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1.
J Allergy Clin Immunol ; 149(2): 557-561.e1, 2022 02.
Article in English | MEDLINE | ID: covidwho-1670624

ABSTRACT

BACKGROUND: Patients with some types of immunodeficiency can experience chronic or relapsing infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This leads to morbidity and mortality, infection control challenges, and the risk of evolution of novel viral variants. The optimal treatment for chronic coronavirus disease 2019 (COVID-19) is unknown. OBJECTIVE: Our aim was to characterize a cohort of patients with chronic or relapsing COVID-19 disease and record treatment response. METHODS: We conducted a UK physician survey to collect data on underlying diagnosis and demographics, clinical features, and treatment response of immunodeficient patients with chronic (lasting ≥21 days) or relapsing (≥2 episodes) of COVID-19. RESULTS: We identified 31 patients (median age 49 years). Their underlying immunodeficiency was most commonly characterized by antibody deficiency with absent or profoundly reduced peripheral B-cell levels; prior anti-CD20 therapy, and X-linked agammaglobulinemia. Their clinical features of COVID-19 were similar to those of the general population, but their median duration of symptomatic disease was 64 days (maximum 300 days) and individual patients experienced up to 5 episodes of illness. Remdesivir monotherapy (including when given for prolonged courses of ≤20 days) was associated with sustained viral clearance in 7 of 23 clinical episodes (30.4%), whereas the combination of remdesivir with convalescent plasma or anti-SARS-CoV-2 mAbs resulted in viral clearance in 13 of 14 episodes (92.8%). Patients receiving no therapy did not clear SARS-CoV-2. CONCLUSIONS: COVID-19 can present as a chronic or relapsing disease in patients with antibody deficiency. Remdesivir monotherapy is frequently associated with treatment failure, but the combination of remdesivir with antibody-based therapeutics holds promise.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/therapy , Immunologic Deficiency Syndromes/therapy , SARS-CoV-2/drug effects , Adenosine Monophosphate/therapeutic use , Adult , Aged , Aged, 80 and over , Alanine/therapeutic use , B-Lymphocytes/immunology , B-Lymphocytes/pathology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Chronic Disease , Female , Humans , Immunization, Passive , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/pathology , Immunologic Deficiency Syndromes/virology , Lymphocyte Count , Male , Middle Aged , Recombinant Fusion Proteins/administration & dosage , Recurrence , SARS-CoV-2/pathogenicity , Treatment Failure
2.
Int J Mol Sci ; 22(22)2021 Nov 21.
Article in English | MEDLINE | ID: covidwho-1524028

ABSTRACT

Aging is characterized by the dynamic remodeling of the immune system designated "immunosenescence," and is associated with altered hematopoiesis, thymic involution, and lifelong immune stimulation by multitudinous chronic stressors, including the cytomegalovirus (CMV). Such alterations may contribute to a lowered proportion of naïve T-cells and to reduced diversity of the T-cell repertoire. In the peripheral circulation, a shift occurs towards accumulations of T and B-cell populations with memory phenotypes, and to accumulation of putatively senescent and exhausted immune cells. The aging-related accumulations of functionally exhausted memory T lymphocytes, commonly secreting pro-inflammatory cytokines, together with mediators and factors of the innate immune system, are considered to contribute to the low-grade inflammation (inflammaging) often observed in elderly people. These senescent immune cells not only secrete inflammatory mediators, but are also able to negatively modulate their environments. In this review, we give a short summary of the ways that immunosenescence, inflammaging, and CMV infection may cause insufficient immune responses, contribute to the establishment of the hyperinflammatory syndrome and impact the severity of the coronavirus disease 2019 (COVID-19) in elderly people.


Subject(s)
COVID-19/pathology , Aging , B-Lymphocytes/pathology , COVID-19/complications , COVID-19/virology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/pathology , Cytomegalovirus/isolation & purification , Cytomegalovirus Infections/pathology , Cytomegalovirus Infections/virology , Humans , SARS-CoV-2/isolation & purification , T-Lymphocytes/pathology
3.
Int J Mol Sci ; 22(21)2021 Oct 30.
Article in English | MEDLINE | ID: covidwho-1512378

ABSTRACT

Autoimmune epithelitis and chronic inflammation are one of the characteristic features of the immune pathogenesis of Sjögren's syndrome (SS)-related dry eye disease. Autoimmune epithelitis can cause the dysfunction of the excretion of tear fluid and mucin from the lacrimal glands and conjunctival epithelia and meibum from the meibomian glands. The lacrimal gland and conjunctival epithelia express major histocompatibility complex class II or human leukocyte antigen-DR and costimulatory molecules, acting as nonprofessional antigen-presenting cells for T cell and B cell activation in SS. Ocular surface epithelium dysfunction can lead to dry eye disease in SS. Considering the mechanisms underlying SS-related dry eye disease, this review highlights autoimmune epithelitis of the ocular surface, chronic inflammation, and several other molecules in the tear film, cornea, conjunctiva, lacrimal glands, and meibomian glands that represent potential targets in the treatment of SS-related dry eye disease.


Subject(s)
B-Lymphocytes/immunology , Conjunctiva/immunology , Lacrimal Apparatus/immunology , Lymphocyte Activation , Meibomian Glands/immunology , Sjogren's Syndrome/immunology , T-Lymphocytes/immunology , B-Lymphocytes/pathology , Chronic Disease , Conjunctiva/pathology , Humans , Lacrimal Apparatus/pathology , Meibomian Glands/pathology , Mucins/immunology , Sjogren's Syndrome/pathology , T-Lymphocytes/pathology
4.
Sci Immunol ; 6(65): eabk1741, 2021 Nov 12.
Article in English | MEDLINE | ID: covidwho-1443345

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) pneumonia survivors often exhibit long-term pulmonary sequelae, but the underlying mechanisms or associated local and systemic immune correlates are not known. Here, we have performed high-dimensional characterization of the pathophysiological and immune traits of aged COVID-19 convalescents, and correlated the local and systemic immune profiles with pulmonary function and lung imaging. We found that chronic lung impairment was accompanied by persistent respiratory immune alterations. We showed that functional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)­specific memory T and B cells were enriched at the site of infection compared with those of blood. Detailed evaluation of the lung immune compartment revealed that dysregulated respiratory CD8+ T cell responses were associated with the impaired lung function after acute COVID-19. Single-cell transcriptomic analysis identified the potential pathogenic subsets of respiratory CD8+ T cells contributing to persistent tissue conditions after COVID-19. Our results have revealed pathophysiological and immune traits that may support the development of lung sequelae after SARS-CoV-2 pneumonia in older individuals, with implications for the treatment of chronic COVID-19 symptoms.


Subject(s)
B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/microbiology , Immunologic Memory , Lung/immunology , SARS-CoV-2/immunology , B-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Female , Humans , Lung/pathology , Lung/virology , Male , Middle Aged
5.
Pathol Res Pract ; 225: 153552, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1440296

ABSTRACT

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by severe vascular remodelling, resulting in increased pulmonary vascular resistance with cardiac hypertrophy and heart failure. However, the diagnosis of PAH is often inaccurate. Many cases of PAH are incorrectly diagnosed or missed, and they are often associated with death. The aim of this study was to verify the morphological and histological criteria of fatal cases of PAH and evaluate the lymphocytic populations associated to lesions with reactive neo-angiogenesis. METHODS: Pulmonary lung sections from 10 cases of sudden unexpected death (SUD) in the absence of previously diagnosed diseases and in an apparent state of well-being, with final histological post autopsy diagnosis of PAH were collected. The pathological findings were compared using ten controls from non-pathological lung from deaths from other causes. The autopsies included 4 males (40%) and 6 females (60%) with an average age of 52.1 ± 10.1 years. Sections stained with hematoxylin and eosin (H&E) were revised for a morphological diagnosis. Subsequently, serial sections were performed and stained with immunohistochemistry for anti-CD20 (B-lymphocytes), anti-CD3 (T-lymphocytes), anti-CD4 (T-helper lumphocytes), anti-CD8 (T-cytotoxic lymphocytes) and anti-CD117/C-Kit (mast cells/MCs) to detect inflammatory infiltrate and different ratios of cell-type. Statistical analysis was conducted using a paired t-test looking at 100 cells in 3 different tissue samples representative of vascular lesion and 3 different random normal lung parenchyma fields without lesion (from 10 normal control lungs), to identify specific lymphocyte subpopulations in inflammatory infiltrates. RESULTS: There was a significant percentage increase of CD20 (p < 0.001), CD8 (p = 0.002), CD4 (p < 0.001), and CD117/C-Kit positive (C-Kit+; p < 0.001) cells mainly detected around wall vessels; while increased MCs positivity and C-Kit+ were observed especially in alveolar septa. In addition, reactive angiomatosis was observed. CONCLUSIONS: The inflammatory infiltrate should be included for a correct diagnosis of PAH besides the vascular remodelling. The inflammatory infiltrate seems to be implicated as a main factor in the pathogenesis. This finding is important to rule out secondary pulmonary hypertension, to identify SUDs of unknown causes and to add new elements to the literature that can explain the immunologically related pathogenesis of PAH.


Subject(s)
B-Lymphocytes/pathology , Lung/pathology , Mast Cells/pathology , Pulmonary Arterial Hypertension/pathology , T-Lymphocytes/pathology , Adult , Autopsy , Female , Humans , Male , Middle Aged
6.
Nat Commun ; 12(1): 3501, 2021 06 09.
Article in English | MEDLINE | ID: covidwho-1263489

ABSTRACT

The characteristics of COVID-19 patients with persistent SARS-CoV-2 infection are not yet well described. Here, we compare the clinical and molecular features of patients with long duration of viral shedding (LDs) with those from patients with short duration patients (SDs), and healthy donors (HDs). We find that several cytokines and chemokines, such as interleukin (IL)-2, tumor necrosis factor (TNF) and lymphotoxin α (LT-α) are present at lower levels in LDs than SDs. Single-cell RNA sequencing shows that natural killer (NK) cells and CD14+ monocytes are reduced, while regulatory T cells are increased in LDs; moreover, T and NK cells in LDs are less activated than in SDs. Importantly, most cells in LDs show reduced expression of ribosomal protein (RP) genes and related pathways, with this inversed correlation between RP levels and infection duration further validated in 103 independent patients. Our results thus indicate that immunosuppression and low RP expression may be related to the persistence of the viral infection in COVID-19 patients.


Subject(s)
COVID-19/immunology , SARS-CoV-2/pathogenicity , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , COVID-19/virology , Cytokines/blood , Gene Expression Profiling , Humans , Killer Cells, Natural/metabolism , Killer Cells, Natural/pathology , Leukocytes, Mononuclear/pathology , Lymphocyte Activation/genetics , Lymphocyte Subsets/metabolism , Lymphocyte Subsets/pathology , Ribosomal Proteins/genetics , SARS-CoV-2/isolation & purification , Signal Transduction/genetics , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Virus Shedding
8.
Viruses ; 13(6)2021 05 21.
Article in English | MEDLINE | ID: covidwho-1244141

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) predominantly have a respiratory tract infection with various symptoms and high mortality is associated with respiratory failure second to severe disease. The risk factors leading to severe disease remain unclear. Here, we reanalyzed a published single-cell RNA-Seq (scRNA-Seq) dataset and found that bronchoalveolar lavage fluid (BALF) of patients with severe disease compared to those with mild disease contained decreased TH17-type cells, decreased IFNA1-expressing cells with lower expression of toll-like receptor 7 (TLR7) and TLR8, increased IgA-expressing B cells, and increased hyperactive epithelial cells (and/or macrophages) expressing matrix metalloproteinases (MMPs), hyaluronan synthase 2 (HAS2), and plasminogen activator inhibitor-1 (PAI-1), which may together contribute to the pulmonary pathology in severe COVID-19. We propose IFN-I (and TLR7/TLR8) and PAI-1 as potential biomarkers to predict the susceptibility to severe COVID-19.


Subject(s)
COVID-19/pathology , Lung/pathology , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Biomarkers/metabolism , Bronchoalveolar Lavage Fluid/immunology , COVID-19/immunology , COVID-19/metabolism , Databases, Genetic , Humans , Hyaluronan Synthases/metabolism , Immunoglobulin A/metabolism , Interferon-alpha/metabolism , Lung/immunology , Lung/metabolism , Matrix Metalloproteinases/metabolism , Mucin-1/metabolism , Plasminogen Activator Inhibitor 1/metabolism , RNA-Seq , SARS-CoV-2 , Th17 Cells/metabolism , Th17 Cells/pathology
10.
Signal Transduct Target Ther ; 6(1): 195, 2021 05 17.
Article in English | MEDLINE | ID: covidwho-1232065

ABSTRACT

B cell response plays a critical role against SARS-CoV-2 infection. However, little is known about the diversity and frequency of the paired SARS-CoV-2 antigen-specific BCR repertoire after SARS-CoV-2 infection. Here, we performed single-cell RNA sequencing and VDJ sequencing using the memory and plasma B cells isolated from five convalescent COVID-19 patients, and analyzed the spectrum and transcriptional heterogeneity of antibody immune responses. Via linking BCR to antigen specificity through sequencing (LIBRA-seq), we identified a distinct activated memory B cell subgroup (CD11chigh CD95high) had a higher proportion of SARS-CoV-2 antigen-labeled cells compared with memory B cells. Our results revealed the diversity of paired BCR repertoire and the non-stochastic pairing of SARS-CoV-2 antigen-specific immunoglobulin heavy and light chains after SARS-CoV-2 infection. The public antibody clonotypes were shared by distinct convalescent individuals. Moreover, several antibodies isolated by LIBRA-seq showed high binding affinity against SARS-CoV-2 receptor-binding domain (RBD) or nucleoprotein (NP) via ELISA assay. Two RBD-reactive antibodies C14646P3S and C2767P3S isolated by LIBRA-seq exhibited high neutralizing activities against both pseudotyped and authentic SARS-CoV-2 viruses in vitro. Our study provides fundamental insights into B cell response following SARS-CoV-2 infection at the single-cell level.


Subject(s)
B-Lymphocytes/immunology , COVID-19/immunology , Convalescence , Immunologic Memory , RNA-Seq , SARS-CoV-2/immunology , Animals , B-Lymphocytes/pathology , COVID-19/genetics , COVID-19/pathology , Cell Line, Tumor , Cell Separation , Chlorocebus aethiops , HEK293 Cells , Humans , SARS-CoV-2/genetics , Vero Cells
11.
Eur J Immunol ; 51(6): 1449-1460, 2021 06.
Article in English | MEDLINE | ID: covidwho-1159935

ABSTRACT

The pathogenesis of autoimmune complications triggered by SARS-CoV2 has not been completely elucidated. Here, we performed an analysis of the cellular immune status, cell ratios, and monocyte populations of patients with COVID-19 treated in the intensive care unit (ICU) (cohort 1, N = 23) and normal care unit (NCU) (cohort 2, n = 10) compared with control groups: patients treated in ICU for noninfectious reasons (cohort 3, n = 30) and patients treated in NCU for infections other than COVID-19 (cohort 4, n = 21). Patients in cohort 1 presented significant differences in comparison with the other cohorts, including reduced frequencies of lymphocytes, reduced CD8+T-cell count, reduced percentage of activated and intermediate monocytes and an increased B/T8 cell ratio. Over time, patients in cohort 1 who died presented with lower counts of B, T, CD4+ T, CD8+ T-lymphocytes, NK cells, and activated monocytes. The B/T8 ratio was significantly lower in the group of survivors. In cohort 1, significantly higher levels of IgG1 and IgG3 were found, whereas cohort 3 presented higher levels of IgG3 compared to controls. Among many immune changes, an elevated B/T8-cell ratio and a reduced rate of activated monocytes were mainly observed in patients with severe COVID-19. Both parameters were associated with death in cohort 1.


Subject(s)
B-Lymphocytes/immunology , COVID-19/immunology , Monocytes/immunology , SARS-CoV-2/immunology , Aged , Antibodies, Viral/immunology , B-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Female , Humans , Immunoglobulin G/immunology , Lymphocyte Count , Male , Middle Aged , Monocytes/pathology , Prospective Studies , Severity of Illness Index
12.
Signal Transduct Target Ther ; 6(1): 113, 2021 03 08.
Article in English | MEDLINE | ID: covidwho-1123128

ABSTRACT

The adaptive immunity that protects patients from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not well characterized. In particular, the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses, but the underlying mechanisms remain unknown; meanwhile, the protective immunity that guide the recovery of these asymptomatic patients is elusive. Here, we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity (mild, n = 10, moderate, n = 32, severe, n = 12) and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center (GC) B cell responses that result in robust and prolonged humoral immunity, assessed by GC response indicators including follicular helper T (TFH) cell and memory B cell responses as well as serum CXCL13 levels. Alternatively, these patients mounted potent virus-specific TH1 and CD8+ T cell responses. In sharp contrast, patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated TFH responses; however, the virus-specific TH1 and CD8+ T cells were minimally induced in these patients. These results, therefore, uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity, providing important insights into rational design of effective COVID-19 vaccines.


Subject(s)
Adaptive Immunity , B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Th1 Cells/immunology , Adult , B-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Female , Humans , Male , Severity of Illness Index , Th1 Cells/pathology
13.
J Virol ; 95(9)2021 04 12.
Article in English | MEDLINE | ID: covidwho-1102152

ABSTRACT

Current influenza vaccines, live attenuated or inactivated, do not protect against antigenically novel influenza A viruses (IAVs) of pandemic potential, which has driven interest in the development of universal influenza vaccines. Universal influenza vaccine candidates targeting highly conserved antigens of IAV nucleoprotein (NP) are promising as vaccines that induce T cell immunity, but concerns have been raised about the safety of inducing robust CD8 T cell responses in the lungs. Using a mouse model, we systematically evaluated effects of recombinant adenovirus vectors (rAd) expressing IAV NP (A/NP-rAd) or influenza B virus (IBV) NP (B/NP-rAd) on pulmonary inflammation and function after vaccination and following live IAV challenge. After A/NP-rAd or B/NP-rAd vaccination, female mice exhibited robust systemic and pulmonary vaccine-specific B cell and T cell responses and experienced no morbidity (e.g., body mass loss). Both in vivo pulmonary function testing and lung histopathology scoring revealed minimal adverse effects of intranasal rAd vaccination compared with unvaccinated mice. After IAV challenge, A/NP-rAd-vaccinated mice experienced significantly less morbidity, had lower pulmonary virus titers, and developed less pulmonary inflammation than unvaccinated or B/NP-rAd-vaccinated mice. Based on analysis of pulmonary physiology using detailed testing not previously applied to the question of T cell damage, mice protected by vaccination also had better lung function than controls. Results provide evidence that, in this model, adenoviral universal influenza vaccine does not damage pulmonary tissue. In addition, adaptive immunity, in particular, T cell immunity in the lungs, does not cause damage when restimulated but instead mitigates pulmonary damage following IAV infection.IMPORTANCE Respiratory viruses can emerge and spread rapidly before vaccines are available. It would be a tremendous advance to use vaccines that protect against whole categories of viruses, such as universal influenza vaccines, without the need to predict which virus will emerge. The nucleoprotein (NP) of influenza virus provides a target conserved among strains and is a dominant T cell target. In animals, vaccination to NP generates powerful T cell immunity and long-lasting protection against diverse influenza strains. Concerns have been raised, but not evaluated experimentally, that potent local T cell responses might damage the lungs. We analyzed lung function in detail in the setting of such a vaccination. Despite CD8 T cell responses in the lungs, lungs were not damaged and functioned normally after vaccination alone and were protected upon subsequent infection. This precedent provides important support for vaccines based on T cell-mediated protection, currently being considered for both influenza and SARS-CoV-2 vaccines.


Subject(s)
Adenoviridae , Genetic Vectors , Influenza B virus , Influenza Vaccines , Lung , Orthomyxoviridae Infections , Adenoviridae/genetics , Adenoviridae/immunology , Animals , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Disease Models, Animal , Female , Genetic Vectors/genetics , Genetic Vectors/immunology , Immunity, Cellular , Influenza B virus/genetics , Influenza B virus/immunology , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Lung/immunology , Lung/pathology , Lung/virology , Mice , Orthomyxoviridae Infections/genetics , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/prevention & control , T-Lymphocytes/immunology , T-Lymphocytes/pathology
14.
Virology ; 556: 79-86, 2021 04.
Article in English | MEDLINE | ID: covidwho-1065650

ABSTRACT

Infection with SARS-COV-2 may result in severe pneumonia potentially leading to mechanical ventilation and intensive care treatment. The aim of the present study was to analyze the immune responses in critically ill coronavirus 2019 (COVID-19) patients requiring mechanical ventilation and assess their potential use as markers of clinical progression and outcome. Confirmed COVID-19 patients were grouped into those requiring mechanical ventilation (intubated) and non-intubated. Immune phenotyping was performed and cytokine levels were determined. A novel ratio of CD8+:B cells was significantly lower in intubated versus non-intubated (p = 0.015) and intubated non-survivors (NSV) versus survivors (SV) (p = 0.015). The same ratio correlated with outcome, CRP, IL-6 levels and neutrophil count. Receiving operating curve (ROC) analysis for prediction of requirement of mechanical ventilation by the CD8+:B cells ratio revealed an AUC of 0.747 and a p = 0.007. The ratio of CD8+:B cells may serve as a useful prognostic marker for disease severity and outcome.


Subject(s)
B-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/pathology , COVID-19/immunology , Aged , Biomarkers/blood , COVID-19/pathology , COVID-19/therapy , Critical Illness , Cytokines/blood , Female , Humans , Immunophenotyping , Lymphocyte Count , Male , Middle Aged , Prognosis , Respiration, Artificial , SARS-CoV-2 , Treatment Outcome
16.
Nature ; 590(7844): 29-31, 2021 02.
Article in English | MEDLINE | ID: covidwho-1038200
17.
J Clin Invest ; 131(1)2021 01 04.
Article in English | MEDLINE | ID: covidwho-1011051

ABSTRACT

SARS-CoV-2 causes a wide spectrum of clinical manifestations and significant mortality. Studies investigating underlying immune characteristics are needed to understand disease pathogenesis and inform vaccine design. In this study, we examined immune cell subsets in hospitalized and nonhospitalized individuals. In hospitalized patients, many adaptive and innate immune cells were decreased in frequency compared with those of healthy and convalescent individuals, with the exception of an increase in B lymphocytes. Our findings show increased frequencies of T cell activation markers (CD69, OX40, HLA-DR, and CD154) in hospitalized patients, with other T cell activation/exhaustion markers (PD-L1 and TIGIT) remaining elevated in hospitalized and nonhospitalized individuals. B cells had a similar pattern of activation/exhaustion, with increased frequency of CD69 and CD95 during hospitalization followed by an increase in PD1 frequencies in nonhospitalized individuals. Interestingly, many of these changes were found to increase over time in nonhospitalized longitudinal samples, suggesting a prolonged period of immune dysregulation after SARS-CoV-2 infection. Changes in T cell activation/exhaustion in nonhospitalized patients were found to positively correlate with age. Severely infected individuals had increased expression of activation and exhaustion markers. These data suggest a prolonged period of immune dysregulation after SARS-CoV-2 infection, highlighting the need for additional studies investigating immune dysregulation in convalescent individuals.


Subject(s)
Antigens, Differentiation/immunology , B-Lymphocytes/immunology , COVID-19/immunology , Lymphocyte Activation , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adult , Aged , Aged, 80 and over , B-Lymphocytes/pathology , COVID-19/pathology , Female , Humans , Male , Middle Aged , T-Lymphocytes/pathology
18.
J Clin Invest ; 130(12): 6409-6416, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1011054

ABSTRACT

BACKGROUNDPatients with coronavirus disease 2019 (COVID-19) develop pneumonia generally associated with lymphopenia and a severe inflammatory response due to uncontrolled cytokine release. These mediators are transcriptionally regulated by the JAK/STAT signaling pathways, which can be disabled by small molecules.METHODSWe treated a group of patients (n = 20) with baricitinib according to an off-label use of the drug. The study was designed as an observational, longitudinal trial and approved by the local ethics committee. The patients were treated with 4 mg baricitinib twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of phosphorylated STAT3 (p-STAT3) in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies against severe acute respiratory syndrome-coronavirus 2 (anti-SARS-CoV-2). In a single treated patient, we also evaluated the alteration of myeloid cell functional activity.RESULTSWe provide evidence that patients treated with baricitinib had a marked reduction in serum levels of IL-6, IL-1ß, and TNF-α, a rapid recovery of circulating T and B cell frequencies, and increased antibody production against the SARS-CoV-2 spike protein, all of which were clinically associated with a reduction in the need for oxygen therapy and a progressive increase in the P/F (PaO2, oxygen partial pressure/FiO2, fraction of inspired oxygen) ratio.CONCLUSIONThese data suggest that baricitinib prevented the progression to a severe, extreme form of the viral disease by modulating the patients' immune landscape and that these changes were associated with a safer, more favorable clinical outcome for patients with COVID-19 pneumonia.TRIAL REGISTRATIONClinicalTrials.gov NCT04438629.FUNDINGThis work was supported by the Fondazione Cariverona (ENACT Project) and the Fondazione TIM.


Subject(s)
Azetidines/administration & dosage , COVID-19 , Off-Label Use , Purines/administration & dosage , Pyrazoles/administration & dosage , SARS-CoV-2 , Sulfonamides/administration & dosage , Aged , Aged, 80 and over , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , COVID-19/blood , COVID-19/drug therapy , COVID-19/immunology , COVID-19/pathology , Cytokines/blood , Cytokines/immunology , Female , Humans , Longitudinal Studies , Male , Middle Aged , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology
19.
Front Immunol ; 11: 607069, 2020.
Article in English | MEDLINE | ID: covidwho-993358

ABSTRACT

Upon recognition of microbial DNA or self-DNA, the cyclic-GMP-AMP synthase (cGAS) of the host catalyzes the production of the cyclic dinucleotide cGAMP. cGAMP is the main activator of STING, stimulator of interferon genes, leading to interferon synthesis through the STING-TBK1-IRF3 pathway. STING is also a hub for activation of NF-κB and autophagy. The present review details the striking similarities between T and B cell responses in severe coronavirus disease 2019 (COVID-19) and both animal or human models of STING gain of function (SAVI syndromes: STING-associated vasculopathy with onset in infancy). Those similarities may be further clues for a delayed activation of STING in severe COVID-19 patients, due to DNA damages following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection and unusual role of STING in SARS-CoV-2 control. In early stages, Th2 differentiation are noticed in both severe COVID-19 and SAVI syndromes; then, CD4+ and CD8+ T cells functional exhaustion/senescent patterns due to TCR hyper-responsiveness are observed. T cell delayed over-responses can contribute to pneumonitis and delayed cytokine secretion with over-production of IL-6. Last, STING over-activation induces progressive CD4+ and CD8+ T lymphopenia in SAVI syndromes, which parallels what is observed in severe COVID-19. ACE2, the main receptor of SARS-CoV-2, is rarely expressed in immune cells, and it has not been yet proven that some human lymphocytes could be infected by SARS-CoV-2 through CD147 or CD26. However, STING, expressed in humans T cells, might be triggered following excessive transfer of cGAMP from infected antigen presenting cells into activated CD4+ and CD8+ T cells lymphocytes. Indeed, those lymphocytes highly express the cGAMP importer SLC19A1. Whereas STING is not expressed in human B cells, B cells counts are much less affected, either in COVID-19 or SAVI syndromes. The recognition of delayed STING over-activation in severe COVID-19 patients could prompt to target STING with specific small molecules inhibitors already designed and/or aspirin, which inhibits cGAS.


Subject(s)
B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Membrane Proteins/immunology , SARS-CoV-2/immunology , Th2 Cells/immunology , Angiotensin-Converting Enzyme 2/immunology , Animals , B-Lymphocytes/pathology , Basigin/immunology , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Dipeptidyl Peptidase 4/immunology , Humans , Interferon Regulatory Factor-3/immunology , Nucleotidyltransferases/immunology , Signal Transduction/immunology , Th2 Cells/pathology
20.
Blood ; 136(20): 2290-2295, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-950941

ABSTRACT

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti-SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/pathology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Immune Sera/administration & dosage , Lymphopenia/therapy , Pneumonia, Viral/immunology , Adult , Aged , B-Lymphocytes/immunology , Blood Component Transfusion , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/therapy , Coronavirus Infections/virology , Female , France , Hematologic Neoplasms/complications , Humans , Immunization, Passive , Lymphopenia/etiology , Lymphopenia/pathology , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , SARS-CoV-2
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