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Peer-reviewedCC BY 4.0Frontiers in Immunology

Single-cell profiling of dysfunctional NK cells in COVID-19: from immunization to acute infection and beyond

  • Alessandro Frigo1,2
  • Sara Terzoli1,3
  • Paolo Marzano1
  • Nicolò Coianiz1
  • Michela Calvi1,2
  • Lara Orlandi1,2
  • Simone Balin1
  • Valentina Cazzetta1
  • Anna Carletti1
  • Silvia Della Bella1,2
  • Joanna Mikulak1
  • Maciej Tarkowski4
10 more authors
  • Matteo Bonfanti5
  • Paolo Ferrari5
  • Eugenia Ricciardelli5
  • Clelia Peano5,6
  • Agostino Riva4,7
  • Giuseppe Testa5,8
  • Antonio Voza3,9
  • Francesca Calcaterra1
  • Clara Di Vito1,2
  • Domenico Mavilio1,2
9 affiliations
  1. 1Unit of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital
  2. 2Department of Medical Biotechnology and Translational Medicine, University of Milan
  3. 3Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
  4. 4Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC, University of Milan
  5. 5Human Technopole
  6. 6Institute of Genetics and Biomedical Research, UoS of Milan, National Research Council
  7. 7Department of Infectious Diseases, Luigi Sacco University Hospital, ASST Fatebenefratelli Sacco
  8. 8Department of Oncology and Hemato-Oncology, University of Milan
  9. 9Department of Biomedical Unit, IRCCS Humanitas Research Hospital
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Abstract

Introduction: Vaccination and natural infection with Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) confer immune protection through distinct mechanisms, however, their effects on Natural Killer (NK) cell responses remain poorly understood, particularly in relation to COVID-19 disease severity. NK cells, key mediators of anti-viral immunity, have been implicated in coronavirus disease 2019 (COVID-19) pathogenesis, where severe disease is associated with hyperactivated yet dysfunctional NK-cell states that likely impair viral control and contribute to tissue damage.

Methods: To define how vaccination and infection shape NK-cell biology, we performed longitudinal single-cell RNA sequencing (scRNA-seq) of NK cells from SARS-CoV-2-naïve individuals receiving two doses of the BNT162b2mRNA vaccine. These longitudinal vaccine profiles were integrated with cross-sectional scRNA-seq datasets from unvaccinated patients with acute COVID-19 and from independent convalescent individuals, all enrolled before vaccine introduction.

Results: We identified distinct NK cell transcriptional programs associated with vaccination, acute infection and convalescence, with the most pronounced infection-related alterations observed in the severe form of the disease. These diverging transcriptional signatures correlate with differences in NK-cell subset composition and activation markers between vaccinated and infected individuals.

Conclusions: Taken together, these findings provide a rationale for future studies examining whether vaccine-associated NK-cell transcriptional programs contribute to durable immune protection.

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Cite

BibTeXRIS
BibTeX
@article{frigo2026singlecell,
  title = {{Single-cell profiling of dysfunctional NK cells in COVID-19: from immunization to acute infection and beyond}},
  author = {Alessandro Frigo and Sara Terzoli and Paolo Marzano and Nicolò Coianiz and Michela Calvi and Lara Orlandi and Simone Balin and Valentina Cazzetta and Anna Carletti and Silvia Della Bella and Joanna Mikulak and Maciej Tarkowski and Matteo Bonfanti and Paolo Ferrari and Eugenia Ricciardelli and Clelia Peano and Agostino Riva and Giuseppe Testa and Antonio Voza and Francesca Calcaterra and Clara Di Vito and Domenico Mavilio},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1972608},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1972608/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Single-cell profiling of dysfunctional NK cells in COVID-19: from immunization to acute infection and beyond
AU  - Alessandro Frigo
AU  - Sara Terzoli
AU  - Paolo Marzano
AU  - Nicolò Coianiz
AU  - Michela Calvi
AU  - Lara Orlandi
AU  - Simone Balin
AU  - Valentina Cazzetta
AU  - Anna Carletti
AU  - Silvia Della Bella
AU  - Joanna Mikulak
AU  - Maciej Tarkowski
AU  - Matteo Bonfanti
AU  - Paolo Ferrari
AU  - Eugenia Ricciardelli
AU  - Clelia Peano
AU  - Agostino Riva
AU  - Giuseppe Testa
AU  - Antonio Voza
AU  - Francesca Calcaterra
AU  - Clara Di Vito
AU  - Domenico Mavilio
PY  - 2026
DA  - 2026/10/20
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1972608
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1972608/full
AB  - Introduction: Vaccination and natural infection with Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) confer immune protection through distinct mechanisms, however, their effects on Natural Killer (NK) cell responses remain poorly understood, particularly in relation to COVID-19 disease severity. NK cells, key mediators of anti-viral immunity, have been implicated in coronavirus disease 2019 (COVID-19) pathogenesis, where severe disease is associated with hyperactivated yet dysfunctional NK-cell states that likely impair viral control and contribute to tissue damage.  Methods: To define how vaccination and infection shape NK-cell biology, we performed longitudinal single-cell RNA sequencing (scRNA-seq) of NK cells from SARS-CoV-2-naïve individuals receiving two doses of the BNT162b2mRNA vaccine. These longitudinal vaccine profiles were integrated with cross-sectional scRNA-seq datasets from unvaccinated patients with acute COVID-19 and from independent convalescent individuals, all enrolled before vaccine introduction.  Results: We identified distinct NK cell transcriptional programs associated with vaccination, acute infection and convalescence, with the most pronounced infection-related alterations observed in the severe form of the disease. These diverging transcriptional signatures correlate with differences in NK-cell subset composition and activation markers between vaccinated and infected individuals.  Conclusions: Taken together, these findings provide a rationale for future studies examining whether vaccine-associated NK-cell transcriptional programs contribute to durable immune protection.
SN  - 1664-3224
ER  -