.
AU - Villano, Jason S.
AU - Littlefield, Kirsten
AU - Castillo, Jennie Ruelas
AU - Marinho, Paula
AU - Jedlicka, Anne E.
AU - Ordonez, Alvaro A.
AU - Bahr, Melissa
AU - Majewska, Natalia
AU - Betenbaugh, Michael J.
AU - Flavahan, Kelly
AU - Mueller, Alice R.L.
AU - Looney, Monika M.
AU - Quijada, Darla
AU - Mota, Filipa
AU - Beck, Sarah E.
AU - Brockhurst, Jacqueline
AU - Braxton, Alicia M.
AU - Castell, Natalie
AU - Stover, Mitchel
AU - D’alessio, Franco R.
AU - Metcalf Pate, Kelly A.
AU - Karakousis, Petros C.
AU - Mankowski, Joseph L.
AU - Pekosz, Andrew
AU - Jain, Sanjay K.
AU - Klein, Sabra L.
N1 - Funding Information:
We are grateful to the Johns Hopkins School of Medicine Vice Dean of Research, Antony Rosen, for providing research funds to develop this model and conduct this research. We also thank the Johns Hopkins COVID-19 Hamster Study Group members for weekly discussions and participation in these studies, particularly the veterinarians and animal care staff who ensured proper care of all animals in this study. A.P. would like to dedicate the manuscript to the memory of R. Mark Buller, whose collaborations on the golden Syrian hamster model for SARS-CoV infection formed the basis for this study. These studies were supported through the generosity of the collective community of donors to the Johns Hopkins University School of Medicine for COVID research with supplemental funds from The Johns Hopkins Center of Excellence in Influenza Research and Surveillance (CEIRS; HHSN272201400007C; A.P. and S.L.K.), the NIH/NCI COVID-19 Serology Center of Excellence U54CA260492 (S.L.K.), the NIH/ORWH/NIA Specialized Center of Research Excellence in Sex Differences U54AG062333 (S.L.K.), R01AI153349 (S.K.J.), support from the Center for Infection and Inflammation Imaging Research (Johns Hopkins University), and NIH T32OD011089 (J.L.M.). The authors report no conflicts of interest. P.C.K., J.L.M., A.P., S.K.J., and S.L.K. conceptualized and designed the study. S.D., C.A.R-B., P.S.C., J.S.V., A.A.O., K.F., A.R.L.M., F.M., S.E.B., A.M.B., J.B., N.C., M.B., F.R.D., M.S., K.A.M-P., and S.K.J. designed and performed animal experiments. C.A.R-B., K.F., F.M., and M.B. performed chest CT scans. A.P., R.Z., P.M., A.E.J., N.M., and M.J.B. grew virus, did virus quantification, and produced antigens required to run ELISAs. S.D., K.L., P.S.C., A.L.M., and A.P. performed antibody assays. S.D., P.S.C., J.R.C., M.M.L., D.Q., and P.C.K. performed cytokine assays. S.D. and C.A.R-B. ran statistical analyses on the data. The Study Group Members performed animal experiments, tissue processing, and data management. S.D. and S.L.K. wrote the manuscript with input from all authors. All authors read and provided edits to drafts and approved the final submission. Additional Johns Hopkins COVID-19 Hamster Study Group members include Cory F. Brayton, Bess Carlson, Selena Guerrero-Martin, Eric K. Hutchinson, Andrew L. Johanson, Maggie Lowman, Amanda Maxwell, Megan E. McCarron, Kathleen R. Mulka, Suzanne E. Queen, Erin N. Shirk, Clarisse V. Solis, Rebecca T. Veenhuis, and Rachel Vistein (Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, MD), Lisa Pieterse (W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD), Patrick M. Tarwater (Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD), and Cynthia A. Zahnow (Department of Oncology, The Johns Hopkins School of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD).
Funding Information:
These studies were supported through the generosity of the collective community of donors to the Johns Hopkins University School of Medicine for COVID research with supplemental funds from The Johns Hopkins Center of Excellence in Influenza Research and Surveillance (CEIRS; HHSN272201400007C; A.P. and S.L.K.), the NIH/NCI COVID-19 Serology Center of Excellence U54CA260492 (S.L.K.), the NIH/ORWH/NIA Specialized Center of Research Excellence in Sex Differences U54AG062333 (S.L.K.), R01AI153349 (S.K.J.), support from the Center for Infection and Inflammation Imaging Research (Johns Hopkins University), and NIH T32OD011089 (J.L.M.). The authors report no conflicts of interest.
Publisher Copyright:
© 2021 Dhakal et al
PY - 2021/8/1
Y1 - 2021/8/1
N2 - In the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more severe outcomes are reported in males than in females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8 to 10weeks of age) were inoculated intranasally with 105 50% tissue culture infective dose (TCID50) of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developed more extensive pneumonia as noted on chest computed tomography, and recovered more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including interferon-b (IFN-b) and tumor necrosis factor-a (TNF-a), were comparable between the sexes. However, during the recovery phase of infection, females mounted 2-fold greater IgM, IgG, and IgA responses against the receptor-binding domain of the spike protein (S-RBD) in both plasma and respiratory tissues. Female hamsters also had significantly greater IgG antibodies against whole-inactivated SARS-CoV-2 and mutant S-RBDs as well as virus-neutralizing antibodies in plasma. The development of an animal model to study COVID-19 sex differences will allow for a greater mechanistic understanding of the SARS-CoV-2-associated sex differences seen in the human population. IMPORTANCE Men experience more severe outcomes from coronavirus disease 2019 (COVID-19) than women. Golden Syrian hamsters were used to explore sex differences in the pathogenesis of a human isolate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After inoculation, male hamsters experienced greater sickness, developed more severe lung pathology, and recovered more slowly than females. Sex differences in disease could not be reversed by estradiol treatment in males and were not explained by either virus replication kinetics or the concentrations of inflammatory cytokines in the lungs. During the recovery period, antiviral antibody responses in the respiratory tract and plasma, including to newly emerging SARS-CoV-2 variants, were greater in female than in male hamsters. Greater lung pathology during the acute phase combined with lower antiviral antibody responses during the recovery phase of infection in males than in females illustrate the utility of golden Syrian hamsters as a model to explore sex differences in the pathogenesis of SARS-CoV-2 and vaccine-induced immunity and protection.
AB - In the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more severe outcomes are reported in males than in females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8 to 10weeks of age) were inoculated intranasally with 105 50% tissue culture infective dose (TCID50) of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developed more extensive pneumonia as noted on chest computed tomography, and recovered more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including interferon-b (IFN-b) and tumor necrosis factor-a (TNF-a), were comparable between the sexes. However, during the recovery phase of infection, females mounted 2-fold greater IgM, IgG, and IgA responses against the receptor-binding domain of the spike protein (S-RBD) in both plasma and respiratory tissues. Female hamsters also had significantly greater IgG antibodies against whole-inactivated SARS-CoV-2 and mutant S-RBDs as well as virus-neutralizing antibodies in plasma. The development of an animal model to study COVID-19 sex differences will allow for a greater mechanistic understanding of the SARS-CoV-2-associated sex differences seen in the human population. IMPORTANCE Men experience more severe outcomes from coronavirus disease 2019 (COVID-19) than women. Golden Syrian hamsters were used to explore sex differences in the pathogenesis of a human isolate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After inoculation, male hamsters experienced greater sickness, developed more severe lung pathology, and recovered more slowly than females. Sex differences in disease could not be reversed by estradiol treatment in males and were not explained by either virus replication kinetics or the concentrations of inflammatory cytokines in the lungs. During the recovery period, antiviral antibody responses in the respiratory tract and plasma, including to newly emerging SARS-CoV-2 variants, were greater in female than in male hamsters. Greater lung pathology during the acute phase combined with lower antiviral antibody responses during the recovery phase of infection in males than in females illustrate the utility of golden Syrian hamsters as a model to explore sex differences in the pathogenesis of SARS-CoV-2 and vaccine-induced immunity and protection.
KW - Animal model
KW - COVID-19
KW - Receptor-binding domain
KW - SARS-CoV-2 variants
KW - Sex differences
UR - http://www.scopus.com/inward/record.url?scp=85113754306&partnerID=8YFLogxK
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U2 - 10.1128/mBio.00974-21
DO - 10.1128/mBio.00974-21
M3 - Article
C2 - 34253053
AN - SCOPUS:85113754306
VL - 12
JO - mBio
JF - mBio
SN - 2161-2129
IS - 4
M1 - e00974-21
ER -