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1.
Front Immunol ; 13: 861666, 2022.
Article in English | MEDLINE | ID: covidwho-1785350

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that spread around the world during the past 2 years, has infected more than 260 million people worldwide and has imposed an important burden on the healthcare system. Several risk factors associated with unfavorable outcome were identified, including elderly age, selected comorbidities, immune suppression as well as laboratory markers. The role of immune system in the pathophysiology of SARS-CoV-2 infection is indisputable: while an appropriate function of the immune system is important for a rapid clearance of the virus, progression to the severe and critical phases of the disease is related to an exaggerated immune response associated with a cytokine storm. We analyzed differences and longitudinal changes in selected immune parameters in 823 adult COVID-19 patients hospitalized in the Martin University Hospital, Martin, Slovakia. Examined parameters included the differential blood cell counts, various parameters of cellular and humoral immunity (serum concentration of immunoglobulins, C4 and C3), lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, NK cells, CD4+CD45RO+), expression of activation (HLA-DR, CD38) and inhibition markers (CD159/NKG2A). Besides already known changes in the differential blood cell counts and basic lymphocyte subsets, we found significantly higher proportion of CD8+CD38+ cells and significantly lower proportion of CD8+NKG2A+ and NK NKG2A+ cells on admission in non-survivors, compared to survivors; recovery in survivors was associated with a significant increase in the expression of HLA-DR and with a significant decrease of the proportion of CD8+CD38+cells. Furthermore, patients with fatal outcome had significantly lower concentrations of C3 and IgM on admission. However, none of the examined parameters had sufficient sensitivity or specificity to be considered a biomarker of fatal outcome. Understanding the dynamic changes in immune profile of COVID-19 patients may help us to better understand the pathophysiology of the disease, potentially improve management of hospitalized patients and enable proper timing and selection of immunomodulator drugs.


Subject(s)
COVID-19 , Adult , Aged , CD8-Positive T-Lymphocytes , HLA-DR Antigens , Humans , Lymphocyte Subsets , SARS-CoV-2
2.
J Nephrol ; 35(3): 745-759, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1650680

ABSTRACT

BACKGROUND: Dialysis and kidney transplant patients with moderate-severe COVID-19 have a high mortality rate, around 30%, that is similar in the two populations, despite differences in their baseline characteristics. In these groups, the immunology of the disease has been poorly explored. METHODS: Thirty-two patients on dialysis or with kidney transplant and SARS-CoV-2 infection requiring hospitalization (COV group) were included in our study. Lymphocyte subsets, dendritic cell (DC) counts and monocyte activation were studied. SARS-CoV-2 anti-spike/anti-nucleocapsid were monitored, and baseline cytokines and chemokines were measured in 10 patients. RESULTS: The COV group, compared to healthy subjects and uninfected dialysis/kidney transplant controls, showed lower numbers of CD4 + and CD8 + T cells, Natural-Killer (NK), B cells, plasmacytoid and myeloid DCs, while the proportion of terminally differentiated B-cells was increased. IL6, IL10, IFN-α and chemokines involved in monocyte and neutrophil recruitment were higher in the COV group, compared to uninfected dialysis/kidney transplant controls. Patients with severe disease had lower CD4 + , CD8 + and B-cell counts and lower monocyte HLA-DR expression. Of note, when comparing dialysis and kidney transplant patients with COVID-19, the latter group presented lower NK and pDC counts and monocyte HLA-DR expression. Up to 60 days after symptom onset, kidney transplant recipients showed lower levels of anti-spike antibodies compared to dialysis patients. CONCLUSIONS: During SARS-CoV-2 infection, dialysis and kidney transplant patients manifest immunophenotype abnormalities; these are similar in the two groups, however kidney transplant recipients show more profound alterations of the innate immune system and lower anti-spike antibody response.


Subject(s)
COVID-19 , Kidney Transplantation , HLA-DR Antigens , Humans , Kidney Transplantation/adverse effects , Renal Dialysis/adverse effects , SARS-CoV-2 , Transplant Recipients
3.
Nat Immunol ; 23(1): 23-32, 2022 01.
Article in English | MEDLINE | ID: covidwho-1585822

ABSTRACT

Systemic immune cell dynamics during coronavirus disease 2019 (COVID-19) are extensively documented, but these are less well studied in the (upper) respiratory tract, where severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates1-6. Here, we characterized nasal and systemic immune cells in individuals with COVID-19 who were hospitalized or convalescent and compared the immune cells to those seen in healthy donors. We observed increased nasal granulocytes, monocytes, CD11c+ natural killer (NK) cells and CD4+ T effector cells during acute COVID-19. The mucosal proinflammatory populations positively associated with peripheral blood human leukocyte antigen (HLA)-DRlow monocytes, CD38+PD1+CD4+ T effector (Teff) cells and plasmablasts. However, there was no general lymphopenia in nasal mucosa, unlike in peripheral blood. Moreover, nasal neutrophils negatively associated with oxygen saturation levels in blood. Following convalescence, nasal immune cells mostly normalized, except for CD127+ granulocytes and CD38+CD8+ tissue-resident memory T cells (TRM). SARS-CoV-2-specific CD8+ T cells persisted at least 2 months after viral clearance in the nasal mucosa, indicating that COVID-19 has both transient and long-term effects on upper respiratory tract immune responses.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Nasopharynx/immunology , Nose/cytology , Respiratory Mucosa/immunology , SARS-CoV-2/immunology , Antibodies, Viral/blood , COVID-19/immunology , COVID-19/pathology , Granulocytes/immunology , HLA-DR Antigens/metabolism , Humans , Killer Cells, Natural/immunology , Monocytes/immunology , Nasopharynx/cytology , Nasopharynx/virology , Neutrophils/immunology , Nose/immunology , Nose/virology , Prospective Studies , Respiratory Mucosa/cytology , Respiratory Mucosa/virology
4.
J Allergy Clin Immunol ; 149(3): 912-922, 2022 03.
Article in English | MEDLINE | ID: covidwho-1536619

ABSTRACT

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is an acute, febrile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated syndrome, often with cardiohemodynamic dysfunction. Insight into mechanism of disease is still incomplete. OBJECTIVE: Our objective was to analyze immunologic features of MIS-C patients compared to febrile controls (FC). METHODS: MIS-C patients were defined by narrow criteria, including having evidence of cardiohemodynamic involvement and no macrophage activation syndrome. Samples were collected from 8 completely treatment-naive patients with MIS-C (SARS-CoV-2 serology positive), 3 patients with unclassified MIS-C-like disease (serology negative), 14 FC, and 5 MIS-C recovery (RCV). Three healthy controls (HCs) were used for comparisons of normal range. Using spectral flow cytometry, we assessed 36 parameters in antigen-presenting cells (APCs) and 29 in T cells. We used biaxial analysis and uniform manifold approximation and projection (UMAP). RESULTS: Significant elevations in cytokines including CXCL9, M-CSF, and IL-27 were found in MIS-C compared to FC. Classic monocytes and type 2 dendritic cells (DCs) were downregulated (decreased CD86, HLA-DR) versus HCs; however, type 1 DCs (CD11c+CD141+CLEC9A+) were highly activated in MIS-C patients versus FC, expressing higher levels of CD86, CD275, and atypical conventional DC markers such as CD64, CD115, and CX3CR1. CD169 and CD38 were upregulated in multiple monocyte subtypes. CD56dim/CD57-/KLRGhi/CD161+/CD38- natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome. CONCLUSION: Orchestrated by complex cytokine signaling, type 1 DC activation and NK dysregulation are key features in the pathophysiology of MIS-C. NK cell findings may suggest a relationship with macrophage activation syndrome, while type 1 DC upregulation implies a role for antigen cross-presentation.


Subject(s)
COVID-19/complications , Dendritic Cells/immunology , Dendritic Cells/virology , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/virology , ADP-ribosyl Cyclase 1/blood , Adolescent , Antigens, Viral/immunology , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Child , Child, Preschool , Cross-Priming , Cytokines/blood , Dendritic Cells/classification , Female , HLA-DR Antigens/blood , Humans , Immunophenotyping , Interferon-gamma/blood , Interleukins/blood , Killer Cells, Natural/immunology , Male , Membrane Glycoproteins/blood , Models, Immunological , Monocytes/immunology , Sialic Acid Binding Ig-like Lectin 1/blood , T-Lymphocytes/immunology , T-Lymphocytes/virology , Up-Regulation
5.
Elife ; 102021 07 22.
Article in English | MEDLINE | ID: covidwho-1513065

ABSTRACT

Immature neutrophils and HLA-DRneg/low monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored. We found an expansion of circulating immature CD16+CD66b+CD10neg neutrophils and CD14+HLA-DRneg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10neg neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10neg neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4+CD28null T-cells. Notably, the expansion of circulating CD4+CD28null T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools, we identified a tight relationship among the peripheral expansion of immature CD10neg neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10neg neutrophils enhanced IFN-γ production by CD4+ T-cells through a contact-independent mechanism involving IL-12. In vitro experiments also highlighted that HLA-DRneg/low monocytes do not suppress T-cell proliferation but secrete high levels of pro-inflammatory cytokines after differentiation to macrophages and IFN-γ stimulation. Lastly, using a mouse model of AMI, we showed that immature neutrophils (CD11bposLy6GposCD101neg cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion. In conclusion, immunoregulatory functions of CD10neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , HLA-DR Antigens/immunology , Monocytes/immunology , Myocardial Infarction/immunology , Neprilysin/immunology , Neutrophils/immunology , Aged , Animals , Biomarkers , Cell Differentiation , Cell Proliferation , Cytokines , Female , Humans , Inflammation , Lymphocyte Activation , Male , Mice , Middle Aged , Myocardial Infarction/pathology , T-Lymphocytes/immunology
7.
Front Immunol ; 12: 739757, 2021.
Article in English | MEDLINE | ID: covidwho-1505515

ABSTRACT

Coronavirus disease 2019 (COVID-19) exhibits a sex bias with males showing signs of more severe disease and hospitalizations compared with females. The mechanisms are not clear but differential immune responses, particularly the initial innate immune response, between sexes may be playing a role. The early innate immune responses to SARS-CoV-2 have not been studied because of the gap in timing between the patient becoming infected, showing symptoms, and getting the treatment. The primary objective of the present study was to compare the response of dendritic cells (DCs) and monocytes from males and females to SARS-CoV-2, 24 h after infection. To investigate this, peripheral blood mononuclear cells (PBMCs) from healthy young individuals were stimulated in vitro with the virus. Our results indicate that PBMCs from females upregulated the expression of HLA-DR and CD86 on pDCs and mDCs after stimulation with the virus, while the activation of these cells was not significant in males. Monocytes from females also displayed increased activation than males. In addition, females secreted significantly higher levels of IFN-α and IL-29 compared with males at 24 h. However, the situation was reversed at 1 week post stimulation and males displayed high levels of IFN-α production compared with females. Further investigations revealed that the secretion of CXCL-10, a chemokine associated with lung complications, was higher in males than females at 24 h. The PBMCs from females also displayed increased induction of CTLs. Altogether, our results suggest that decreased activation of pDCs, mDCs, and monocytes and the delayed and prolonged IFN-α secretion along with increased CXCL-10 secretion may be responsible for the increased morbidity and mortality of males to COVID-19.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , Leukocytes, Mononuclear/immunology , SARS-CoV-2/physiology , Adaptive Immunity , Adult , Chemokine CXCL1/metabolism , Female , HLA-DR Antigens/metabolism , Healthy Volunteers , Humans , Immunity, Innate , Interferon-gamma/metabolism , Male , Middle Aged , Sex Characteristics , Up-Regulation , Young Adult
8.
EBioMedicine ; 73: 103622, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1471942

ABSTRACT

BACKGROUND: SARS-CoV-2 has been responsible for considerable mortality worldwide, owing in particular to pulmonary failures such as ARDS, but also to other visceral failures and secondary infections. Recent progress in the characterization of the immunological mechanisms that result in severe organ injury led to the emergence of two successive hypotheses simultaneously tested here: hyperinflammation with cytokine storm syndrome or dysregulation of protective immunity resulting in immunosuppression and unrestrained viral dissemination. METHODS: In a prospective observational monocentric study of 134 patients, we analysed a panel of plasma inflammatory and anti-inflammatory cytokines and measured monocyte dysregulation via their membrane expression of HLA-DR. We first compared the results of patients with moderate forms hospitalized in an infectious disease unit with those of patients with severe forms hospitalized in an intensive care unit. In the latter group of patients, we then analysed the differences between the surviving and non-surviving groups and between the groups with or without secondary infections. FINDINGS: Higher blood IL-6 levels, lower quantitative expression of HLA-DR on blood monocytes and higher IL-6/mHLA-DR ratios were statistically associated with the risk of severe forms of the disease and among the latter with death and the early onset of secondary infections. INTERPRETATION: The unique immunological profile in patients with severe COVID-19 corresponds to a moderate cytokine inflammation associated with severe monocyte dysregulation. Individuals with major CSS were rare in our cohort of hospitalized patients, especially since the use of corticosteroids, but formed a very severe subgroup of the disease. FUNDING: None.


Subject(s)
COVID-19/pathology , Cytokines/blood , Monocytes/metabolism , Aged , COVID-19/complications , COVID-19/virology , Cytokine Release Syndrome/etiology , Female , HLA-DR Antigens/metabolism , Humans , Intensive Care Units , Interleukin-6/blood , Male , Middle Aged , Monocytes/cytology , Monocytes/immunology , Prospective Studies , SARS-CoV-2/isolation & purification , Severity of Illness Index
10.
Front Immunol ; 12: 735125, 2021.
Article in English | MEDLINE | ID: covidwho-1441109

ABSTRACT

Background: The global outbreak of coronavirus disease 2019 (COVID-19) has turned into a worldwide public health crisis and caused more than 100,000,000 severe cases. Progressive lymphopenia, especially in T cells, was a prominent clinical feature of severe COVID-19. Activated HLA-DR+CD38+ CD8+ T cells were enriched over a prolonged period from the lymphopenia patients who died from Ebola and influenza infection and in severe patients infected with SARS-CoV-2. However, the CD38+HLA-DR+ CD8+ T population was reported to play contradictory roles in SARS-CoV-2 infection. Methods: A total of 42 COVID-19 patients, including 32 mild or moderate and 10 severe or critical cases, who received care at Beijing Ditan Hospital were recruited into this retrospective study. Blood samples were first collected within 3 days of the hospital admission and once every 3-7 days during hospitalization. The longitudinal flow cytometric data were examined during hospitalization. Moreover, we evaluated serum levels of 45 cytokines/chemokines/growth factors and 14 soluble checkpoints using Luminex multiplex assay longitudinally. Results: We revealed that the HLA-DR+CD38+ CD8+ T population was heterogeneous, and could be divided into two subsets with distinct characteristics: HLA-DR+CD38dim and HLA-DR+CD38hi. We observed a persistent accumulation of HLA-DR+CD38hi CD8+ T cells in severe COVID-19 patients. These HLA-DR+CD38hi CD8+ T cells were in a state of overactivation and consequent dysregulation manifested by expression of multiple inhibitory and stimulatory checkpoints, higher apoptotic sensitivity, impaired killing potential, and more exhausted transcriptional regulation compared to HLA-DR+CD38dim CD8+ T cells. Moreover, the clinical and laboratory data supported that only HLA-DR+CD38hi CD8+ T cells were associated with systemic inflammation, tissue injury, and immune disorders of severe COVID-19 patients. Conclusions: Our findings indicated that HLA-DR+CD38hi CD8+ T cells were correlated with disease severity of COVID-19 rather than HLA-DR+CD38dim population.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immune System Diseases/immunology , SARS-CoV-2 , Adult , Aged , CD8 Antigens/immunology , Cytokines/immunology , Female , HLA-DR Antigens/immunology , Humans , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Young Adult
11.
Front Immunol ; 12: 693269, 2021.
Article in English | MEDLINE | ID: covidwho-1389185

ABSTRACT

Chronic immune activation has been considered as the driving force for CD4+ T cell depletion in people infected with HIV-1. Interestingly, the normal immune profile of adult HIV-negative individuals living in Africa also exhibit chronic immune activation, reminiscent of that observed in HIV-1 infected individuals. It is characterized by increased levels of soluble immune activation markers, such as the cytokines interleukin (IL)-4, IL-10, TNF-α, and cellular activation markers including HLA-DR, CD-38, CCR5, coupled with reduced naïve and increased memory cells in CD4+ and CD8+ subsets. In addition, it is accompanied by low CD4+ T cell counts when compared to Europeans. There is also evidence that mononuclear cells from African infants secrete less innate cytokines than South and North Americans and Europeans in vitro. Chronic immune activation in Africans is linked to environmental factors such as parasitic infections and could be responsible for previously observed immune hypo-responsiveness to infections and vaccines. It is unclear whether the immunogenicity and effectiveness of anti-SARS-CoV-2 vaccines will also be reduced by similar mechanisms. A review of studies investigating this phenomenon is urgently required as they should inform the design and delivery for vaccines to be used in African populations.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Immunogenicity, Vaccine/immunology , Lymphocyte Activation/immunology , SARS-CoV-2/immunology , ADP-ribosyl Cyclase 1/blood , Africa , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/immunology , COVID-19/prevention & control , HLA-DR Antigens/blood , Humans , Interleukin-10/blood , Interleukin-4/blood , Leukocytes, Mononuclear/metabolism , Membrane Glycoproteins/blood , Receptors, CCR5/blood , Tumor Necrosis Factor-alpha/blood
12.
Front Immunol ; 12: 720109, 2021.
Article in English | MEDLINE | ID: covidwho-1348492

ABSTRACT

COVID-19 is a contagious viral disease caused by SARS-CoV-2 that led to an ongoing pandemic with massive global health and socioeconomic consequences. The disease is characterized primarily, but not exclusively, by respiratory clinical manifestations ranging from mild common cold symptoms, including cough and fever, to severe respiratory distress and multi-organ failure. Macrophages, a heterogeneous group of yolk-sac derived, tissue-resident mononuclear phagocytes of complex ontogeny present in all mammalian organs, play critical roles in developmental, homeostatic and host defense processes with tissue-dependent plasticity. In case of infection, they are responsible for early pathogen recognition, initiation and resolution of inflammation, as well as repair of tissue damage. Monocytes, bone-marrow derived blood-resident phagocytes, are recruited under pathological conditions such as viral infections to the affected tissue to defend the organism against invading pathogens and to aid in efficient resolution of inflammation. Given their pivotal function in host defense and the potential danger posed by their dysregulated hyperinflammation, understanding monocyte and macrophage phenotypes in COVID-19 is key for tackling the disease's pathological mechanisms. Here, we outline current knowledge on monocytes and macrophages in homeostasis and viral infections and summarize concepts and key findings on their role in COVID-19. While monocytes in the blood of patients with moderate COVID-19 present with an inflammatory, interferon-stimulated gene (ISG)-driven phenotype, cellular dysfunction epitomized by loss of HLA-DR expression and induction of S100 alarmin expression is their dominant feature in severe disease. Pulmonary macrophages in COVID-19 derived from infiltrating inflammatory monocytes are in a hyperactivated state resulting in a detrimental loop of pro-inflammatory cytokine release and recruitment of cytotoxic effector cells thereby exacerbating tissue damage at the site of infection.


Subject(s)
COVID-19/immunology , HLA-DR Antigens/immunology , Macrophages/immunology , Monocytes/immunology , SARS-CoV-2/immunology , COVID-19/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Macrophages/pathology , Monocytes/pathology , Severity of Illness Index
13.
Sci Immunol ; 6(59)2021 05 25.
Article in English | MEDLINE | ID: covidwho-1337429

ABSTRACT

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vß21.3 T cell receptor ß chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vß21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vß21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/pathology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/pathology , Adult , Child , Child, Preschool , Cytokines/blood , HLA-DR Antigens/immunology , Humans , Lymphocyte Activation/immunology , SARS-CoV-2/immunology
14.
Cell Rep Med ; 2(6): 100291, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1307253

ABSTRACT

Acute respiratory distress syndrome (ARDS) is the main complication of coronavirus disease 2019 (COVID-19), requiring admission to the intensive care unit (ICU). Despite extensive immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS differs from other causes of ARDS remains unknown. To address this question, here, we build 3 cohorts of patients categorized in COVID-19-ARDS+, COVID-19+ARDS+, and COVID-19+ARDS-, and compare, by high-dimensional mass cytometry, their immune landscape. A cell signature associating S100A9/calprotectin-producing CD169+ monocytes, plasmablasts, and Th1 cells is found in COVID-19+ARDS+, unlike COVID-19-ARDS+ patients. Moreover, this signature is essentially shared with COVID-19+ARDS- patients, suggesting that severe COVID-19 patients, whether or not they experience ARDS, display similar immune profiles. We show an increase in CD14+HLA-DRlow and CD14lowCD16+ monocytes correlating to the occurrence of adverse events during the ICU stay. We demonstrate that COVID-19-associated ARDS displays a specific immune profile and may benefit from personalized therapy in addition to standard ARDS management.


Subject(s)
COVID-19/pathology , Leukocytes, Mononuclear/metabolism , Respiratory Distress Syndrome/immunology , Aged , COVID-19/complications , COVID-19/virology , Cohort Studies , Evolution, Molecular , Female , HLA-DR Antigens/metabolism , Humans , Intensive Care Units , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunology , Lipopolysaccharide Receptors/metabolism , Machine Learning , Male , Middle Aged , Monocytes/cytology , Monocytes/immunology , Monocytes/metabolism , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/pathology , SARS-CoV-2/isolation & purification , Sialic Acid Binding Ig-like Lectin 1/metabolism , Th1 Cells/cytology , Th1 Cells/immunology , Th1 Cells/metabolism
15.
Front Immunol ; 12: 625732, 2021.
Article in English | MEDLINE | ID: covidwho-1291351

ABSTRACT

The etiological agent of COVID-19 SARS-CoV-2, is primarily a pulmonary-tropic coronavirus. Infection of alveolar pneumocytes by SARS-CoV-2 requires virus binding to the angiotensin I converting enzyme 2 (ACE2) monocarboxypeptidase. ACE2, present on the surface of many cell types, is known to be a regulator of blood pressure homeostasis through its ability to catalyze the proteolysis of Angiotensin II (Ang II) into Angiotensin-(1-7) [Ang-(1-7)]. We therefore hypothesized that SARS-CoV-2 could trigger variations of ACE2 expression and Ang II plasma concentration in SARS-CoV-2-infected patients. We report here, that circulating blood cells from COVID-19 patients express less ACE2 mRNA than cells from healthy volunteers. At the level of circulating cells, this ACE2 gene dysregulation mainly affects the monocytes, which also show a lower expression of membrane ACE2 protein. Moreover, soluble ACE2 (sACE2) plasma concentrations are lower in prolonged viral shedders than in healthy controls, while the concentration of sACE2 returns to normal levels in short viral shedders. In the plasma of prolonged viral shedders, we also found higher concentrations of Ang II and angiotensin I (Ang I). On the other hand, the plasma levels of Ang-(1-7) remains almost stable in prolonged viral shedders but seems insufficient to prevent the adverse effects of Ang II accumulation. Altogether, these data evidence that the SARS-CoV-2 may affect the expression of blood pressure regulators with possible harmful consequences on COVID-19 outcome.


Subject(s)
Angiotensin II/blood , Angiotensin I/blood , Angiotensin-Converting Enzyme 2/blood , COVID-19/blood , Peptide Fragments/blood , Adult , Angiotensin-Converting Enzyme 2/genetics , COVID-19/virology , Female , Gene Expression Profiling , HLA-DR Antigens , Humans , Lipopolysaccharide Receptors , Male , Middle Aged , Monocytes/immunology , Monocytes/metabolism , Pilot Projects , Prospective Studies , RNA, Messenger , Virus Shedding
16.
J Intern Med ; 290(3): 677-692, 2021 09.
Article in English | MEDLINE | ID: covidwho-1255442

ABSTRACT

BACKGROUND: Prognostic markers for disease severity and identification of therapeutic targets in COVID-19 are urgently needed. We have studied innate and adaptive immunity on protein and transcriptomic level in COVID-19 patients with different disease severity at admission and longitudinally during hospitalization. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected at three time points from 31 patients included in the Norwegian SARS-CoV-2 cohort study and analysed by flow cytometry and RNA sequencing. Patients were grouped as either mild/moderate (n = 14), severe (n = 11) or critical (n = 6) disease in accordance with WHO guidelines and compared with patients with SARS-CoV-2-negative bacterial sepsis (n = 5) and healthy controls (n = 10). RESULTS: COVID-19 severity was characterized by decreased interleukin 7 receptor alpha chain (CD127) expression in naïve CD4 and CD8 T cells. Activation (CD25 and HLA-DR) and exhaustion (PD-1) markers on T cells were increased compared with controls, but comparable between COVID-19 severity groups. Non-classical monocytes and monocytic HLA-DR expression decreased whereas monocytic PD-L1 and CD142 expression increased with COVID-19 severity. RNA sequencing exhibited increased plasma B-cell activity in critical COVID-19 and yet predominantly reduced transcripts related to immune response pathways compared with milder disease. CONCLUSION: Critical COVID-19 seems to be characterized by an immune profile of activated and exhausted T cells and monocytes. This immune phenotype may influence the capacity to mount an efficient T-cell immune response. Plasma B-cell activity and calprotectin were higher in critical COVID-19 while most transcripts related to immune functions were reduced, in particular affecting B cells. The potential of these cells as therapeutic targets in COVID-19 should be further explored.


Subject(s)
COVID-19/genetics , COVID-19/immunology , Leukocytes, Mononuclear/immunology , Transcriptome , Adaptive Immunity , Adult , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Female , HLA-DR Antigens/immunology , Humans , Immunity, Innate , Interleukin-2 Receptor alpha Subunit/immunology , Interleukin-7/immunology , Leukocyte L1 Antigen Complex/blood , Male , Middle Aged , Monocytes/immunology , Phenotype , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes, Regulatory/immunology , Thromboplastin/immunology , Thromboplastin/metabolism
17.
Science ; 372(6548): 1336-1341, 2021 06 18.
Article in English | MEDLINE | ID: covidwho-1234278

ABSTRACT

The identification of CD4+ T cell epitopes is instrumental for the design of subunit vaccines for broad protection against coronaviruses. Here, we demonstrate in COVID-19-recovered individuals a robust CD4+ T cell response to naturally processed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein and nucleoprotein (N), including effector, helper, and memory T cells. By characterizing 2943 S-reactive T cell clones from 34 individuals, we found that the receptor-binding domain (RBD) is highly immunogenic and that 33% of RBD-reactive clones and 94% of individuals recognized a conserved immunodominant S346-S365 region comprising nested human leukocyte antigen DR (HLA-DR)- and HLA-DP-restricted epitopes. Using pre- and post-COVID-19 samples and S proteins from endemic coronaviruses, we identified cross-reactive T cells targeting multiple S protein sites. The immunodominant and cross-reactive epitopes identified can inform vaccination strategies to counteract emerging SARS-CoV-2 variants.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunodominant Epitopes , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Coronavirus/immunology , Cross Reactions , Epitopes, T-Lymphocyte/immunology , Genes, T-Cell Receptor beta , HLA-DP Antigens/immunology , HLA-DR Antigens/immunology , Humans , Immunologic Memory , Nucleocapsid Proteins/immunology , Protein Domains , Receptors, Antigen, T-Cell, alpha-beta/immunology , Spike Glycoprotein, Coronavirus/chemistry , T Follicular Helper Cells/immunology , T-Lymphocyte Subsets/immunology
18.
Front Immunol ; 12: 645124, 2021.
Article in English | MEDLINE | ID: covidwho-1201169

ABSTRACT

Background: The major histocompatibility complex (MHC) class II characterized by monocytes CD14+ expression of human leukocyte antigen receptors (HLA-DR), is essential for the synapse between innate and adaptive immune response in infectious disease. Its reduced expression is associated with a high risk of secondary infections in septic patients and can be safely corrected by Interferon-y (IFNy) injection. Coronavirus disease (COVID-19) induces an alteration of Interferon (IFN) genes expression potentially responsible for the observed low HLA-DR expression in circulating monocytes (mHLA-DR). Methods: We report a case of one-time INFy injection (100 mcg s.c.) in a superinfected 61-year-old man with COVID-19-associated acute respiratory distress syndrome (ARDS), with monitoring of mHLA-DR expression and clinical tolerance. Observations: Low mHLA-DR pretreatment expression (26.7%) was observed. IFNy therapy leading to a rapid increase in mHLA-DR expression (83.1%). Conclusions: Severe ARDS in a COVID-19 patient has a deep reduction in mHLA-DR expression concomitantly with secondary infections. The unique IFNy injection was safe and led to a sharp increase in the expression of mHLA-DR. Based on immune and infection monitoring, more cases of severe COVID-19 patients with low mHLA-DR should be treated by IFNy to test the clinical effectiveness.


Subject(s)
Acquired Immunodeficiency Syndrome , COVID-19 , HLA-DR Antigens/immunology , Interferon-gamma/administration & dosage , Monocytes/immunology , SARS-CoV-2/immunology , Severity of Illness Index , Acquired Immunodeficiency Syndrome/drug therapy , Acquired Immunodeficiency Syndrome/immunology , Acquired Immunodeficiency Syndrome/pathology , COVID-19/drug therapy , COVID-19/immunology , COVID-19/pathology , Humans , Male , Middle Aged , Monocytes/pathology
19.
J Med Virol ; 93(2): 760-765, 2021 02.
Article in English | MEDLINE | ID: covidwho-1196398

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 emerged in China in December 2019 and then rapidly spread worldwide. Why COVID-19 patients with the same clinical condition have different outcomes remains unclear. This study aimed to examine the differences in the phenotype and functions of major populations of immune cells between COVID-19 patients with same severity but different outcomes. Four common type adult inpatients with laboratory confirmed COVID-19 from Beijing YouAn Hospital, Capital Medical University were included in this study. The patients were divided into two groups based on whether or not COVID-19 polymerase chain reaction (PCR)-negative conversion occurred within 3 weeks. Peripheral blood samples were collected to compare the differences in the phenotype and functions of major populations of immune cells between the two groups of patients. The result shows that the proportions of CD3+ CD8+ CD38+ HLA-DR+ CD27- effector T killer cells generally declined, whereas that of CD3+ CD4+ CD8+ double-positive T cells (DPTs) increased in the persistently PCR-positive patients. In summary, considering the imbalance between effector T killer cells/CD3+CD4+CD8+ DPTs was a possible key factor for PCR-negative conversion in patients with COVID-19.


Subject(s)
Biological Variation, Individual , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/pathology , Natural Killer T-Cells/immunology , SARS-CoV-2/pathogenicity , Adult , Aged , Antigens, CD/genetics , Antigens, CD/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/virology , COVID-19/immunology , COVID-19/virology , COVID-19 Testing , Female , Gene Expression , HLA-DR Antigens/genetics , HLA-DR Antigens/immunology , Humans , Immunity, Innate , Immunophenotyping , Lymphocyte Count , Male , Middle Aged , Natural Killer T-Cells/virology , Phenotype , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , Severity of Illness Index
20.
J Infect Dis ; 225(7): 1162-1167, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1155787

ABSTRACT

This study evaluated the impact of human immunodeficiency virus (HIV) and combination antiretroviral therapy (cART) on immune activation during pregnancy in a Zambian cohort of HIV-exposed but uninfected children followed up from birth. Activated CD8+ T cells (CD38+ and HLA-DR+) were compared among HIV-uninfected (n = 95), cART experienced HIV-infected (n = 111), and cART-naive HIV-infected (n = 21) pregnant women. Immune activation was highest among HIV-infected/cART-naive women but decreased during pregnancy. Immune activation HIV-infected women who started cART during pregnancy was reduced but not to levels similar to those in HIV-uninfected women. The effects of elevated maternal immune activation in pregnancy on subsequent infant health and immunity remain to be determined.


Subject(s)
Antiretroviral Therapy, Highly Active , HIV Infections , Female , HIV , HIV Infections/drug therapy , HLA-DR Antigens , Humans , Infant , Infant, Newborn , Pregnancy , Pregnant Women
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