Project description:Protective immunity against COVID-19 likely depends on the production of SARS-CoV-2 binding plasma cells and memory B cells after infection or vaccination. Previous work has shown evidence that germinal center reactions, a critical component of the B cell response, are disrupted in severe COVID-19. This may adversely affect protective immunity from re-infection. Consistent with an extrafollicular B cell response, severe COVID-19 patients have large scale changes in B cell populations such as elevated frequencies of clonally expanded, class switched, unmutated plasmablasts. However, it is not clear whether mild or asymptomatically infected individuals show similar differences in B cell repertoires. Here, we use single cell RNA sequencing of B cells to show that, in contrast to hospitalized COVID-19 patients, mildly symptomatic COVID-19 subjects have B cell repertoires skewed towards clonally diverse, somatically hypermutated memory B cells approximately 30 days after the onset of symptoms. This provides evidence that B cell responses are less disrupted in mild COVID-19, and that the infection resolves with the production of memory B cells.
Project description:Protective immunity against COVID-19 likely depends on the production of SARS-CoV-2 binding plasma cells and memory B cells after infection or vaccination. Previous work has shown evidence that germinal center reactions, a critical component of the B cell response, are disrupted in severe COVID-19. This may adversely affect protective immunity from re-infection. Consistent with an extrafollicular B cell response, severe COVID-19 patients have large scale changes in B cell populations such as elevated frequencies of clonally expanded, class switched, unmutated plasmablasts. However, it is not clear whether mild or asymptomatically infected individuals show similar differences in B cell repertoires. Here, we use single cell RNA sequencing of B cells to show that, in contrast to hospitalized COVID-19 patients, mildly symptomatic COVID-19 subjects have B cell repertoires skewed towards clonally diverse, somatically hypermutated memory B cells approximately 30 days after the onset of symptoms. This provides evidence that B cell responses are less disrupted in mild COVID-19, and that the infection resolves with the production of memory B cells.
Project description:Red blood cells (RBC) depleted whole blood from COVID-19 patients and controls was harvested and processed in order to performed 10X single cell RNA-seq. For COVID-19 patients 2 samples 10 days a part were analyzed.
Project description:Analysis of COVID-19 hospitalized patients, with different kind of symptoms, by human rectal swabs collection and 16S sequencing approach.
Project description:We utilize single-cell sequencing (scSeq) of lymphocyte immune repertoires and transcriptomes to quantitatively profile the adaptive immune response in COVID-19 patients of varying age. Our scSeq analysis defines the adaptive immune repertoire and transcriptome in convalescent COVID-19 patients and shows important age-related differences implicated in immunity against SARS-CoV-2.
Project description:Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
Project description:An early analysis of circulating monocytes may be critical for predicting COVID-19 course and its sequelae. In 131 untreated, acute COVID-19 patients at emergency room (ER) arrival, monocytes showed decreased surface molecules expression, including HLA-DR, in association to an inflammatory cytokine status and limited anti-SARS-CoV-2-specific T cell response. These alterations were mostly normalized in post-COVID-19 patients, 6 months after discharge. Acute COVID-19 monocytes transcriptome showed upregulation of anti-inflammatory, tissue repair genes such as BCL6, AREG and IL-10 and increased accessibility of chromatin. Some of these transcriptomic and epigenetic features still remained in post-COVID-19 monocytes. Importantly, a poorer expression of surface markers and low IRF1 gene transcription in circulating monocytes at ER defined a COVID-19 patients group with impaired SARS-CoV-2-specific T cell response and increased risk of requiring intensive care or dying. An early analysis of monocytes may be useful for COVID-19 patients stratification and to designing innate immunity-focused therapies.
Project description:Although most SARS-CoV-2-infected individuals experience mild COVID-19, some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly upregulation of the TNF/IL-1beta-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1beta-driven inflammation, and this was not seen in patients with milder COVID-19 infection. Based on this, we propose that the type I IFN response exacerbates inflammation in patients with severe COVID-19 infection.
Project description:Pre-existing memory T-cells against SARS-CoV-2 are present in a fraction of unexposed individuals and their induction by common cold corona viruses (CCCoVs) infection is suggested. Here we demonstrate that SARS-CoV-2-reactive T-cells were present in the memory compartment of virtually all unexposed individuals but possessed only low functional avidity. They harbored multiple, highly variable cross-reactivities that were not restricted to CCCoVs. Cross-reactivity to CCCoV was almost absent in COVID-19 patients. This was irrespective of strong T-cell memory against CCCoV in all donors. In severe but not mild COVID-19, SARS-CoV-2-specific T-cells also displayed low functional avidity and reduced clonal expansion, despite strongly increased frequencies. Our data question a major protective role of CCCoV for COVID-19. Instead, we suggest that a low avidity pre-existing T-cell memory may contribute to the excessive but low avidity T-cell responses, which we identified here as a hallmark of severe COVID-19.
Project description:Clinical outcomes of COVID-19 patients are worsened by the presence of co-morbidities, especially cancer for which mortality rate in cancer patients affected by COVID-19 is elevated. SARS-CoV-2 infection is known to alter immune system homeostasis. Whether cancer patients developing COVID-19 present alterations of immune functions which might contribute to worse outcomes has been so far poorly investigated. We conducted a multi-omic analysis of immunological parameters in COVID-19 patients with and without cancer. We found that 8 pro-inflammatory factors out of 27 analysed serum cytokines were modulated in COVID-19 patients irrespective of cancer status. Diverse subpopulations of T lymphocytes such as CD8+ T, CD4+ T central memory, Mucosal associated invariant T cells (MAIT) NKT and T cells were reduced while B memory cells, plasmablasts, late NK and plasmacytoid dendritic cells were expanded in COVID-19 cancer patients. A 19 gene expression signature of peripheral blood cells was able to discriminate COVID-19 cancer and without cancer patients. Gene set enrichment analysis highlights an increased gene expression in Interferon response and signalling which paired with aberrant cell cycle regulation in cancer patients. Ten out of these 19 genes were specific of COVID-19 cancer patients. Our findings illustrate a repertoire of aberrant alterations of gene expression in circulating immune cells of COVID-19 cancer patients that might contribute to decipher their higher frequency of severe events. We also unveil a transcriptional network involving gene regulators of both inflammation response and proliferation in PBMCs of COVID-19 cancer patients. This might also lead to design of novel therapeutic strategies for COVID-19 cancer patients.