Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model
Santosh Dhakal,
Camilo A. Ruiz-Bedoya,
Ruifeng Zhou,
Patrick S. Creisher,
Jason S. Villano,
Kirsten Littlefield,
Jennie Ruelas Castillo,
Paula Marinho,
Anne E. Jedlicka,
Alvaro A. Ordonez,
Melissa Bahr,
Natalia Majewska,
Michael J. Betenbaugh,
Kelly Flavahan,
Alice R. L. Mueller,
Monika M. Looney,
Darla Quijada,
Filipa Mota,
Sarah E. Beck,
Jacqueline Brockhurst,
Alicia M. Braxton,
Natalie Castell,
Mitchel Stover,
Franco R. D’Alessio,
Kelly A. Metcalf Pate,
Petros C. Karakousis,
Joseph L. Mankowski,
Andrew Pekosz,
Sanjay K. Jain,
Sabra L. Klein
Affiliations
Santosh Dhakal
W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Camilo A. Ruiz-Bedoya
Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Ruifeng Zhou
W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Patrick S. Creisher
W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Jason S. Villano
Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Kirsten Littlefield
W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Jennie Ruelas Castillo
Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Paula Marinho
W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Anne E. Jedlicka
W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Alvaro A. Ordonez
Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Melissa Bahr
Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Natalia Majewska
Advanced Mammalian Biomanufacturing Innovation Center, Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
Michael J. Betenbaugh
Advanced Mammalian Biomanufacturing Innovation Center, Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
Kelly Flavahan
Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Alice R. L. Mueller
W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Monika M. Looney
Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Darla Quijada
Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Filipa Mota
Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Sarah E. Beck
Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Jacqueline Brockhurst
Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Alicia M. Braxton
Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Natalie Castell
Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Mitchel Stover
Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Franco R. D’Alessio
Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Kelly A. Metcalf Pate
Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Petros C. Karakousis
Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Joseph L. Mankowski
Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA
Andrew Pekosz
W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Sanjay K. Jain
Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Sabra L. Klein
W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
ABSTRACT 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 10 weeks 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-β (IFN-β) and tumor necrosis factor-α (TNF-α), 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.
