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1.
Frontiers in immunology ; 13, 2022.
Article in English | EuropePMC | ID: covidwho-1837338

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Viral replication in the respiratory tract induces the death of infected cells and the release of pathogen- associated molecular patterns (PAMPs). PAMPs give rise to local inflammation, increasing the secretion of pro- inflammatory cytokines and chemokines, which attract immune cells from the blood into the infected lung. In most individuals, lung-recruited cells clear the infection, and the immune response retreats. However, in some cases, a dysfunctional immune response occurs, which triggers a cytokine storm in the lung, leading to acute respiratory distress syndrome (ARDS). Severe COVID-19 is characterized by an impaired innate and adaptive immune response and by a massive expansion of myeloid-derived suppressor cells (MDSCs). MDSCs function as protective regulators of the immune response, protecting the host from over-immunoreactivity and hyper-inflammation. However, under certain conditions, such as chronic inflammation and cancer, MDSCs could exert a detrimental role. Accordingly, the early expansion of MDSCs in COVID-19 is able to predict the fatal outcome of the infection. Here, we review recent data on MDSCs during COVID-19, discussing how they can influence the course of the disease and whether they could be considered as biomarker and possible targets for new therapeutic approaches.

2.
Sci Rep ; 12(1): 6687, 2022 04 23.
Article in English | MEDLINE | ID: covidwho-1805648

ABSTRACT

Vaccine is the main public health measure to reduce SARS-CoV-2 transmission and hospitalization, and a massive scientific effort worldwide resulted in the rapid development of effective vaccines. This work aimed to define the dynamics and persistence of humoral and cell-mediated immune response in Health Care Workers who received a two-dose BNT162b2-mRNA vaccination. Serological response was evaluated by quantifying anti-RBD and neutralizing antibodies while cell-mediated response was performed by a whole blood test quantifying Th1 cytokines (IFN-γ, TNF-α, IL-2) produced in response to Spike peptides. BNT162b2-mRNA vaccine induced both humoral and cell-mediated immune response against Spike in all HCW early after the second dose. After 12 weeks from vaccination, the titer of anti-RBD antibodies as well as their neutralization function decreased while the Spike-specific T-cells persisted at the same level as soon after vaccine boost. Of note, a correlation between cellular and humoral response persevered, suggesting the persistence of a coordinated immune response. The long lasting cell-mediated immune response after 3 months from vaccination highlight its importance in the maintaining of specific immunity able to expand again to fight eventual new antigen encountering.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunity, Cellular , Immunity, Humoral , T-Lymphocytes , Vaccination , Vaccines, Synthetic
3.
Front Oncol ; 12: 855723, 2022.
Article in English | MEDLINE | ID: covidwho-1775732

ABSTRACT

Background: Frail patients are considered at relevant risk of complications due to coronavirus disease 2019 (COVID-19) infection and, for this reason, are prioritized candidates for vaccination. As these patients were originally not included in the registration trials, fear related to vaccine adverse events and disease worsening was one of the reasons for vaccine hesitancy. Herein, we report the safety profile of the prospective, multicenter, national VAX4FRAIL study (NCT04848493) to evaluate vaccines in a large trans-disease cohort of patients with solid or hematological malignancies and neurological and rheumatological diseases. Methods: Between March 3 and September 2, 2021, 566 patients were evaluable for safety endpoint: 105 received the mRNA-1273 vaccine and 461 the BNT162b2 vaccine. Frail patients were defined per protocol as patients under treatment with hematological malignancies (n = 131), solid tumors (n = 191), immune-rheumatological diseases (n = 86), and neurological diseases (n = 158), including multiple sclerosis and generalized myasthenia. The impact of the vaccination on the health status of patients was assessed through a questionnaire focused on the first week after each vaccine dose. Results: The most frequently reported moderate-severe adverse events were pain at the injection site (60.3% after the first dose, 55.4% after the second), fatigue (30.1%-41.7%), bone pain (27.4%-27.2%), and headache (11.8%-18.9%). Risk factors associated with the occurrence of severe symptoms after vaccine administration were identified through a multivariate logistic regression analysis: age was associated with severe fever presentation (younger patients vs. middle-aged vs. older ones), female individuals presented a higher probability of severe pain at the injection site, fatigue, headache, and bone pain; and the mRNA-1237 vaccine was associated with a higher probability of severe pain at the injection site and fever. After the first dose, patients presenting a severe symptom were at a relevant risk of recurrence of the same severe symptom after the second one. Overall, 11 patients (1.9%) after the first dose and 7 (1.2%) after the second one required postponement or suspension of the disease-specific treatment. Finally, two fatal events occurred among our 566 patients. These two events were considered unrelated to the vaccine. Conclusions: Our study reports that mRNA-COVID-19 vaccination is safe also in frail patients; as expected, side effects were manageable and had a minimum impact on patient care path.

4.
iScience ; 25(2): 103854, 2022 Feb 18.
Article in English | MEDLINE | ID: covidwho-1683209

ABSTRACT

To assess the cross-talk between immune cells and respiratory tract during SARS-CoV-2 infection, we analyzed the relationships between the inflammatory response induced by SARS-CoV-2 replication and immune cells phenotype in a reconstituted organotypic human airway epithelium (HAE). The results indicated that immune cells failed to inhibit SARS-CoV-2 replication in the HAE model. In contrast, immune cells strongly affected the inflammatory profile induced by SARS-CoV-2 infection, dampening the production of several immunoregulatory/inflammatory signals (e.g., IL-35, IL-27, and IL-34). Moreover, these mediators were found inversely correlated with innate immune cell frequency (NK and γδ T cells) and directly with CD8 T cells. The enriched signals associated with NK and CD8 T cells highlighted the modulation of pathways induced by SARS-CoV-2 infected HAE. These findings are useful to depict the cell-cell communication mechanisms necessary to develop novel therapeutic strategies aimed to promote an effective immune response.

5.
iScience ; 2022.
Article in English | EuropePMC | ID: covidwho-1660975

ABSTRACT

To assess the cross talk between immune cells and respiratory tract during SARS-CoV-2 infection, we analysed the relationships between the inflammatory response induced by SARS-CoV-2 replication and immune cells phenotype in a reconstituted organotypic human airway epithelium (HAE). The results indicated that immune cells failed to inhibit SARS-CoV-2 replication in HAE model. In contrast, immune cells strongly affected the inflammatory profile induced by SARS-CoV-2 infection, dampening the production of several immunoregulatory/inflammatory signals (e.g., IL-35, IL-27 and IL-34). Moreover, these mediators were found inversely correlated with innate immune cell frequency (NK and γδ T cells) and directly with CD8 T cells. The enriched signals associated with NK and CD8 T cells highlighted the modulation of pathways induced by SARS-CoV-2 infected HAE. These findings are useful to depict the cell-cell communication mechanisms necessary to develop novel therapeutic strategies aimed to promote an effective immune response. Graphical

6.
Biol Sex Differ ; 12(1): 63, 2021 11 22.
Article in English | MEDLINE | ID: covidwho-1528694

ABSTRACT

BACKGROUND: Several biomarkers have been identified to predict the outcome of COVID-19 severity, but few data are available regarding sex differences in their predictive role. Aim of this study was to identify sex-specific biomarkers of severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19. METHODS: Plasma levels of sex hormones (testosterone and 17ß-estradiol), sex-hormone dependent circulating molecules (ACE2 and Angiotensin1-7) and other known biomarkers for COVID-19 severity were measured in male and female COVID-19 patients at admission to hospital. The association of plasma biomarker levels with ARDS severity at admission and with the occurrence of respiratory deterioration during hospitalization was analysed in aggregated and sex disaggregated form. RESULTS: Our data show that some biomarkers could be predictive both for males and female patients and others only for one sex. Angiotensin1-7 plasma levels and neutrophil count predicted the outcome of ARDS only in females, whereas testosterone plasma levels and lymphocytes counts only in males. CONCLUSIONS: Sex is a biological variable affecting the choice of the correct biomarker that might predict worsening of COVID-19 to severe respiratory failure. The definition of sex specific biomarkers can be useful to alert patients to be safely discharged versus those who need respiratory monitoring.


Subject(s)
Biomarkers/blood , COVID-19/complications , Hospitalization , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/diagnosis , Respiratory Insufficiency/complications , Respiratory Insufficiency/diagnosis , Sex Characteristics , Adult , Angiotensin-Converting Enzyme 2/blood , Angiotensins/blood , COVID-19/blood , Estradiol/blood , Female , Humans , Male , Middle Aged , Respiratory Distress Syndrome/blood , Respiratory Insufficiency/blood , SARS-CoV-2 , Testosterone/blood
7.
Nutrients ; 13(10)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1463781

ABSTRACT

To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC-PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.


Subject(s)
Alkynes/blood , Alkynes/therapeutic use , Benzoxazines/blood , Benzoxazines/therapeutic use , Cyclopropanes/blood , Cyclopropanes/therapeutic use , HIV Infections/blood , HIV Infections/drug therapy , Vitamin D/pharmacology , Vitamins/pharmacology , Adult , Cohort Studies , Female , Humans , Italy , Male , Middle Aged , Retrospective Studies , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/therapeutic use , Seasons , Treatment Outcome , Vitamin D/blood , Vitamins/blood
8.
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
9.
Microorganisms ; 9(6)2021 Jun 16.
Article in English | MEDLINE | ID: covidwho-1278501

ABSTRACT

Vaccination is the main public health measure to reduce SARS-CoV-2 transmission and hospitalization, and a massive worldwide scientific effort resulted in the rapid development of effective vaccines. This work aimed to define the dynamics of humoral and cell-mediated immune response in a cohort of health care workers (HCWs) who received a two-dose BNT162b2-mRNA vaccination. The serological response was evaluated by quantifying the anti-RBD and neutralizing antibodies. The cell-mediated response was performed by a whole blood test quantifying Th1 cytokines (IFN-γ, TNF-α, IL-2), produced in response to spike peptides. The BNT162b2-mRNA vaccine induced both humoral and cell-mediated immune responses against spike peptides in virtually all HCWs without previous SARS-CoV-2 infection, with a moderate inverse relation with age in the anti-RBD response. Spike-specific T cells produced several Th1 cytokines (IFN-γ, TNF-α, and IL-2), which correlated with the specific-serological response. Overall, our study describes the ability of the BNT162b2 mRNA vaccine to elicit a coordinated neutralizing humoral and spike-specific T cell response in HCWs. Assessing the dynamics of these parameters by an easy immune monitoring protocol can allow for the evaluation of the persistence of the vaccine response in order to define the optimal vaccination strategy.

10.
Front Pharmacol ; 12: 683529, 2021.
Article in English | MEDLINE | ID: covidwho-1247897

ABSTRACT

The outcome of COVID-19 appears to be influenced by vitamin D status of population. Although epidemiological data indicate that COVID-19 produces more severe symptoms and higher mortality in elderly in comparison to young patients and in men in comparison to women to date sex and age differences in vitamin D status in infected patients have not been evaluated yet. In this study we evaluated the levels of circulating 25(OH)D in patients hospitalized for COVID-19 divided accordingly to their sex and age. We also correlated 25(OH)D levels with patient's respiratory status (i.e., PaO2/FiO2 ratio) and with sex hormones plasma levels to analyze the potential relationship of these parameters. We found no significant differences in plasma levels of 25(OH)D between pre- and post-menopausal female patients and age matched male patients. Interestingly, the 25(OH)D plasma levels positively correlated to PaO2/FiO2 ratio only in young patients, regardless of their sex. We also found a significantly positive correlation between 17ß-estradiol and 25(OH)D in elderly women and between testosterone and 25(OH)D in elderly men, supporting the role of sex hormones in maintaining 25(OH)D levels. In conclusion, we suggest that a synergy between vitamin D and sex hormones could contribute to the age-related outcome of COVID-19.

11.
Clin Infect Dis ; 71(16): 2272-2275, 2020 11 19.
Article in English | MEDLINE | ID: covidwho-1165366

ABSTRACT

Increased production of inflammatory cytokines and myeloid-derived suppressor cells occurs in patients with coronavirus disease 2019. These inversely correlated with perforin-expressing natural killer (NK) and CD3+ T cells. We observed a lower number of perforin-expressing NK cells in intensive care unit (ICU) patients compared with non-ICU patients, suggesting an impairment of the immune cytotoxic arm as a pathogenic mechanism.


Subject(s)
COVID-19/immunology , Inflammation/blood , Killer Cells, Natural/immunology , Perforin/immunology , T-Lymphocytes, Cytotoxic/immunology , Aged , COVID-19/blood , Cytokines/immunology , Female , Humans , Inflammation/complications , Inflammation/immunology , Intensive Care Units/statistics & numerical data , Italy , Lymphocyte Activation/immunology , Male , Middle Aged , SARS-CoV-2
12.
Int J Infect Dis ; 105: 49-53, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1071458

ABSTRACT

BACKGROUND/OBJECTIVES: A dysregulated inflammatory profile plays an important role in coronavirus disease-2019 (COVID-19) pathogenesis. Moreover, the depletion of lymphocytes is typically associated with an unfavourable disease course. We studied the role and impact of p53 and deacetylase Sirtuin 1 (SIRT1) on lymph-monocyte homeostasis and their possible effect on T and B cell signalling. METHODS: Gene expression analysis and flow cytometry were performed on peripheral blood mononuclear cells (PBMC) of 35 COVID-19 patients and 10 healthy donors (HD). Inflammatory cytokines, the frequency of Annexin+ cells among CD3+ T cells and CD19+ B cell subsets were quantified. RESULTS: PBMC from COVID-19 patients had a higher p53 expression, and higher concentrations of plasma proinflammatory cytokines (IL1ß, TNF-α, IL8, and IL6) than HD. Deacetylase Sirtuin 1 (SIRT1) expression was significantly decreased in COVID-19 patients and was negatively correlated with p53 (p = 0.003 and r = -0.48). A lower expression of IL-7R and B Cell linker (BLNK), key genes for lymphocyte homeostasis and function, was observed in COVID-19 than in HD. The reduction of IgK and IgL chains was seen in lymphopenic COVID-19 patients. A significant increase in both apoptotic B and T cells were observed. Inflammatory cytokines correlated positively with p53 (IL-1ß: r = 0.5 and p = 0.05; IL-8: r = 0.5 and p = 0.05) and negatively with SIRT1 (IL1-ß: r = -0.5 and p = 0.04; TNF-α: r = -0.4 and p = 0.04). CONCLUSIONS: Collectively, our data indicate that the inflammatory environment, the dysregulated p53/SIRT1 axis and low expression of IL7R and BLNK may impact cell survival, B cell signalling and antibody production in COVID-19 patients. Further studies are required to define the functional impact of low BLNK/IL7R expression during severe acute respiratory syndrome coronavirus-2 infection.


Subject(s)
COVID-19/immunology , Homeostasis , Lymphocytes/immunology , SARS-CoV-2 , Sirtuin 1/physiology , Tumor Suppressor Protein p53/physiology , Aged , Cytokines/blood , Female , Humans , Male , Middle Aged
13.
Front Pediatr ; 8: 576912, 2020.
Article in English | MEDLINE | ID: covidwho-983735

ABSTRACT

Background: In severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) critically ill adults, hyperinflammation plays a key role in disease progression. The clinical manifestations of SARS-CoV-2 infection among children are much less severe compared with adult patients and usually associated with a good prognosis. However, hyperinflammation in SARS-CoV-2-infected pediatric patients has been described as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 or as Kawasaki-like disease but is still little known, and optimal management has to be defined. The World Health Organization (WHO) on the 15th of May 2020 has developed a preliminary case definition for multisystem inflammatory disorder in children and adolescents with coronavirus disease 2019 (COVID-19) and stated for an urgent need to collect data on this condition. Here, we report two adolescent patients affected by COVID-19 presenting with multisystem inflammatory disorder, 3-4 weeks after the first symptoms of SARS-CoV-2 infection, treated with the interleukin-1 receptor antagonist anakinra and glucocorticoids with good clinical response. Cases: We report two patients chronically ill appearing, with high fever, severe gastrointestinal involvement, and increased biomarkers of inflammation onset 3-4 weeks after paucisymptomatic SARS-CoV-2 infection. They had no lung involvement, but abdominal ultrasound and CT scan showed thickening of the bowel wall. SARS-CoV-2 PCR was positive on ileum biopsy in both patients, whereas it was negative on other common sampled sites. They have been admitted to the pediatric intensive care unit and have been treated with a combination of anakinra 6-8 mg/kg/day i.v. and a standard dose of methylprednisolone 2 mg/kg/day in addition to lopinavir/ritonavir 400 mg q12h and low molecular weight heparin 100 UI/kg q12h with good clinical response.

14.
Cell Death Dis ; 11(10): 921, 2020 10 27.
Article in English | MEDLINE | ID: covidwho-894382

ABSTRACT

The immunological mechanisms underlying the clinical presentation of SARS-CoV-2 infection and those influencing the disease outcome remain to be defined. Myeloid-derived suppressor cells (MDSC) have been described to be highly increased during COVID-19, however, their role remains elusive. We performed an in depth analysis of MDSC in 128 SARS-CoV-2 infected patients. Polymorphonuclear (PMN)-MDSC expanded during COVID-19, in particular in patients who required intensive care treatments, and correlated with IL-1ß, IL-6, IL-8, and TNF-α plasma levels. PMN-MDSC inhibited T-cells IFN-γ production upon SARS-CoV-2 peptides stimulation, through TGF-ß- and iNOS-mediated mechanisms, possibly contrasting virus elimination. Accordingly, a multivariate regression analysis found a strong association between PMN-MDSC percentage and fatal outcome of the disease. The PMN-MDSC frequency was higher in non-survivors than survivors at the admission time, followed by a decreasing trend. Interestingly, this trend was associated with IL-6 increase in non-survivors but not in survivors. In conclusion, this study indicates PMN-MDSC as a novel factor in the pathogenesis of SARS-CoV2 infection, and open up to new therapeutic options.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Myeloid-Derived Suppressor Cells/immunology , Pneumonia, Viral/pathology , T-Lymphocytes/immunology , Aged , Area Under Curve , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Female , Humans , Interferon-gamma/metabolism , Interleukin-1beta/blood , Interleukin-6/blood , Male , Middle Aged , Myeloid-Derived Suppressor Cells/cytology , Neutrophils/cytology , Neutrophils/immunology , Neutrophils/metabolism , Nitric Oxide Synthase Type II/metabolism , Pandemics , Peptides/immunology , Peptides/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Proportional Hazards Models , ROC Curve , SARS-CoV-2 , Survival Rate , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Transforming Growth Factor beta/blood , Transforming Growth Factor beta/metabolism
15.
J Antimicrob Chemother ; 75(10): 2977-2980, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-626863

ABSTRACT

BACKGROUND: Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients. OBJECTIVES: To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients. METHODS: Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method. RESULTS: We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure. CONCLUSIONS: We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adenosine Triphosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacokinetics , Betacoronavirus , Coronavirus Infections/metabolism , Critical Illness/therapy , Pneumonia, Viral/metabolism , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/therapeutic use , Adenosine Triphosphate/pharmacokinetics , Adenosine Triphosphate/therapeutic use , Aged , Alanine/pharmacokinetics , Alanine/therapeutic use , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Female , Humans , Male , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Recovery of Function/drug effects , Recovery of Function/physiology , SARS-CoV-2
16.
Cell Death Differ ; 27(11): 3196-3207, 2020 11.
Article in English | MEDLINE | ID: covidwho-591591

ABSTRACT

SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-ß, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-ß and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Lymphocyte Activation/immunology , Myeloid-Derived Suppressor Cells/cytology , Pneumonia, Viral/virology , Adult , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , COVID-19 , Coronavirus Infections/immunology , Cytokines/metabolism , Disease Progression , Female , Humans , Inflammation/immunology , Myeloid-Derived Suppressor Cells/immunology , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2
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