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Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype

After more than one year since the COVID-19 outbreak, patients with severe disease still constitute the bottleneck of the pandemic management. Aberrant inflammatory responses, ranging from cytokine storm to immune-suppression, were described in COVID-19 and no treatment was demonstrated to change th...

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Autores principales: Trombetta, Amelia C., Farias, Guilherme B., Gomes, André M. C., Godinho-Santos, Ana, Rosmaninho, Pedro, Conceição, Carolina M., Laia, Joel, Santos, Diana F., Almeida, Afonso R. M., Mota, Catarina, Gomes, Andreia, Serrano, Marta, Veldhoen, Marc, Sousa, Ana E., Fernandes, Susana M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265310/
https://www.ncbi.nlm.nih.gov/pubmed/34248984
http://dx.doi.org/10.3389/fimmu.2021.691725
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author Trombetta, Amelia C.
Farias, Guilherme B.
Gomes, André M. C.
Godinho-Santos, Ana
Rosmaninho, Pedro
Conceição, Carolina M.
Laia, Joel
Santos, Diana F.
Almeida, Afonso R. M.
Mota, Catarina
Gomes, Andreia
Serrano, Marta
Veldhoen, Marc
Sousa, Ana E.
Fernandes, Susana M.
author_facet Trombetta, Amelia C.
Farias, Guilherme B.
Gomes, André M. C.
Godinho-Santos, Ana
Rosmaninho, Pedro
Conceição, Carolina M.
Laia, Joel
Santos, Diana F.
Almeida, Afonso R. M.
Mota, Catarina
Gomes, Andreia
Serrano, Marta
Veldhoen, Marc
Sousa, Ana E.
Fernandes, Susana M.
author_sort Trombetta, Amelia C.
collection PubMed
description After more than one year since the COVID-19 outbreak, patients with severe disease still constitute the bottleneck of the pandemic management. Aberrant inflammatory responses, ranging from cytokine storm to immune-suppression, were described in COVID-19 and no treatment was demonstrated to change the prognosis significantly. Therefore, there is an urgent need for understanding the underlying pathogenic mechanisms to guide therapeutic interventions. This study was designed to assess myeloid cell activation and phenotype leading to recovery in patients surviving severe COVID-19. We evaluated longitudinally patients with COVID-19 related respiratory insufficiency, stratified according to the need of intensive care unit admission (ICU, n = 11, and No-ICU, n = 9), and age and sex matched healthy controls (HCs, n = 11), by flow cytometry and a wide array of serum inflammatory/immune-regulatory mediators. All patients featured systemic immune-regulatory myeloid cell phenotype as assessed by both unsupervised and supervised analysis of circulating monocyte and dendritic cell subsets. Specifically, we observed a reduction of CD14lowCD16+ monocytes, and reduced expression of CD80, CD86, and Slan. Moreover, mDCs, pDCs, and basophils were significantly reduced, in comparison to healthy subjects. Contemporaneously, both monocytes and DCs showed increased expression of CD163, CD204, CD206, and PD-L1 immune-regulatory markers. The expansion of M2-like monocytes was significantly higher at admission in patients featuring detectable SARS-CoV-2 plasma viral load and it was positively correlated with the levels of specific antibodies. In No-ICU patients, we observed a peak of the alterations at admission and a progressive regression to a phenotype similar to HCs at discharge. Interestingly, in ICU patients, the expression of immuno-suppressive markers progressively increased until discharge. Notably, an increase of M2-like HLA-DRhighPD-L1+ cells in CD14++CD16− monocytes and in dendritic cell subsets was observed at ICU discharge. Furthermore, IFN-γ and IL-12p40 showed a decline over time in ICU patients, while high values of IL1RA and IL-10 were maintained. In conclusion, these results support that timely acquisition of a myeloid cell immune-regulatory phenotype might contribute to recovery in severe systemic SARS-CoV-2 infection and suggest that therapeutic agents favoring an innate immune system regulatory shift may represent the best strategy to be implemented at this stage.
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spelling pubmed-82653102021-07-09 Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype Trombetta, Amelia C. Farias, Guilherme B. Gomes, André M. C. Godinho-Santos, Ana Rosmaninho, Pedro Conceição, Carolina M. Laia, Joel Santos, Diana F. Almeida, Afonso R. M. Mota, Catarina Gomes, Andreia Serrano, Marta Veldhoen, Marc Sousa, Ana E. Fernandes, Susana M. Front Immunol Immunology After more than one year since the COVID-19 outbreak, patients with severe disease still constitute the bottleneck of the pandemic management. Aberrant inflammatory responses, ranging from cytokine storm to immune-suppression, were described in COVID-19 and no treatment was demonstrated to change the prognosis significantly. Therefore, there is an urgent need for understanding the underlying pathogenic mechanisms to guide therapeutic interventions. This study was designed to assess myeloid cell activation and phenotype leading to recovery in patients surviving severe COVID-19. We evaluated longitudinally patients with COVID-19 related respiratory insufficiency, stratified according to the need of intensive care unit admission (ICU, n = 11, and No-ICU, n = 9), and age and sex matched healthy controls (HCs, n = 11), by flow cytometry and a wide array of serum inflammatory/immune-regulatory mediators. All patients featured systemic immune-regulatory myeloid cell phenotype as assessed by both unsupervised and supervised analysis of circulating monocyte and dendritic cell subsets. Specifically, we observed a reduction of CD14lowCD16+ monocytes, and reduced expression of CD80, CD86, and Slan. Moreover, mDCs, pDCs, and basophils were significantly reduced, in comparison to healthy subjects. Contemporaneously, both monocytes and DCs showed increased expression of CD163, CD204, CD206, and PD-L1 immune-regulatory markers. The expansion of M2-like monocytes was significantly higher at admission in patients featuring detectable SARS-CoV-2 plasma viral load and it was positively correlated with the levels of specific antibodies. In No-ICU patients, we observed a peak of the alterations at admission and a progressive regression to a phenotype similar to HCs at discharge. Interestingly, in ICU patients, the expression of immuno-suppressive markers progressively increased until discharge. Notably, an increase of M2-like HLA-DRhighPD-L1+ cells in CD14++CD16− monocytes and in dendritic cell subsets was observed at ICU discharge. Furthermore, IFN-γ and IL-12p40 showed a decline over time in ICU patients, while high values of IL1RA and IL-10 were maintained. In conclusion, these results support that timely acquisition of a myeloid cell immune-regulatory phenotype might contribute to recovery in severe systemic SARS-CoV-2 infection and suggest that therapeutic agents favoring an innate immune system regulatory shift may represent the best strategy to be implemented at this stage. Frontiers Media S.A. 2021-06-23 /pmc/articles/PMC8265310/ /pubmed/34248984 http://dx.doi.org/10.3389/fimmu.2021.691725 Text en Copyright © 2021 Trombetta, Farias, Gomes, Godinho-Santos, Rosmaninho, Conceição, Laia, Santos, Almeida, Mota, Gomes, Serrano, Veldhoen, Sousa and Fernandes https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Trombetta, Amelia C.
Farias, Guilherme B.
Gomes, André M. C.
Godinho-Santos, Ana
Rosmaninho, Pedro
Conceição, Carolina M.
Laia, Joel
Santos, Diana F.
Almeida, Afonso R. M.
Mota, Catarina
Gomes, Andreia
Serrano, Marta
Veldhoen, Marc
Sousa, Ana E.
Fernandes, Susana M.
Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype
title Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype
title_full Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype
title_fullStr Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype
title_full_unstemmed Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype
title_short Severe COVID-19 Recovery Is Associated with Timely Acquisition of a Myeloid Cell Immune-Regulatory Phenotype
title_sort severe covid-19 recovery is associated with timely acquisition of a myeloid cell immune-regulatory phenotype
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265310/
https://www.ncbi.nlm.nih.gov/pubmed/34248984
http://dx.doi.org/10.3389/fimmu.2021.691725
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