TLR2/4 are novel activating receptors for SARS-CoV-2 spike protein on NK cells.

Autor:	Landolina N; Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Ricci B; Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Veneziani I; Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Alicata C; Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Mariotti FR; Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Pelosi A; Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Quatrini L; Innate Lymphoid Cells Unit, Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Mortari EP; B cell Unit, Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Carsetti R; B cell Unit, Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Vacca P; Innate Lymphoid Cells Unit, Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Tumino N; Innate Lymphoid Cells Unit, Immunology Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Azzarone B; Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Moretta L; Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy., Maggi E; Tumor Immunology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 May 31; Vol. 15, pp. 1368946. Date of Electronic Publication: 2024 May 31 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1368946
Abstrakt:	Background: In early infected or severe coronavirus disease 2019 (COVID-19) patients, circulating NK cells are consistently reduced, despite being highly activated or exhausted. The aim of this paper was to establish whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (SP) may directly trigger NK cells and through which receptor(s). Methods: SP-stimulated human NK cells have been evaluated for the expression of activation markers, cytokine release, and cytotoxic activity, as well as for gene expression profiles and NF-kB phosphorylation, and they have been silenced with specific small interfering RNAs. Results: SPs from the Wuhan strain and other variants of concern (VOCs) directly bind and stimulate purified NK cells by increasing activation marker expression, cytokine release, and cytolytic activity, prevalently in the CD56 bright NK cell subset. VOC-SPs differ in their ability to activate NK cells, G614, and Delta-Plus strains providing the strongest activity in the majority of donors. While VOC-SPs do not trigger ACE2, which is not expressed on NK cells, or other activating receptors, they directly and variably bind to both Toll-like receptor 2 (TLR2) and TLR4. Moreover, SP-driven NK cell functions are inhibited upon masking such receptors or silencing the relative genes. Lastly, VOC-SPs upregulate CD56 dim NK cell functions in COVID-19 recovered, but not in non-infected, individuals. Conclusions: TLR2 and TLR4 are novel activating receptors for SP in NK cells, suggesting a new role of these cells in orchestrating the pathophysiology of SARS-CoV-2 infection. The pathogenic relevance of this finding is highlighted by the fact that free SP providing NK cell activation is frequently detected in a SARS-CoV-2 inflamed environment and in plasma of infected and long-COVID-19 subjects. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Landolina, Ricci, Veneziani, Alicata, Mariotti, Pelosi, Quatrini, Mortari, Carsetti, Vacca, Tumino, Azzarone, Moretta and Maggi.)
Databáze:	MEDLINE
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