Robust, persistent adaptive immune responses to SARS-CoV-2 in the oropharyngeal lymphoid tissue of children.
Qin Xu, Pedro Milanez-Almeida, Andrew J Martins, Andrea J Radtke, Kenneth B Hoehn, Jinguo Chen, Can Liu, Juanjie Tang, Gabrielle Grubbs, Sydney Stein, Sabrina Ramelli, Juraj Kabat, Hengameh Behzadpour, Maria Karkanitsa, Jacquelyn Spathies, Heather Kalish, Lela Kardava, Martha Kirby, Foo Cheung, Silvia Preite, Patrick C Duncker, Nahir Romero, Diego Preciado, Lyuba Gitman, Galina Koroleva, Grace Smith, Arthur Shaffer, Ian T McBain, Stefania Pittaluga, Ronald N Germain, Richard Apps, Kaitlyn Sadtler, Susan Moir, Daniel S Chertow, Steven H Kleinstein, Surender Khurana, John S Tsang, Pamela Mudd, Pamela L Schwartzberg, Kalpana Manthiram
Author Information
Qin Xu: Cell Signaling and Immunity Section, Laboratory of Immune System Biology (LISB), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD. ORCID
Pedro Milanez-Almeida: Center for Human Immunology, NIAID, NIH, Bethesda, MD. ORCID
Andrew J Martins: Multiscale Systems Biology Section, LISB, NIAID, NIH, Bethesda, MD. ORCID
Andrea J Radtke: Center for Advanced Tissue Imaging, LISB, NIAID, NIH Bethesda, MD. ORCID
Kenneth B Hoehn: Department of Pathology, Yale School of Medicine, New Haven, CT. ORCID
Jinguo Chen: Center for Human Immunology, NIAID, NIH, Bethesda, MD.
Can Liu: Multiscale Systems Biology Section, LISB, NIAID, NIH, Bethesda, MD. ORCID
Juanjie Tang: Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, MD.
Gabrielle Grubbs: Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, MD. ORCID
Sydney Stein: Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center (CC), NIH, Bethesda, MD. ORCID
Sabrina Ramelli: Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center (CC), NIH, Bethesda, MD.
Juraj Kabat: Center for Advanced Tissue Imaging, LISB, NIAID, NIH Bethesda, MD.
Hengameh Behzadpour: Division of Pediatric Otolaryngology, Children's National Hospital, Washington, DC.
Maria Karkanitsa: Laboratory of Immuno-Engineering, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH, Bethesda, MD.
Jacquelyn Spathies: Trans-NIH Shared Resource on Biomedical Engineering and Physical Science, NIBIB, NIH, Bethesda, MD.
Heather Kalish: Trans-NIH Shared Resource on Biomedical Engineering and Physical Science, NIBIB, NIH, Bethesda, MD.
Martha Kirby: National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD.
Foo Cheung: Center for Human Immunology, NIAID, NIH, Bethesda, MD.
Silvia Preite: Cell Signaling and Immunity Section, Laboratory of Immune System Biology (LISB), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD.
Patrick C Duncker: Cytek Biosciences, Fremont, CA.
Nahir Romero: Division of Otolaryngology, Department of Surgery, George Washington University School of Medicine and Health Sciences, Washington, DC.
Diego Preciado: Division of Pediatric Otolaryngology, Children's National Hospital, Washington, DC.
Lyuba Gitman: Division of Pediatric Otolaryngology, Children's National Hospital, Washington, DC.
Galina Koroleva: Center for Human Immunology, NIAID, NIH, Bethesda, MD.
Grace Smith: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, MD. ORCID
Arthur Shaffer: Lymphoid Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD.
Ian T McBain: Cell Signaling and Immunity Section, Laboratory of Immune System Biology (LISB), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD.
Stefania Pittaluga: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, MD. ORCID
Ronald N Germain: Center for Advanced Tissue Imaging, LISB, NIAID, NIH Bethesda, MD. ORCID
Richard Apps: Center for Human Immunology, NIAID, NIH, Bethesda, MD.
Kaitlyn Sadtler: Laboratory of Immuno-Engineering, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH, Bethesda, MD.
Susan Moir: B-cell Immunology Section, Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD.
Daniel S Chertow: Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center (CC), NIH, Bethesda, MD. ORCID
Steven H Kleinstein: Department of Pathology, Yale School of Medicine, New Haven, CT. ORCID
Surender Khurana: Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Silver Spring, MD. ORCID
John S Tsang: Center for Human Immunology, NIAID, NIH, Bethesda, MD. ORCID
Pamela Mudd: Division of Pediatric Otolaryngology, Children's National Hospital, Washington, DC.
Pamela L Schwartzberg: Cell Signaling and Immunity Section, Laboratory of Immune System Biology (LISB), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD. ORCID
Kalpana Manthiram: Cell Signaling and Immunity Section, Laboratory of Immune System Biology (LISB), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD.
SARS-CoV-2 infection triggers adaptive immune responses from both T and B cells. However, most studies focus on peripheral blood, which may not fully reflect immune responses in lymphoid tissues at the site of infection. To evaluate both local and systemic adaptive immune responses to SARS-CoV-2, we collected peripheral blood, tonsils, and adenoids from 110 children undergoing tonsillectomy/adenoidectomy during the COVID-19 pandemic and found 24 with evidence of prior SARS-CoV-2 infection, including detectable neutralizing antibodies against multiple viral variants. We identified SARS-CoV-2-specific germinal center (GC) and memory B cells; single cell BCR sequencing showed that these virus-specific B cells were class-switched and somatically hypermutated, with overlapping clones in the adenoids and tonsils. Oropharyngeal tissues from COVID-19-convalescent children showed persistent expansion of GC and anti-viral lymphocyte populations associated with an IFN-γ-type response, with particularly prominent changes in the adenoids, as well as evidence of persistent viral RNA in both tonsil and adenoid tissues of many participants. Our results show robust, tissue-specific adaptive immune responses to SARS-CoV-2 in the upper respiratory tract of children weeks to months after acute infection, providing evidence of persistent localized immunity to this respiratory virus.
References
PLoS Pathog. 2015 Feb 06;11(2):e1004637
[PMID: 25658939]
Cell. 2020 Oct 1;183(1):143-157.e13
[PMID: 32877699]
J Immunol. 2010 Dec 15;185(12):7405-12
[PMID: 21068405]
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D256-61
[PMID: 15608191]
