1. Extensive activation, tissue trafficking, turnover and functional impairment of NK cells in COVID-19 patients at disease onset associates with subsequent disease severity
- Author
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Bozzano, F., Dentone, C., Perrone, C., Di Biagio, A., Fenoglio, D., Parodi, A., Mikulska, M., Bruzzone, B., Giacobbe, D. R., Vena, A., Taramasso, L., Nicolini, L., Patroniti, N., Pelosi, P., Gratarola, A., de Palma, R., Filaci, G., Bassetti, M., de Maria, A., Alessandrini, A., Camera, M., Delfino, E., Dodi, F., Ferrazin, A., Mazzarello, G., Toscanini, F., Balletto, E., Portunato, F., Schenone, E., Rosseti, N., Baldi, F., Berruti, M., Briano, F., Dettori, S., Labate, L., Magnasco, L., Mirabella, M., Pincino, R., Russo, C., Sarteschi, G., Sepulcri, C., Tutino, S., Pontremoli, R., Beccati, V., Casciaro, S., Casu, M., Gavaudan, F., Ghinatti, M., Gualco, E., Leoncini, G., Pitto, P., Salam, K., Bixio, M., Amelia, A., Balestra, A., Ballarino, P., Bardi, N., Boccafogli, R., Caserza, F., Calzolari, E., Castelli, M., Cenni, E., Cortese, P., Cuttone, G., Feltrin, S., Giovinazzo, S., Giuntini, P., Natale, L., Orsi, D., Pastorino, M., Perazzo, T., Pescetelli, F., Schenone, F., Serra, M. G., Sottano, M., Brunetti, I., Robba, C., Ball, L., Loconte, M., Battaglini, D., de Rito, M. R., Cerana, M., Fasce, R., Insorsi, A., Molin, A., Tallone, R., Amelotti, M., Majabo, M. J., Merlini, M., Perazzo, F., Ahamd, N., Barbera, P., Bovio, M., Cam-Podonico, P., Collida, A., Cutuli, O., Lomeo, A., Fezza, F., Genti-Lucci, N., Hussein, N., Malvezzi, E., Massobrio, L., Motta, G., Pastorino, L., Pollicardo, N., Sartini, S., Virga, P. V. V., Porto, I., Bezante, G. P., Bona, R. D., Malfa, G. L., Valbusa, A., V. G., Ad, Barisione, E., Bellotti, M., Teresita, A., Blanco, A., Grosso, M., Piroddi, M. G., Moscatelli, P., Caiti, M., Magnani, O., Sukkar, S., Cogorno, L., Gradaschi, R., Guiddo, E., Martino, E., Pisciotta, L., Cavagliere, B., Cristina, R., Francesca, F., Garibotto, G., Esposito, P., Passalacqua, G., Bagnasco, D., Braido, F., Riccio, A., Tagliabue, E., Gustavino, C., Ferraiolo, A., Giuffrida, S., Rosso, N., Morando, A., Papalia, R., Passerini, D., Tiberio, G., Orengo, G., Battaglini, A., Ruffoni, S., and Caglieris, S.
- Subjects
RNA viruses ,Male ,Viral Diseases ,Coronaviruses ,medicine.medical_treatment ,Cytotoxicity ,Cell ,NK cells ,Aged ,Aged, 80 and over ,COVID-19 ,Cohort Studies ,Female ,Flow Cytometry ,Humans ,Interferon-gamma ,Italy ,Killer Cells, Natural ,Lymphocyte Activation ,Middle Aged ,Severity of Illness Index ,Toxicology ,0302 clinical medicine ,Medical Conditions ,Spectrum Analysis Techniques ,Cellular types ,80 and over ,Killer Cells ,Lymphocytes ,Biology (General) ,Receptor ,Immune Response ,Pathology and laboratory medicine ,0303 health sciences ,medicine.diagnostic_test ,Immune cells ,hemic and immune systems ,Medical microbiology ,Cytokine ,medicine.anatomical_structure ,Infectious Diseases ,Spectrophotometry ,Viruses ,Natural ,White blood cells ,Cytophotometry ,medicine.symptom ,SARS CoV 2 ,Pathogens ,Research Article ,Cell biology ,Blood cells ,SARS coronavirus ,Precursor Cells ,QH301-705.5 ,Immunology ,Inflammation ,chemical and pharmacologic phenomena ,Biology ,Research and Analysis Methods ,Microbiology ,Flow cytometry ,03 medical and health sciences ,Immune system ,Signs and Symptoms ,Virology ,Genetics ,medicine ,Molecular Biology ,030304 developmental biology ,Medicine and health sciences ,Biology and life sciences ,Organisms ,Viral pathogens ,Covid 19 ,RC581-607 ,NKG2D ,Microbial pathogens ,Perforin ,Animal cells ,biology.protein ,Parasitology ,Clinical Medicine ,Immunologic diseases. Allergy ,030215 immunology - Abstract
The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5–20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage. Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19. NK cells contribute to early phases of virus control and to the regulation of adaptive responses. The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover. We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19. Relevant decreases in CD56brightCD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56dimCD16+KIR+NKG2A+ and “memory” KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules. Impaired cytotoxicity and IFN-γ production were associated with conserved expression of natural cytotoxicity receptors and perforin. Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1brightCXCR4+ inflammatory precursors to mature functional NK cells. Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1brightCXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells. Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration. Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches., Author summary This is a detailed study of activating and inhibitory receptors in NK cells of COVID-19 patients when first admitted to the hospital for respiratory insufficiency. NK cells are known to be the first line of defense against invading viruses, and regulate downstream B and T cell responses, including antibody production. We observed intense NK cell activation with decreased functional activity, as well as intense circulation of putative tissue resident CD69+CD103+CXCR6+ NK cells, with a related surge in inflammatory CD34+ precursors from the bone marrow. The findings suggest that there is unprecedented trafficking of NK cells from peripheral tissues, their increased death with recruitment of emergency precursors from the bone marrow, and a relationship with the subsequent course of the disease of the patients. This in turn suggests possible areas of treatment and prevention.
- Published
- 2021