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1.
Sci Immunol ; 5(44)2020 02 21.
Article in English | MEDLINE | ID: covidwho-1575907

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we sought to determine the molecular features of breast cancer-associated MDSCs using the widely studied mouse model based on the mouse mammary tumor virus (MMTV) promoter-driven expression of the polyomavirus middle T oncoprotein (MMTV-PyMT). To identify MDSCs in an unbiased manner, we used single-cell RNA sequencing to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice with wild-type controls. Our computational analysis of 14,646 single-cell transcriptomes revealed that MDSCs emerge through an aberrant neutrophil maturation trajectory in the spleen that confers them an immunosuppressive cell state. We establish the MDSC-specific gene signature and identify CD84 as a surface marker for improved detection and enrichment of MDSCs in breast cancers.


Subject(s)
Breast Neoplasms/pathology , Myeloid-Derived Suppressor Cells/pathology , Single-Cell Analysis , Transcriptome , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/immunology , Breast Neoplasms/immunology , Cell Differentiation/genetics , Female , Humans , Mice , Mice, Inbred Strains , Mice, Transgenic , Myeloid-Derived Suppressor Cells/immunology , RNA, Neoplasm/genetics , RNA, Neoplasm/immunology , Signaling Lymphocytic Activation Molecule Family/genetics , Signaling Lymphocytic Activation Molecule Family/immunology
2.
Viral Immunol ; 34(9): 639-645, 2021 11.
Article in English | MEDLINE | ID: covidwho-1517820

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may produce a systemic disease, the coronavirus disease-19 (COVID-19), with high morbidity and mortality. Even though we do not fully understand the interaction of innate and adaptive immunity in the control and complications of the viral infection, it is well recognized that SARS-CoV-2 induces an immunodepression that impairs the elimination of the virus and favors its rapid dissemination in the organism. Even less is known about the possible participation of inhibitory cells of the innate immune system, such as the myeloid-derived suppressor cells (MDSCs), or the adaptive immune system, such as the T regulatory cells (Tregs). That is why we aimed to study blood levels of MDSCs, as well as lymphocyte subpopulations, including Tregs, and activated (OX-40+) and inhibited (PD-1) T lymphocytes in patients with mild COVID-19 in comparison with data obtained from control donors. We have found that 20 hospitalized patients with COVID-19 and no health history of immunosuppression had a significant increase in the number of peripheral monocytic MDSCs (M-MDSC), but a decrease in Tregs, as well as an increase in the number of inhibited or exhausted T cells, whereas the number of activated T cells was significantly decreased compared with that from 20 healthy controls. Moreover, there was a significant negative correlation (r = 0.496) between the number of M-MDSC and the number of activated T cells. Therefore, M-MDSC rather than Tregs may contribute to the immunosuppression observed in patients with COVID-19.


Subject(s)
COVID-19/immunology , Myeloid-Derived Suppressor Cells/immunology , SARS-CoV-2/immunology , T-Lymphocytes, Regulatory/immunology , Aged , COVID-19/blood , COVID-19/classification , Female , Humans , Lymphocyte Activation , Lymphocyte Count/methods , Lymphocyte Subsets , Male , Middle Aged , SARS-CoV-2/pathogenicity
3.
Front Immunol ; 12: 748097, 2021.
Article in English | MEDLINE | ID: covidwho-1477829

ABSTRACT

The SARS-CoV-2 infection [coronavirus disease 2019 (COVID-19)] is associated with severe lymphopenia and impaired immune response, including expansion of myeloid cells with regulatory functions, e.g., so-called low-density neutrophils, containing granulocytic myeloid-derived suppressor cells (LDNs/PMN-MDSCs). These cells have been described in both infections and cancer and are known for their immunosuppressive activity. In the case of COVID-19, long-term complications have been frequently observed (long-COVID). In this context, we aimed to investigate the immune response of COVID-19 convalescents after a mild or asymptomatic course of disease. We enrolled 13 convalescents who underwent a mild or asymptomatic infection with SARS-CoV-2, confirmed by a positive result of the PCR test, and 13 healthy donors without SARS-CoV-2 infection in the past. Whole blood was used for T-cell subpopulation and LDNs/PMN-MDSCs analysis. LDNs/PMN-MDSCs and normal density neutrophils (NDNs) were sorted out by FACS and used for T-cell proliferation assay with autologous T cells activated with anti-CD3 mAb. Serum samples were used for the detection of anti-SARS-CoV-2 neutralizing IgG and GM-CSF concentration. Our results showed that in convalescents, even 3 months after infection, an elevated level of LDNs/PMN-MDSCs is still maintained in the blood, which correlates negatively with the level of CD8+ and double-negative T cells. Moreover, LDNs/PMN-MDSCs and NDNs showed a tendency for affecting the production of anti-SARS-CoV-2 S1 neutralizing antibodies. Surprisingly, our data showed that in addition to LDNs/PMN-MDSCs, NDNs from convalescents also inhibit proliferation of autologous T cells. Additionally, in the convalescent sera, we detected significantly higher concentrations of GM-CSF, indicating the role of emergency granulopoiesis. We conclude that in mild or asymptomatic COVID-19 convalescents, the neutrophil dysfunction, including propagation of PD-L1-positive LDNs/PMN-MDSCs and NDNs, is responsible for long-term endotype of immunosuppression.


Subject(s)
Antibodies, Neutralizing/blood , COVID-19/complications , Myeloid-Derived Suppressor Cells/immunology , Neutrophils/immunology , SARS-CoV-2/immunology , Adult , Antibodies, Viral/blood , Asymptomatic Infections , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/pathology , Cell Proliferation , Female , Granulocyte-Macrophage Colony-Stimulating Factor/blood , Humans , Immunocompromised Host/immunology , Immunoglobulin G/blood , Lymphocyte Activation/immunology , Male , Middle Aged
4.
Front Immunol ; 12: 645210, 2021.
Article in English | MEDLINE | ID: covidwho-1383856

ABSTRACT

Vaccination is one of the most efficient public healthcare measures to fight infectious diseases. Nevertheless, the immune mechanisms induced in vivo by vaccination are still unclear. The route of administration, an important vaccination parameter, can substantially modify the quality of the response. How the route of administration affects the generation and profile of immune responses is of major interest. Here, we aimed to extensively characterize the profiles of the innate and adaptive response to vaccination induced after intradermal, subcutaneous, or intramuscular administration with a modified vaccinia virus Ankara model vaccine in non-human primates. The adaptive response following subcutaneous immunization was clearly different from that following intradermal or intramuscular immunization. The subcutaneous route induced a higher level of neutralizing antibodies than the intradermal and intramuscular vaccination routes. In contrast, polyfunctional CD8+ T-cell responses were preferentially induced after intradermal or intramuscular injection. We observed the same dichotomy when analyzing the early molecular and cellular immune events, highlighting the recruitment of cell populations, such as CD8+ T lymphocytes and myeloid-derived suppressive cells, and the activation of key immunomodulatory gene pathways. These results demonstrate that the quality of the vaccine response induced by an attenuated vaccine is shaped by early and subtle modifications of the innate immune response. In this immunization context, the route of administration must be tailored to the desired type of protective immune response. This will be achieved through systems vaccinology and mathematical modeling, which will be critical for predicting the efficacy of the vaccination route for personalized medicine.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD8-Positive T-Lymphocytes/immunology , Myeloid-Derived Suppressor Cells/immunology , Vaccination , Vaccinia virus/immunology , Vaccinia/immunology , Viral Vaccines/pharmacology , Animals , Injections, Intradermal , Injections, Intramuscular , Macaca fascicularis , Male , Vaccines, Attenuated/pharmacology
5.
Cells ; 10(8)2021 08 17.
Article in English | MEDLINE | ID: covidwho-1360725

ABSTRACT

Massive platelet activation and thrombotic events characterize severe COVID-19, highlighting their critical role in SARS-CoV-2-induced immunopathology. Since there is a well-described expansion of myeloid-derived suppressor cells (MDSC) in severe COVID-19, we evaluated their possible role in platelet activation during SARS-CoV-2 infection. During COVID-19, a lower plasmatic L-arginine level was observed compared to healthy donors, which correlated with MDSC frequency. Additionally, activated GPIIb/IIIa complex (PAC-1) expression was higher on platelets from severe COVID-19 patients compared to healthy controls and inversely correlated with L-arginine plasmatic concentration. Notably, MDSC were able to induce PAC-1 expression in vitro by reducing L-arginine concentration, indicating a direct role of PMN-MDSC in platelet activation. Accordingly, we found a positive correlation between ex vivo platelet PAC-1 expression and PMN-MDSC frequency. Overall, our data demonstrate the involvement of PMN-MDSC in triggering platelet activation during COVID-19, highlighting a novel role of MDSC in driving COVID-19 pathogenesis.


Subject(s)
Arginine/immunology , COVID-19/immunology , Myeloid-Derived Suppressor Cells/immunology , Platelet Activation , Thrombosis/etiology , Adult , Aged , Aged, 80 and over , Arginine/physiology , COVID-19/complications , COVID-19/physiopathology , Female , Humans , Male , Middle Aged , Myeloid-Derived Suppressor Cells/physiology , Young Adult
6.
Front Immunol ; 12: 695972, 2021.
Article in English | MEDLINE | ID: covidwho-1339498

ABSTRACT

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1+ G-MDSC (Arg+G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg+G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.


Subject(s)
COVID-19/immunology , Granulocytes/immunology , Myeloid-Derived Suppressor Cells/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Arginase/antagonists & inhibitors , Arginase/metabolism , Arginine/administration & dosage , Arginine/blood , Arginine/metabolism , Asymptomatic Infections , COVID-19/blood , COVID-19/diagnosis , COVID-19/drug therapy , Case-Control Studies , Drug Therapy, Combination/methods , Enzyme Inhibitors/administration & dosage , Female , Granulocytes/metabolism , Healthy Volunteers , Humans , Interferon Type I/metabolism , Male , Middle Aged , Myeloid-Derived Suppressor Cells/metabolism , Severity of Illness Index , Signal Transduction/immunology , T-Lymphocytes/immunology
7.
Front Immunol ; 12: 691725, 2021.
Article in English | MEDLINE | ID: covidwho-1305646

ABSTRACT

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.


Subject(s)
COVID-19/immunology , Monocytes/immunology , Myeloid-Derived Suppressor Cells/immunology , SARS-CoV-2/physiology , Adult , Aged , Cell Differentiation , Critical Care , Cytokines/metabolism , Female , Humans , Immunomodulation , Male , Middle Aged , Phenotype , Respiratory Insufficiency , Severity of Illness Index , Th2 Cells/immunology
8.
Int J Mol Sci ; 22(13)2021 Jun 26.
Article in English | MEDLINE | ID: covidwho-1304664

ABSTRACT

Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, especially, cellular immune response to them, more effective adjuvants are needed. Here, we evaluated a panel of compounds as potential adjuvants using the HCV NS5B protein as an immunogen. These compounds included inhibitors of polyamine biosynthesis and urea cycle, the mTOR pathway, antioxidants, and cellular receptors. A pronounced stimulation of cell proliferation and interferon-γ (IFN-γ) secretion in response to concanavalin A was shown for antioxidant N-acetylcysteine (NAC), polyamine biosynthesis inhibitor 2-difluoromethylornithine (DFMO), and TLR9 agonist CpG ODN 1826 (CpG). Their usage during the immunization of mice with the recombinant NS5B protein significantly increased antibody titers, enhanced lymphocyte proliferation and IFN-γ production. NAC and CpG decreased relative Treg numbers; CpG increased the number of myeloid-derived suppressor cells (MDSCs), whereas neither NAC nor DFMO affected MDSC counts. NAC and DFMO suppressed NO and interleukin 10 (IL-10) production by splenocytes, while DFMO increased the levels of IL-12. This is the first evidence of immunomodulatory activity of NAC and DFMO during prophylactic immunization against infectious diseases.


Subject(s)
Acetylcysteine/pharmacology , Adjuvants, Immunologic/pharmacology , Eflornithine/pharmacology , Hepatitis C/immunology , Immunity, Active/drug effects , Viral Nonstructural Proteins/immunology , Animals , Cell Proliferation , Cells, Cultured , Female , Immunogenicity, Vaccine/drug effects , Interferon-gamma/metabolism , Interleukin-10/metabolism , Interleukin-12/metabolism , Mice , Mice, Inbred DBA , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/immunology , Nitric Oxide/metabolism , Oligodeoxyribonucleotides/pharmacology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Viral Hepatitis Vaccines/immunology
9.
Front Immunol ; 12: 697405, 2021.
Article in English | MEDLINE | ID: covidwho-1295643

ABSTRACT

Clinical presentations of COVID-19 are highly variable, yet the precise mechanisms that govern the pathophysiology of different disease courses remain poorly defined. Across the spectrum of disease severity, COVID-19 impairs both innate and adaptive host immune responses by activating innate immune cell recruitment, while resulting in low lymphocyte counts. Recently, several reports have shown that patients with severe COVID-19 exhibit a dysregulated myeloid cell compartment, with increased myeloid-derived suppressor cells (MDSCs) correlating with disease severity. MDSCs, in turn, promote virus survival by suppressing T-cell responses and driving a highly pro-inflammatory state through the secretion of various mediators of immune activation. Here, we summarize the evidence on MDSCs and myeloid cell dysregulation in COVID-19 infection and discuss the potential of MDSCs as biomarkers and therapeutic targets in COVID-19 pneumonia and associated disease.


Subject(s)
COVID-19/pathology , Myeloid-Derived Suppressor Cells/cytology , Myeloid-Derived Suppressor Cells/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Biomarkers , Humans , Inflammation/immunology , Inflammation/pathology , Severity of Illness Index
10.
Cell Immunol ; 364: 104347, 2021 06.
Article in English | MEDLINE | ID: covidwho-1157177

ABSTRACT

Myeloid-derived suppressor cells (MDSC) are important immune-regulatory cells but their identification remains difficult. Here, we provide a critical view on selected surface markers, transcriptional and translational pathways commonly used to identify MDSC by specific, their developmental origin and new possibilities by transcriptional or proteomic profiling. Discrimination of MDSC from their non-suppressive counterparts is a prerequisite for the development of successful therapies. Understanding the switch mechanisms that direct granulocytic and monocytic development into a pro-inflammatory or anti-inflammatory direction will be crucial for therapeutic strategies. Manipulation of these myeloid checkpoints are exploited by tumors and pathogens, such as M. tuberculosis (Mtb), HIV or SARS-CoV-2, that induce MDSC for immune evasion. Thus, specific markers for MDSC identification may reveal also novel molecular candidates for therapeutic intervention at the level of MDSC.


Subject(s)
Biomarkers/metabolism , Gene Expression Profiling/methods , Myeloid-Derived Suppressor Cells/immunology , Proteomics/methods , Signal Transduction/immunology , Animals , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , B7-H1 Antigen/metabolism , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Cells, Cultured , Humans , Mice , Myeloid-Derived Suppressor Cells/metabolism , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/metabolism , Programmed Cell Death 1 Receptor/genetics , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Signal Transduction/genetics , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism
11.
Aging (Albany NY) ; 13(5): 6236-6246, 2021 02 26.
Article in English | MEDLINE | ID: covidwho-1154948

ABSTRACT

BACKGROUND: The immune responses, hyper-inflammation or immunosuppression, may be closely related to COVID-19 progression. We aimed to evaluate the changes of frequency of CD14+HLA-DRlo/neg MDSCs, a population of cells with potent immunosuppressive capacity, in COVID-19 patients. METHODS: The levels of CD14+HLA-DRlo/neg MDSCs were determined by flow cytometry in 27 COVID-19 patients, and their association with clinical characteristics and laboratory data were analyzed. RESULTS: The frequency of CD14+HLA-DRlo/neg MDSCs was elevated in COVID-19 patients, particularly severe patients. A follow-up comparison revealed a decline of CD14+HLA-DRlo/neg MDSCs percentages in most patients 1 day after testing negative for SARS-CoV-2 nucleic acid, but the levels of CD14+HLA-DRlo/neg MDSCs were still greater than 50.0% in 3 ICU patients 4-10 days after negative SARS-CoV-2 results. Elevated frequency of CD14+HLA-DRlo/neg MDSCs was positively correlated with oropharyngeal viral loads and length of hospital stay, while negatively correlated with lymphocyte counts and serum albumin. Moreover, strong correlations were observed between the frequency of CD14+HLA-DRlo/neg MDSCs and T cell subsets, NK cell counts, and B cell percentages. The frequency of CD14+HLA-DRlo/neg MDSCs could be used as a predictor of COVID-19 severity. CONCLUSIONS: A high frequency of CD14+HLA-DRlo/neg MDSCs, especially in severe patients, may indicate an immunoparalysis status and could be a predictor of disease severity and prognosis.


Subject(s)
COVID-19/immunology , HLA-DR Antigens/immunology , Lipopolysaccharide Receptors/immunology , Myeloid-Derived Suppressor Cells/pathology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/pathology , Female , HLA-DR Antigens/analysis , Humans , Immune Tolerance , Lipopolysaccharide Receptors/analysis , Male , Middle Aged , Myeloid-Derived Suppressor Cells/immunology , Prognosis , SARS-CoV-2/isolation & purification
12.
J Immunother Cancer ; 9(3)2021 03.
Article in English | MEDLINE | ID: covidwho-1133309

ABSTRACT

While vaccines directed against the SARS-CoV-2 spike protein will have varying degrees of effectiveness in preventing SARS-CoV-2 infections, the severity of infection will be determined by multiple host factors including the ability of immune cells to lyse virus-infected cells. This review will discuss the complexity of both adaptive and innate immunomes and how a flow-based assay can detect up to 158 distinct cell subsets in the periphery. This assay has been employed to show the effect of age on differences in specific immune cell subsets, and the differences in the immunome between healthy donors and age-matched cancer patients. Also reviewed are the numerous soluble factors, in addition to cytokines, that may vary in the pathogenesis of SARS-CoV-2 infections and may also be employed to help define the effectiveness of a given vaccine or other antiviral agents. Various steroids have been employed in the management of autoimmune adverse events in cancer patients receiving immunotherapeutics and may be employed in the management of SARS-CoV-2 infections. The influence of steroids on multiple immune cells subsets will also be discussed.


Subject(s)
Adaptive Immunity/immunology , B-Lymphocytes/immunology , COVID-19/immunology , Dendritic Cells/immunology , Immunity, Innate/immunology , Killer Cells, Natural/immunology , Neoplasms/immunology , T-Lymphocytes/immunology , Age Factors , B7-H1 Antigen/immunology , CD40 Ligand/immunology , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Cytokines/immunology , Disease Susceptibility , Glucocorticoids/therapeutic use , Granzymes/immunology , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immunosenescence/immunology , Myeloid-Derived Suppressor Cells/immunology , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/immunology , Proteome , SARS-CoV-2 , Severity of Illness Index , T-Lymphocyte Subsets/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology
13.
Front Immunol ; 12: 614599, 2021.
Article in English | MEDLINE | ID: covidwho-1127983

ABSTRACT

Widespread coronavirus disease (COVID)-19 is causing pneumonia, respiratory and multiorgan failure in susceptible individuals. Dysregulated immune response marks severe COVID-19, but the immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, which is hampering the development of efficient treatments. Here we analyzed ~140 parameters of cellular and humoral immune response in peripheral blood of 41 COVID-19 patients and 16 age/gender-matched healthy donors by flow-cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with ~30 common clinical and laboratory parameters. We found that lymphocytopenia in severe COVID-19 patients (n=20) strongly affects T, NK and NKT cells, but not B cells and antibody production. Unlike increased activation of ICOS-1+ CD4+ T cells in mild COVID-19 patients (n=21), T cells in severe patients showed impaired activation, low IFN-γ production and high functional exhaustion, which correlated with significantly down-regulated HLA-DR expression in monocytes, dendritic cells and B cells. The latter phenomenon was followed by lower interferon responsive factor (IRF)-8 and autophagy-related genes expressions, and the expansion of myeloid derived suppressor cells (MDSC). Intriguingly, PD-L1-, ILT-3-, and IDO-1-expressing monocytic MDSC were the dominant producers of IL-6 and IL-10, which correlated with the increased inflammation and accumulation of regulatory B and T cell subsets in severe COVID-19 patients. Overall, down-regulated IRF-8 and autophagy-related genes expression, and the expansion of MDSC subsets could play critical roles in dysregulating T cell response in COVID-19, which could have large implications in diagnostics and design of novel therapeutics for this disease.


Subject(s)
Autophagy-Related Proteins/biosynthesis , COVID-19/immunology , Myeloid-Derived Suppressor Cells/immunology , SARS-CoV-2/immunology , T-Lymphocyte Subsets/immunology , Adult , Aged , Aged, 80 and over , Autophagy/immunology , Autophagy-Related Proteins/immunology , Autophagy-Related Proteins/metabolism , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Cohort Studies , Female , Humans , Immunity , Lymphocyte Activation , Male , Middle Aged , Monocytes/immunology , Myeloid-Derived Suppressor Cells/pathology , T-Lymphocyte Subsets/pathology , T-Lymphocytes/immunology
14.
Aging (Albany NY) ; 13(5): 6236-6246, 2021 02 26.
Article in English | MEDLINE | ID: covidwho-1112910

ABSTRACT

BACKGROUND: The immune responses, hyper-inflammation or immunosuppression, may be closely related to COVID-19 progression. We aimed to evaluate the changes of frequency of CD14+HLA-DRlo/neg MDSCs, a population of cells with potent immunosuppressive capacity, in COVID-19 patients. METHODS: The levels of CD14+HLA-DRlo/neg MDSCs were determined by flow cytometry in 27 COVID-19 patients, and their association with clinical characteristics and laboratory data were analyzed. RESULTS: The frequency of CD14+HLA-DRlo/neg MDSCs was elevated in COVID-19 patients, particularly severe patients. A follow-up comparison revealed a decline of CD14+HLA-DRlo/neg MDSCs percentages in most patients 1 day after testing negative for SARS-CoV-2 nucleic acid, but the levels of CD14+HLA-DRlo/neg MDSCs were still greater than 50.0% in 3 ICU patients 4-10 days after negative SARS-CoV-2 results. Elevated frequency of CD14+HLA-DRlo/neg MDSCs was positively correlated with oropharyngeal viral loads and length of hospital stay, while negatively correlated with lymphocyte counts and serum albumin. Moreover, strong correlations were observed between the frequency of CD14+HLA-DRlo/neg MDSCs and T cell subsets, NK cell counts, and B cell percentages. The frequency of CD14+HLA-DRlo/neg MDSCs could be used as a predictor of COVID-19 severity. CONCLUSIONS: A high frequency of CD14+HLA-DRlo/neg MDSCs, especially in severe patients, may indicate an immunoparalysis status and could be a predictor of disease severity and prognosis.


Subject(s)
COVID-19/immunology , HLA-DR Antigens/immunology , Lipopolysaccharide Receptors/immunology , Myeloid-Derived Suppressor Cells/pathology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/pathology , Female , HLA-DR Antigens/analysis , Humans , Immune Tolerance , Lipopolysaccharide Receptors/analysis , Male , Middle Aged , Myeloid-Derived Suppressor Cells/immunology , Prognosis , SARS-CoV-2/isolation & purification
15.
Cell Rep ; 34(11): 108863, 2021 03 16.
Article in English | MEDLINE | ID: covidwho-1108116

ABSTRACT

It is unclear why some SARS-CoV-2 patients readily resolve infection while others develop severe disease. By interrogating metabolic programs of immune cells in severe and recovered coronavirus disease 2019 (COVID-19) patients compared with other viral infections, we identify a unique population of T cells. These T cells express increased Voltage-Dependent Anion Channel 1 (VDAC1), accompanied by gene programs and functional characteristics linked to mitochondrial dysfunction and apoptosis. The percentage of these cells increases in elderly patients and correlates with lymphopenia. Importantly, T cell apoptosis is inhibited in vitro by targeting the oligomerization of VDAC1 or blocking caspase activity. We also observe an expansion of myeloid-derived suppressor cells with unique metabolic phenotypes specific to COVID-19, and their presence distinguishes severe from mild disease. Overall, the identification of these metabolic phenotypes provides insight into the dysfunctional immune response in acutely ill COVID-19 patients and provides a means to predict and track disease severity and/or design metabolic therapeutic regimens.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Immunity/immunology , Adult , Aged , Aged, 80 and over , Apoptosis/immunology , Caspases/immunology , Caspases/metabolism , Female , Humans , Lymphopenia/immunology , Lymphopenia/metabolism , Male , Middle Aged , Mitochondria/immunology , Mitochondria/metabolism , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , SARS-CoV-2/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Voltage-Dependent Anion Channel 1/metabolism , Young Adult
16.
Cell Immunol ; 362: 104302, 2021 04.
Article in English | MEDLINE | ID: covidwho-1085577

ABSTRACT

MDSC are a heterogeneous population of immature myeloid cells that are released by biological stress such as tissue damage and inflammation. Conventionally, MDSC are known for their detrimental role in chronic inflammation and neoplastic conditions. However, their intrinsic functions in immunoregulation, wound healing, and angiogenesis are intended to protect from over-reactive immune responses, maintenance of immunotolerance, tissue repair, and homeostasis. Paradoxically, under certain conditions, MDSC can impair protective immune responses and exacerbate the disease. The transition from protective to harmful MDSC is most likely driven by environmental and epigenetic mechanisms induced by prolonged exposure to unresolved inflammatory triggers. Here, we review several examples of the dual impact of MDSC in conditions such as maternal-fetal tolerance, self-antigens immunotolerance, obesity-associated cancer, sepsis and trauma. Moreover, we also highlighted the evidence indicating that MDSC have a role in COVID-19 pathophysiology. Finally, we have summarized the evidence indicating epigenetic mechanisms associated with MDSC function.


Subject(s)
Myeloid-Derived Suppressor Cells/immunology , Animals , COVID-19/immunology , Epigenesis, Genetic , Female , Humans , Immune Tolerance/immunology , Inflammation/immunology , Male , Neoplasms/immunology , Obesity/immunology , Pregnancy , Wound Healing/immunology
17.
Int Immunol ; 33(4): 241-247, 2021 03 31.
Article in English | MEDLINE | ID: covidwho-1066348

ABSTRACT

An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with IL-8 levels, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Our data indicate that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.


Subject(s)
COVID-19/pathology , Interleukin-8/blood , Myeloid-Derived Suppressor Cells/immunology , Neutrophils/immunology , SARS-CoV-2/immunology , Humans , Interleukin-8/immunology , Japan , Leukocyte Count , Myeloid Cells/immunology , Neutrophil Activation/immunology
18.
Nat Rev Immunol ; 21(8): 485-498, 2021 08.
Article in English | MEDLINE | ID: covidwho-1060053

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity. They are implicated in the regulation of immune responses in many pathological conditions and are closely associated with poor clinical outcomes in cancer. Recent studies have indicated key distinctions between MDSCs and classical neutrophils and monocytes, and, in this Review, we discuss new data on the major genomic and metabolic characteristics of MDSCs. We explain how these characteristics shape MDSC function and could facilitate therapeutic targeting of these cells, particularly in cancer and in autoimmune diseases. Additionally, we briefly discuss emerging data on MDSC involvement in pregnancy, neonatal biology and COVID-19.


Subject(s)
Cytokines/immunology , Monocytes/immunology , Myeloid Cells/immunology , Myeloid-Derived Suppressor Cells/immunology , Neutrophils/immunology , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Cytokines/metabolism , Humans , Monocytes/metabolism , Myeloid Cells/metabolism , Myeloid-Derived Suppressor Cells/metabolism , Neoplasms/immunology , Neoplasms/metabolism , Neutrophils/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/physiology
19.
J Clin Invest ; 131(6)2021 03 15.
Article in English | MEDLINE | ID: covidwho-1045635

ABSTRACT

The immunopathology of coronavirus disease 2019 (COVID-19) remains enigmatic, causing immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSCs) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied the blood and airways of patients with COVID-19 across disease severities at multiple time points. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of patients with COVID-19 compared with healthy controls. M-MDSCs isolated from patients with COVID-19 suppressed T cell proliferation and IFN-γ production partly via an arginase 1-dependent (Arg-1-dependent) mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. Patients with COVID-19 had fewer T cells and downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expanded in the blood of patients with COVID-19, suppressed T cells, and were strongly associated with disease severity, indicating a role for M-MDSCs in the dysregulated COVID-19 immune response.


Subject(s)
COVID-19/immunology , Myeloid-Derived Suppressor Cells/immunology , Adult , Aged , Aged, 80 and over , Arginase/blood , COVID-19/blood , COVID-19/pathology , Case-Control Studies , Cohort Studies , Female , Humans , Influenza, Human/blood , Influenza, Human/immunology , Influenza, Human/pathology , Interferon-gamma/blood , Interleukin-6/blood , Leukocyte Count , Male , Middle Aged , Myeloid-Derived Suppressor Cells/pathology , Pandemics , Respiratory System/immunology , Respiratory System/pathology , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Young Adult
20.
Cell Immunol ; 360: 104259, 2021 02.
Article in English | MEDLINE | ID: covidwho-978233

ABSTRACT

Vitamin D regulates homeostasis, anti-microbial response, and inflammation. The vitamin D receptors are expressed in the macrophages and other immune cells, regulating the transcription of many different genes, including those coding the anti-microbial peptides. One of the most severe complications of the SARS-CoV-2 infection is the acute respiratory distress syndrome (ARDS) caused by the hyperinflammatory response (commonly called cytokine storm) of the lung macrophages. Studies showed that Vitamin D deficiency increases the severity of the ARDS in COVID-19 infection. We discuss here how the vitamin D supplementation may influence macrophage and myeloid-derived suppressor cells (MDSCs) inflammatory response, subdue the hyperinflammatory response, and lessen the ARDS in COVID-19 patients.


Subject(s)
COVID-19/drug therapy , COVID-19/pathology , Lung/pathology , Vitamin D/administration & dosage , Vitamins/administration & dosage , Animals , COVID-19/complications , COVID-19/immunology , Child , Humans , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Inflammation/prevention & control , Lung/immunology , Macrophages/immunology , Macrophages/metabolism , Myeloid-Derived Suppressor Cells/immunology , Myeloid-Derived Suppressor Cells/metabolism , Receptors, Calcitriol/metabolism , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/prevention & control
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