Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model

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 inte...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	animal model COVID-19 sex differences SARS-CoV-2 variants receptor-binding domain Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c26a3303ffd040088f12495ee7b31392
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spelling	oai:doaj.org-article:c26a3303ffd040088f12495ee7b313922021-11-10T18:37:50ZSex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model10.1128/mBio.00974-212150-7511https://doaj.org/article/c26a3303ffd040088f12495ee7b313922021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00974-21https://doaj.org/toc/2150-7511ABSTRACT 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.Santosh DhakalCamilo A. Ruiz-BedoyaRuifeng ZhouPatrick S. CreisherJason S. VillanoKirsten LittlefieldJennie Ruelas CastilloPaula MarinhoAnne E. JedlickaAlvaro A. OrdonezMelissa BahrNatalia MajewskaMichael J. BetenbaughKelly FlavahanAlice R. L. MuellerMonika M. LooneyDarla QuijadaFilipa MotaSarah E. BeckJacqueline BrockhurstAlicia M. BraxtonNatalie CastellMitchel StoverFranco R. D’AlessioKelly A. Metcalf PatePetros C. KarakousisJoseph L. MankowskiAndrew PekoszSanjay K. JainSabra L. KleinAmerican Society for Microbiologyarticleanimal modelCOVID-19sex differencesSARS-CoV-2 variantsreceptor-binding domainMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	animal model COVID-19 sex differences SARS-CoV-2 variants receptor-binding domain Microbiology QR1-502
spellingShingle	animal model COVID-19 sex differences SARS-CoV-2 variants receptor-binding domain Microbiology QR1-502 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 Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model
description	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.
format	article
author	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
author_facet	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
author_sort	Santosh Dhakal
title	Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model
title_short	Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model
title_full	Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model
title_fullStr	Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model
title_full_unstemmed	Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model
title_sort	sex differences in lung imaging and sars-cov-2 antibody responses in a covid-19 golden syrian hamster model
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/c26a3303ffd040088f12495ee7b31392
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Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model

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