Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome

Sacchi, Alessandra; Grassi, Germana; Bordoni, Veronica; Lorenzini, Patrizia; Cimini, Eleonora; Casetti, Rita; Tartaglia, Eleonora; Marchioni, Luisa; Petrosillo, Nicola; Palmieri, Fabrizio; D’Offizi, Gianpiero; Notari, Stefania; Tempestilli, Massimo; Capobianchi, Maria Rosaria; Nicastri, Emanuele; Maeurer, Markus; Zumla, Alimuddin; Locatelli, Franco; Antinori, Andrea; Ippolito, Giuseppe; Agrati, Chiara

doi:10.1038/s41419-020-03125-1

Cited by 99 publications

(122 citation statements)

References 43 publications

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“…As neutrophilia, neutrophilic infiltration, and NLR are considered hallmarked of COVID-19 (32,33), the association of IL-8 with duration of illness may be suggestive of a role of IL-8 signaling in the evolution of COVID-19. A recent study provides evidence that early polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSC) expansion inhibits SARS-CoV-2 specific T-cell responses, and that the frequency of PMN-MDSC at the time of admission is associated with fatal outcome in patients with COVID-19, with a higher frequency of PMN-MDSC in the non-survivor compared with the survivor group (34). In addition, the frequency of PMN-MDSC is positively correlated with plasma levels of IL-8 at the admission time (34).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study provides evidence that early polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSC) expansion inhibits SARS-CoV-2 specific T-cell responses, and that the frequency of PMN-MDSC at the time of admission is associated with fatal outcome in patients with COVID-19, with a higher frequency of PMN-MDSC in the non-survivor compared with the survivor group (34). In addition, the frequency of PMN-MDSC is positively correlated with plasma levels of IL-8 at the admission time (34). Therefore, one possible mechanism underlying the role of IL-8 in the evolution of COVID-19 could be that it recruits PMN-MDSC which further inhibits the SARS-CoV-2 specific T-cell responses.…”

Section: Discussionmentioning

confidence: 99%

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High Levels of Circulating IL-8 and Soluble IL-2R Are Associated With Prolonged Illness in Patients With Severe COVID-19

Zhang

et al. 2021

Front. Immunol.

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ObjectivesThe coordinated immune response of the host is the key of the successful combat of the body against SARS-CoV-2 infection and is decisive for the development and progression of COVID-19. In this study, we aimed to investigate whether the immunological phenotype of patients are associated with duration of illness in patients with severe COVID-19.MethodIn this single-center study, 69 patients with severe or critical COVID-19 were recruited retrospectively. Immunological parameters including counts of white blood cells, neutrophils, lymphocytes, the neutrophil-to-lymphocyte ratio, and levels of circulating cytokines and cytokine receptors were screened for their association with disease severity, survival and duration of illness of COVID-19.ResultsOur data confirmed previous results that neutrophil-to-lymphocyte ratio and circulating levels of IL-6 represent prominent biomarker for the prediction of disease severity and survival of COVID-19. However, this study shows for the first time that duration of illness in patients with severe COVID-19 is positively associated with serum levels of IL-8 (P=0.004) and soluble IL-2Rα (P=0.025).ConclusionThe significant association of duration of illness with circulating levels of IL-8 and soluble IL-2Rα in patients with severe COVID-19 implicates that neutrophils and T cells are involved in the evolution of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

High Levels of Circulating IL-8 and Soluble IL-2R Are Associated With Prolonged Illness in Patients With Severe COVID-19

Zhang

et al. 2021

Front. Immunol.

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“…Moreover, two mature neutrophil clusters were found to be specific for severe disease course and resemble phenotypes of granulocytic MDSCs ( 62 ) and PD-L1 + neutrophils after LPS challenge in vivo ( 63 ). Later studies were able to isolate MDSC-like neutrophils from COVID-19 patients and provided evidence for their capacity to inhibit T cell proliferation and IFNγ production ( 64 , 65 ). As lower levels of IFNγ production by lymphocytes have been reported early on ( 66 ), these immunosuppressive neutrophils may contribute to this phenotype.…”

Section: Neutrophils In Covid-19mentioning

confidence: 99%

Neutrophils in COVID-19

et al. 2021

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Strong evidence has been accumulated since the beginning of the COVID-19 pandemic that neutrophils play an important role in the pathophysiology, particularly in those with severe disease courses. While originally considered to be a rather homogeneous cell type, recent attention to neutrophils has uncovered their fascinating transcriptional and functional diversity as well as their developmental trajectories. These new findings are important to better understand the many facets of neutrophil involvement not only in COVID-19 but also many other acute or chronic inflammatory diseases, both communicable and non-communicable. Here, we highlight the observed immune deviation of neutrophils in COVID-19 and summarize several promising therapeutic attempts to precisely target neutrophils and their reactivity in patients with COVID-19.

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“…ORF3A encodes a putative ion channel and its dimeric and tetrameric structures have been reported using cryo-EM (Kern et al, 2020). TGF-beta signaling has been implicated as a potential therapeutic target in several studies of COVID-19, both in vivo and in silico, along with other major inflammatory cytokines such as IL-6 and TNF-alpha (Carlson et al, 2020;Chen, 2020;Murthy P et al, 2021;Park et al, 2020;Sacchi et al, 2020;Wei et al, 2020;Yousefi et al, 2020;Zhang et al, 2020). Although no drug has been found to target ORF3A, 8 of those 34 indispensable ORF3A interactors in Fig.…”

Section: Discussionmentioning

confidence: 99%

Network controllability enrichment analysis reveals that SARS-CoV-2 infection tends to target indispensable nodes of a directed human protein-protein interaction network

Lee¹

2021

Preprint

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The COVID-19 disease has been a global threat caused by the new coronavirus species, SARS-CoV-2, since early 2020 with an urgent need for therapeutic interventions. In order to provide insight into human proteins targeted by SARS-CoV-2, here we study a directed human protein-protein interaction network (dhPPIN) based on our previous work on network controllability of virus targets. We previously showed that human proteins targeted by viruses tend to be those whose removal in a dhPPIN requires more control of the network dynamics, which were classified as indispensable nodes. In this study we introduce a more comprehensive rank-based enrichment analysis of our previous dhPPIN for SARS-CoV-2 infection and show that SARS-CoV-2 also tends to target indispensable nodes in the dhPPIN using multiple proteomics datasets, supporting validity and generality of controllability analysis of viral infection in humans. Also, we find differential controllability among SARS-CoV-2, SARS-CoV-1, and MERS-CoV from a comparative proteomics study. Moreover, we show functional significance of indispensable nodes by analyzing heterogeneous datasets from a genome-wide CRISPR screening study, a time-course phosphoproteomics study, and a genome-wide association study. Specifically, we identify SARS-CoV-2 ORF3A as most frequently interacting with indispensable proteins in the dhPPIN, which are enriched in TGF-beta signaling and tend to be sources nodes and interact with each other. Finally, we built an integrated network model of ORF3A-interacting indispensable proteins with multiple functional supports to provide hypotheses for experimental validation as well as therapeutic opportunities. Therefore, a sub-network of indispensable proteins targeted by SARS-CoV-2 could serve as a prioritized network of drug targets and a basis for further functional and mechanistic studies from a network controllability perspective.

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Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome

Cited by 99 publications

References 43 publications

High Levels of Circulating IL-8 and Soluble IL-2R Are Associated With Prolonged Illness in Patients With Severe COVID-19

High Levels of Circulating IL-8 and Soluble IL-2R Are Associated With Prolonged Illness in Patients With Severe COVID-19

Neutrophils in COVID-19

Network controllability enrichment analysis reveals that SARS-CoV-2 infection tends to target indispensable nodes of a directed human protein-protein interaction network

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