NK Cell and Monocyte Dysfunction in Multisystem Inflammatory Syndrome in Children
Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection characterized by multiorgan involvement and inflammation. Testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Despite strong Ab production in MIS-C, SARS-CoV-2 nucleic acid testing can remain positive for 4-6 wk postinfection. Therefore, we hypothesized that dysfunctional cell-mediated Ab responses downstream of Ab production may be responsible for delayed clearance of viral products in MIS-C. In MIS-C, monocytes were hyperfunctional for phagocytosis and cytokine production, whereas NK cells were hypofunctional for both killing and cytokine production. The decreased NK cell cytotoxicity correlated with an NK exhaustion marker signature and systemic IL-6 levels. Potentially providing a therapeutic option, cellular engagers of CD16 and SARS-CoV-2 proteins were found to rescue NK cell function in vitro. Taken together, our results reveal dysregulation in Ab-mediated cellular responses of myeloid and NK cells that likely contribute to the immune pathology of this disease.
Authors
- Laura Covill (ORCID: https://orcid.org/0000-0002-5086-9877)
- Aaron Khaimraj (ORCID: https://orcid.org/0000-0002-2588-0900)
- Keenan Ernste (ORCID: https://orcid.org/0000-0002-2988-6429)
- Yenan T. Bryceson (ORCID: https://orcid.org/0000-0002-7783-9934)
- Richard A. Koup (ORCID: https://orcid.org/0000-0002-3090-7282)
- Jules Sangala (ORCID: https://orcid.org/0000-0002-6432-4966)
- Dustin Hicks (ORCID: https://orcid.org/0000-0002-6934-4050)
- Geoffrey T. Hart (ORCID: https://orcid.org/0000-0003-0483-307X)
- Carly Baehr (ORCID: https://orcid.org/0000-0002-3395-6776)
- Alberto Orioles (ORCID: https://orcid.org/0000-0002-3875-9501)
- Jeffrey S. Miller (ORCID: https://orcid.org/0000-0002-0339-4944)
- Alexander K. Johnson (ORCID: https://orcid.org/0000-0002-2341-6311)
- Christine Henzler (ORCID: https://orcid.org/0000-0003-4566-2211)
- Chandy C. John (ORCID: https://orcid.org/0000-0002-1634-1411)
- Angela Panoskaltsis‐Mortari (ORCID: https://orcid.org/0000-0003-1802-1785)
- Marco Pravetoni (ORCID: https://orcid.org/0000-0003-1036-0184)
- Jianming Wu
- Spencer M Erickson (ORCID: https://orcid.org/0000-0003-0220-4712)
- Maxim C.‐J. Cheeran (ORCID: https://orcid.org/0000-0002-5331-4746)
- Jenna K. Dick (ORCID: https://orcid.org/0000-0003-2553-7536)
- Michael Ehrhardt (ORCID: https://orcid.org/0000-0001-8265-8049)
- Petter Brodin (ORCID: https://orcid.org/0000-0002-8103-0046)
- Beth K Thielen (ORCID: https://orcid.org/0000-0001-5922-0241)
- Venkatramana D. Krishna (ORCID: https://orcid.org/0000-0002-1980-5525)
- Caleb P Skipper (ORCID: https://orcid.org/0000-0002-0000-8876)
- Yvette Soigner
- Marie E. Steiner (ORCID: https://orcid.org/0000-0003-4169-1920)
- Alka Khaitan (ORCID: https://orcid.org/0000-0001-8547-8756)
- Lydia Hamel
Institutions
- Indiana University Health (US)
- National Institutes of Health (US)
- University of Minnesota (US)
- Fairview Health Services (US)
- Children’s Minnesota - St. Paul Hospital (US)
- Karolinska University Hospital (SE)
- University of Washington (US)
- University of Minnesota System (US)
- Karolinska Institutet (SE)
- Children's Minnesota (US)
- National Institute of Allergy and Infectious Diseases (US)
- University of Minnesota Medical Center (US)
- Indiana University School of Medicine
- University of Bergen (NO)
- Imperial College London (GB)
- Indiana University – Purdue University Indianapolis (US)
Publication Details
- Journal
- The Journal of Immunology
- Published
- 2024-10-11
- DOI
- https://doi.org/10.4049/jimmunol.2400395
- Citations
- 4
- Primary Topic
- COVID-19 Clinical Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.56
Funders
- University of Minnesota
- National Institutes of Health
- Centers for Disease Control and Prevention
- National Institute on Aging
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Center for Advancing Translational Sciences
- Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases