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Due to its stimulatory potential for immunomodulatory CD4+ regulatory T (Treg) cells, low-dose interleukin-2 (IL-2) immunotherapy has gained considerable attention for the treatment of autoimmune diseases. In this investigator-initiated single-arm non-placebo-controlled phase-2 clinical trial of low-dose IL-2 immunotherapy in systemic lupus erythematosus (SLE) patients, we generated a comprehensive atlas of in vivo human immune responses to low-dose IL-2. We performed an in-depth study of circulating and cutaneous immune cells by imaging mass cytometry, high-parameter flow cytometry, transcriptomics, and targeted serum proteomics. Low-dose IL-2 stimulated various circulating immune cells, including Treg cells with a skin-homing phenotype that appeared in the skin of SLE patients in close interaction with endothelial cells. Analysis of surface proteins and transcriptomes revealed different IL-2-driven Treg cell activation programs, including gut-homing CD38+, skin-homing HLA-DR+, and highly proliferative inflammation-homing CD38+ HLA-DR+ Treg cells. Collectively, these data define the distinct human Treg cell subsets that are responsive to IL-2 immunotherapy.
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Mn or Co supported CeO2 fiber catalysts were synthesized following a biotemplating route and evaluated in soot combustion and benzene total oxidation. The catalysts were characterized by SEM, EDX, N2 physisorption, FTIR-ATR, XRD, RAMAN and XPS. SEM results confirmed that the "twisted ribbon" morphology of the biotemplate was mostly maintained. XRD and Raman showed that Mn and Co cations partially insert into ceria lattice and also segregate at the surface of the fibers. XPS allowed to determine that both set of catalysts exhibit Ce3+ and Ce4+ species, in addition to adsorbed and lattice oxygen. Also, the average oxidation state (AOS) of surface Mn could be calculated. Compared to bare Fib Ce, the performances for both reactions were improved for the supported catalysts, except from the catalyst with lowest Mn content for soot combustion. The catalytic activity was discussed in terms of the physicochemical features of the supported catalysts.
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Benzeno , Cério , Cobalto , Manganês , Oxirredução , Fuligem , Cério/química , Benzeno/química , Catálise , Manganês/química , Cobalto/química , Fuligem/químicaRESUMO
Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome coronavirus 2 infection. Analysis of >6500 proteins in 268 longitudinal samples revealed dysregulated activation of the complement system, an innate immune protection and homeostasis mechanism, in individuals experiencing Long Covid. Thus, active Long Covid was characterized by terminal complement system dysregulation and ongoing activation of the alternative and classical complement pathways, the latter associated with increased antibody titers against several herpesviruses possibly stimulating this pathway. Moreover, markers of hemolysis, tissue injury, platelet activation, and monocyte-platelet aggregates were increased in Long Covid. Machine learning confirmed complement and thromboinflammatory proteins as top biomarkers, warranting diagnostic and therapeutic interrogation of these systems.
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Ativação do Complemento , Proteínas do Sistema Complemento , Síndrome de COVID-19 Pós-Aguda , Proteoma , Tromboinflamação , Humanos , Proteínas do Sistema Complemento/análise , Proteínas do Sistema Complemento/metabolismo , Síndrome de COVID-19 Pós-Aguda/sangue , Síndrome de COVID-19 Pós-Aguda/complicações , Síndrome de COVID-19 Pós-Aguda/imunologia , Tromboinflamação/sangue , Tromboinflamação/imunologia , Biomarcadores/sangue , Proteômica , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , IdosoRESUMO
The B cell response to different pathogens uses tailored effector mechanisms and results in functionally specialized memory B (Bm) cell subsets, including CD21+ resting, CD21-CD27+ activated and CD21-CD27- Bm cells. The interrelatedness between these Bm cell subsets remains unknown. Here we showed that single severe acute respiratory syndrome coronavirus 2-specific Bm cell clones showed plasticity upon antigen rechallenge in previously exposed individuals. CD21- Bm cells were the predominant subsets during acute infection and early after severe acute respiratory syndrome coronavirus 2-specific immunization. At months 6 and 12 post-infection, CD21+ resting Bm cells were the major Bm cell subset in the circulation and were also detected in peripheral lymphoid organs, where they carried tissue residency markers. Tracking of individual B cell clones by B cell receptor sequencing revealed that previously fated Bm cell clones could redifferentiate upon antigen rechallenge into other Bm cell subsets, including CD21-CD27- Bm cells, demonstrating that single Bm cell clones can adopt functionally different trajectories.
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Subpopulações de Linfócitos B , COVID-19 , Humanos , SARS-CoV-2 , Células B de Memória , Linfócitos BRESUMO
BACKGROUND: The cytokine interleukin-2 (IL-2) can stimulate both effector immune cells and regulatory T (Treg) cells. The ability of selectively engaging either of these effects has spurred interest in using IL-2 for immunotherapy of cancer and autoimmune diseases. Thus, numerous IL-2-based biologic agents with improved bias or delivery towards effector immune cells or Treg cells have been developed. This study systematically reviews clinical results of improved IL-2-based compounds. METHODS: We searched the ClinicalTrials.gov database for registered trials using improved IL-2-based agents and different databases for available results of these studies. FINDINGS: From 576 registered clinical trials we extracted 36 studies on different improved IL-2-based compounds. Adding another nine agents reported in recent literature reviews and based on our knowledge totalled in 45 compounds. A secondary search for registered clinical trials of each of these 45 compounds resulted in 141 clinical trials included in this review, with 41 trials reporting results. INTERPRETATION: So far, none of the improved IL-2-based compounds has gained regulatory approval for the treatment of cancer or autoimmune diseases. NKTR-214 is the only compound completing phase 3 studies. The PIVOT IO-001 trial testing the combination of NKTR-214 plus Pembrolizumab compared to Pembrolizumab monotherapy in metastatic melanoma missed its primary endpoints. Also the PIVOT-09 study, combining NKTR-214 with Nivolumab compared to Sunitinib or Cabozantinib in advanced renal cell carcinoma, missed its primary endpoint. Trials in autoimmune diseases are currently in early stages, thus not allowing definite conclusions on efficacy. FUNDING: This work was supported by public funding agencies.
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Antineoplásicos , Doenças Autoimunes , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Antineoplásicos/uso terapêutico , Interleucina-2/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/patologia , Imunoterapia/métodos , Doenças Autoimunes/tratamento farmacológicoRESUMO
PURPOSE: To compare the detection of human cytomegalovirus (HCMV) in bronchoalveolar lavage (BAL) fluid by viral culture and quantitative polymerase chain reaction (qPCR), and to establish a viral load threshold that can identify cases of HCMV replication indicative of pneumonitis. There is currently no universal viral load cut-off to differentiate between patients with and without pneumonitis, and the interpretation of qPCR results is challenging. METHODS: 176 consecutive BAL samples from immunosuppressed hosts with signs and/or symptoms of respiratory infection were prospectively studied by viral culture and qPCR. RESULTS: Concordant results were obtained in 81.25% of the BAL samples. The rest were discordant, as only 34% of the qPCR-positive BAL samples were positive by culture. The median HCMV load was significantly higher in culture-positive than in culture-negative BAL samples (5038 vs 178 IU/mL). Using a cut-off value of 1258 IU/mL of HCMV in BAL, pneumonia was diagnosed with a sensitivity of 76%, a specificity of 100%, a VPP of 100% and VPN of 98%, and HCMV was isolated in 100% of the BAL cultures. CONCLUSION: We found that a qPCR-negative was a quick and reliable way of ruling out HCMV pneumonitis, but a positive result did not always indicate clinically significant replication in the lung. However, an HCMV load in BAL fluid of ≥ 1258 IU/mL was always associated with disease, whereas < 200 IU/mL rarely so.
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Infecções por Citomegalovirus , Transplante de Pulmão , Pneumonia , Humanos , Citomegalovirus/genética , Líquido da Lavagem Broncoalveolar , Infecções por Citomegalovirus/diagnóstico , Pneumonia/diagnóstico , DNA Viral , Hospedeiro ImunocomprometidoRESUMO
Achieving adequate immunosuppression for lung transplant recipients in the first year after lung transplantation is a key challenge. Prophylaxis of allograft rejection must be balanced with the adverse events associated with immunosuppressive drugs, for example infection, renal failure, and diabetes. A triple immunosuppressive combination is standard, including a steroid, a calcineurin inhibitor, and an antiproliferative compound beginning with the highest levels of immunosuppression and a subsequent tapering of the dose, usually guided by therapeutic drug monitoring and considering clinical results, bronchoscopy sampling results, and additional biomarkers such as serum viral replication or donor-specific antibodies. Balancing the net immunosuppression level required to prevent rejection without overly increasing the risk of infection and other complications during the tapering phase is not well standardized and requires repeated assessments for dose-adjustments. In our adaptive immunosuppression approach, we additionally consider results from the white blood cell counts, in particular lymphocytes and eosinophils, as biomarkers for monitoring the level of immunosuppression and additionally use them as therapeutic targets to fine-tune the immunosuppressive strategy over time. The concept and its rationale are outlined, and areas of future research mentioned.
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Imunossupressores , Transplantados , Humanos , Imunossupressores/efeitos adversos , Terapia de Imunossupressão/efeitos adversos , Biomarcadores , Pulmão , Rejeição de Enxerto/prevenção & controleRESUMO
OBJECTIVE: To estimate the prevalence of unknown HIV infection in patients who consulted in hospital emergency services (ED) for conditions defined in the SEMES-GESIDA Consensus Document (DC), evaluate the efficiency of its im-plementation and investigate the efficiency of HIV serology determination in other conditions. METHODS: Results were reviewed in 10 Catalan EDs for 12 months (July-21-June-22) after implementing CD recommendations: request HIV serology in case of suspected sexually transmitted infection, chemsex, post-exposure prophylaxis (PEP), mononucleosis syndrome, community pneumonia (18-65 y-o) or herpes zoster (18-65 y-o). Other reasons for request were included. Prevalence (%) of global seropositivity and for each circumstance was calculated, with a 95% confidence interval (95%CI). The efficient strategy was considered if the lower limit of the CI95%>0.1%. RESULTS: A total of5,107 HIV serologies were performed: 2,847(56%) in situations specified in CD, and 2,266 (44%) in other 138 circumstances. Forty-eight unknown HIV infections were detected (prevalence=0.94%;95%CI=0.69-1.24). The prevalence was somewhat higher in DC requests (30 cas-es 1.12%) than the rest (18 cases 0.71%; p=0.16). The individualized prevalence of CD reasons ranged between 7.41% (95%CI=0.91-24.3) in chemsex and 0.42% 95%CI=0.14-0.98) in PPE, always efficient except herpes zoster (0.76%; CI95%=0.02-4.18). In other reasons, cases were detected in 12 circumstances, and in four the determination could be efficient: lymphopenia (10%;CI95%=0.25-44.5), fever with polyarthralgia-polyarthritis (7.41%;CI95% =0.91-24.3), behavioral alteration-confusion-encephalopathy (3.45%;95%CI=0.42-11.9) and fever of unknown origin (2.50%;95%CI=0.82-5.74). CONCLUSIONS: The determination of HIV serology in HES in the processes defined by DC SEMES-GESIDA is efficient. Some circumstances are identified that could be added to those previously contemplated to increase efficiency.
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Infecções por HIV , Herpes Zoster , Infecções Sexualmente Transmissíveis , Humanos , Infecções por HIV/epidemiologia , Infecções Sexualmente Transmissíveis/epidemiologiaRESUMO
Molecular insights into the mechanism of beneficial and adverse effects of interleukin-2 (IL-2) have resulted in the development of improved IL-2 formulations with IL-2 receptor bias and tissue-targeting properties. Several of these compounds are currently in clinical development and are ushering IL-2 therapy into the current era of cancer immunotherapy.
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Interleucina-2 , Neoplasias , Humanos , Interleucina-2/uso terapêutico , Imunoterapia/métodos , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: T-cell lymphopenia and functional impairment is a hallmark of severe acute coronavirus disease 2019 (COVID-19). How T-cell numbers and function evolve at later timepoints after clinical recovery remains poorly investigated. METHODS: We prospectively enrolled and longitudinally sampled 173 individuals with asymptomatic to critical COVID-19 and analyzed phenotypic and functional characteristics of T cells using flow cytometry, 40-parameter mass cytometry, targeted proteomics, and functional assays. RESULTS: The extensive T-cell lymphopenia observed particularly in patients with severe COVID-19 during acute infection had recovered 6 months after infection, which was accompanied by a normalization of functional T-cell responses to common viral antigens. We detected persisting CD4+ and CD8+ T-cell activation up to 12 months after infection, in patients with mild and severe COVID-19, as measured by increased HLA-DR and CD38 expression on these cells. Persistent T-cell activation after COVID-19 was independent of administration of a COVID-19 vaccine post-infection. Furthermore, we identified a subgroup of patients with severe COVID-19 that presented with persistently low CD8+ T-cell counts at follow-up and exhibited a distinct phenotype during acute infection consisting of a dysfunctional T-cell response and signs of excessive pro-inflammatory cytokine production. CONCLUSION: Our study suggests that T-cell numbers and function recover in most patients after COVID-19. However, we find evidence of persistent T-cell activation up to 12 months after infection and describe a subgroup of severe COVID-19 patients with persistently low CD8+ T-cell counts exhibiting a dysregulated immune response during acute infection.
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COVID-19 , Linfopenia , Linfócitos T CD8-Positivos , Vacinas contra COVID-19 , Humanos , Linfopenia/etiologia , Linfopenia/metabolismo , SARS-CoV-2RESUMO
BACKGROUND: Several autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for disease course, immunity, and autoimmune pathology. In this study, we longitudinally screened for clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, and association with immunity, comorbidities, and severity of COVID-19. METHODS: We performed highly sensitive indirect immunofluorescence assays to detect antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA), along with serum proteomics and virome-wide serological profiling in a multicentric cohort of 175 COVID-19 patients followed up to 1 year after infection, eleven vaccinated individuals, and 41 unexposed controls. RESULTS: Compared with healthy controls, similar prevalence and patterns of ANA were present in patients during acute COVID-19 and recovery. However, the paired analysis revealed a subgroup of patients with transient presence of certain ANA patterns during acute COVID-19. Furthermore, patients with severe COVID-19 exhibited a high prevalence of ANCA during acute disease. These autoantibodies were quantitatively associated with higher SARS-CoV-2-specific antibody titers in COVID-19 patients and in vaccinated individuals, thus linking autoantibody production to increased antigen-specific humoral responses. Notably, the qualitative breadth of antibodies cross-reactive with other coronaviruses was comparable in ANA-positive and ANA-negative individuals during acute COVID-19. In autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature during acute COVID-19 and alterations of the B-cell compartment after recovery. CONCLUSION: Highly sensitive indirect immunofluorescence assays revealed transient autoantibody production during acute SARS-CoV-2 infection, while the presence of autoantibodies in COVID-19 patients correlated with increased antiviral humoral immune responses and inflammatory immune signatures.
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Autoanticorpos , COVID-19 , Anticorpos Anticitoplasma de Neutrófilos , Anticorpos Antinucleares , Antivirais , Humanos , Imunidade Humoral , SARS-CoV-2RESUMO
Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which - combined with age, history of asthma bronchiale, and five symptoms during primary infection - is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS.
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Anticorpos Antivirais/imunologia , COVID-19/complicações , COVID-19/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Antivirais/sangue , COVID-19/sangue , COVID-19/diagnóstico , Estudos de Coortes , Tosse/sangue , Tosse/complicações , Tosse/imunologia , Dispneia/sangue , Dispneia/complicações , Dispneia/imunologia , Fadiga/sangue , Fadiga/complicações , Fadiga/imunologia , Feminino , Febre/sangue , Febre/complicações , Febre/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Curva ROC , SARS-CoV-2/fisiologia , Síndrome de COVID-19 Pós-AgudaRESUMO
BackgroundSeveral autoimmune features occur during coronavirus disease 2019 (COVID-19), with possible implications for disease course, immunity, and autoimmune pathology. In this study, we longitudinally screened for clinically relevant systemic autoantibodies to assess their prevalence, temporal trajectory, and association with immunity, comorbidities, and severity of COVID-19. MethodsWe performed highly sensitive indirect immunofluorescence assays to detect anti-nuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA), along with serum proteomics and virome-wide serological profiling in a multicentric cohort of 175 COVID-19 patients followed-up to one year after infection, eleven vaccinated individuals, and 41 unexposed controls. ResultsCompared to healthy controls, similar prevalence and patterns of ANA were present in patients during acute COVID-19 and recovery. However, paired analysis revealed a subgroup of patients with transient presence of certain ANA patterns during acute COVID-19. Furthermore, patients with severe COVID-19 exhibited a high prevalence of ANCA during acute disease. These autoantibodies were quantitatively associated with higher SARS-CoV-2-specific antibody titers in COVID-19 patients and in vaccinated individuals, thus linking autoantibody production to increased antigen-specific humoral responses. Notably, the qualitative breadth of antibodies cross-reactive with other coronaviruses was comparable in ANA-positive and ANA- negative individuals during acute COVID-19. In autoantibody-positive patients, multiparametric characterization demonstrated an inflammatory signature during acute COVID-19 and alterations of the B cell compartment after recovery. ConclusionHighly sensitive indirect immunofluorescence assays revealed transient autoantibody production during acute SARS-CoV-2 infection, while the presence of autoantibodies in COVID-19 patients correlated with increased anti-viral humoral immune responses and inflammatory immune signatures.
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Immunological memory is a hallmark of adaptive immunity and facilitates an accelerated and enhanced immune response upon re-infection with the same pathogen1,2. Since the outbreak of the ongoing COVID-19 pandemic, a key question has focused on which SARS-CoV-2-specific T cells stimulated during acute infection give rise to long-lived memory T cells3. Here, using spectral flow cytometry combined with cellular indexing of transcriptomes and T cell receptor sequencing, we longitudinally characterized individual SARS-CoV-2-specific CD8+ T cells of patients with COVID-19 from acute infection to 1 year into recovery and found a distinct signature identifying long-lived memory CD8+ T cells. SARS-CoV-2-specific memory CD8+ T cells persisting 1 year after acute infection express CD45RA, IL-7 receptor-α and T cell factor 1, but they maintain low expression of CCR7, thus resembling CD45RA+ effector memory T cells. Tracking individual clones of SARS-CoV-2-specific CD8+ T cells, we reveal that an interferon signature marks clones that give rise to long-lived cells, whereas prolonged proliferation and mechanistic target of rapamycin signalling are associated with clonal disappearance from the blood. Collectively, we describe a transcriptional signature that marks long-lived, circulating human memory CD8+ T cells following an acute viral infection.
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Antígenos Virais/imunologia , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19/imunologia , Células T de Memória/imunologia , Células T de Memória/metabolismo , SARS-CoV-2/imunologia , Doença Aguda , COVID-19/virologia , Proliferação de Células , Células Clonais/citologia , Células Clonais/imunologia , Humanos , Interferons/imunologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Estudos Longitudinais , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores CCR7/metabolismo , Fator 1 de Transcrição de Linfócitos T/metabolismo , Fatores de Tempo , TranscriptomaRESUMO
Immunological memory is a hallmark of adaptive immunity and facilitates an accelerated and enhanced immune response upon re-infection with the same pathogen1,2. Since the outbreak of the ongoing coronavirus disease 19 (COVID-19) pandemic, a key question has focused on whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells stimulated during acute infection give rise to long-lived memory T cells3. Using spectral flow cytometry combined with cellular indexing of transcriptomes and T cell receptor (TCR) sequencing we longitudinally characterize individual SARS-CoV-2-specific CD8+ T cells of COVID-19 patients from acute infection to one year into recovery and find a distinct signature identifying long-lived memory CD8+ T cells. SARS-CoV-2-specific memory CD8+ T cells persisting one year after acute infection re-express CD45RA and interleukin-7 receptor (CD127), upregulate T cell factor-1 (TCF1), and maintain low CCR7, thus resembling CD45RA+ effector-memory T (TEMRA) cells. Tracking individual clones of SARS-CoV-2-specific CD8+ T cells, we reveal that an interferon signature marks clones giving rise to long-lived cells, whereas prolonged proliferation and mammalian target of rapamycin (mTOR) signaling are associated with clone contraction and disappearance. Collectively, we identify a transcriptional signature differentiating short-from long-lived memory CD8+ T cells following an acute virus infection in humans.
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OBJECTIVE: To determine the approaches used in Spanish emergency departments (EDs) in patients suspected of having sexually transmitted diseases (STD) analysed according to the size of the hospital, ED census and autonomous community. METHODS: Questionnaire to the heads of 282 public EDs (7/24) related to emergency routines for patients with suspected STD. Results compared using odds-ratio (OR) and 95% confidence interval (95%CI) according to hospital size (large vs medium-small: ≥500 vs. <500 beds) and ED census (high vs. medium-low: ≥200 vs. <200 patients/day), by autonomous community. RESULTS: A total of 250 EDs responded (89%). With protocol for STD 36% of EDs [>60% Catalonia, Vasque Country, more in large hospitals (LH), (OR=2.65, 95%CI=1.46-4.82) and high census (HCEN) EDs, (OR=3.49, 95%CI=2.03-5.98)]. 70% obtained exudate sampling (>80% Catalonia, Madrid, Castilla-La Mancha, Aragón, Navarra, Vasque Country), 44% STD serology (>60% Madrid) and 35% HIV serology [(>60% Navarra, Baleares; more in LH (OR=2.43, 95%CI=1.34-4.42) and HCEN EDs (OR=1.94, 95%CI=1.15-3.29)]. At discharge, follow-up in hospital outpatients clinics 53% of EDs [>60% Catalonia, Comunidad Valenciana, Murcia, Castilla-La Mancha, Vasque Country, Asturias; more in LH (OR=2.45, 95%CI=1.31-4.57) and HCEN EDs (OR=2.25, 95%CI=1.35-3.76)] and by primary care 28% (>80% Cantabria). In 55% of EDs, patients are discharged with a scheduled follow-up (>80% Extremadura, La Rioja, Navarra) and 32% visit next workday [>60% Vasque Country; more in LH (OR=3.43, 95%CI=1.87-6.30) and HCEN EDs (OR=3.63, 95%CI=2.08-6.37)]. CONCLUSIONS: The care of patients with suspected STD is not homogeneous in Spanish EDs. Areas of improvement were detected, especially the need for specific diagnostic and follow-up protocols.
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Serviço Hospitalar de Emergência , Infecções Sexualmente Transmissíveis , Humanos , Infecções Sexualmente Transmissíveis/tratamento farmacológico , Infecções Sexualmente Transmissíveis/epidemiologiaRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and shows a broad clinical presentation ranging from asymptomatic infection to fatal disease. A very prominent feature associated with severe COVID-19 is T cell lymphopenia. However, homeostatic and functional properties of T cells are ill-defined in COVID-19. METHODS: We prospectively enrolled individuals with mild and severe COVID-19 into our multicenter cohort and performed a cross-sectional analysis of phenotypic and functional characteristics of T cells using 40-parameter mass cytometry, flow cytometry, targeted proteomics, and functional assays. RESULTS: Compared with mild disease, we observed strong perturbations of peripheral T cell homeostasis and function in severe COVID-19. Individuals with severe COVID-19 showed T cell lymphopenia and redistribution of T cell populations, including loss of naïve T cells, skewing toward CD4+ T follicular helper cells and cytotoxic CD4+ T cells, and expansion of activated and exhausted T cells. Extensive T cell apoptosis was particularly evident with severe disease and T cell lymphopenia, which in turn was accompanied by impaired T cell responses to several common viral antigens. Patients with severe disease showed elevated interleukin-7 and increased T cell proliferation. Furthermore, patients sampled at late time points after symptom onset had higher T cell counts and improved antiviral T cell responses. CONCLUSION: Our study suggests that severe COVID-19 is characterized by extensive T cell dysfunction and T cell apoptosis, which is associated with signs of homeostatic T cell proliferation and T cell recovery.
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COVID-19 , Estudos Transversais , Homeostase , Humanos , Ativação Linfocitária , SARS-CoV-2RESUMO
Coronavirus disease 2019 (COVID-19) manifests with a range of severities, but immune signatures of mild and severe disease are still not fully understood. Here, we use mass cytometry and targeted proteomics to profile the innate immune response of patients with mild or severe COVID-19 and of healthy individuals. Sampling at different stages allows us to reconstruct a pseudo-temporal trajectory of the innate response. A surge of CD169+ monocytes associated with an IFN-γ+MCP-2+ signature rapidly follows symptom onset. At later stages, we observe a persistent inflammatory phenotype in patients with severe disease, dominated by high CCL3 and CCL4 abundance correlating with the re-appearance of CD16+ monocytes, whereas the response of mild COVID-19 patients normalizes. Our data provide insights into the dynamic nature of inflammatory responses in COVID-19 patients and identify sustained innate immune responses as a likely mechanism in severe patients, thus supporting the investigation of targeted interventions in severe COVID-19.