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Single cell sequencing unraveling genetic basis of shared immunologic switch between Severe COVID19 and Obesity

ABSTRACT: COVID-19 has shown a substantial variation in the rate and severity by which it impacts different demographic groups. Specifically, it has shown a predilection towards obese patients as well as as well as other vulnerable groups including predilection of males over females, old age over young age and black races over Caucasian ones.. Single cell sequencing studies have highlighted the role of cell polarity and the co-expression of proteases, such as Furin, along with ACE2 in the genesis of coronavirus disease rather than exclusively link tissue involvement with ACE2 levels thought previously. It has also forged a connection between the genetic and immune cellular mechanisms underlying COVID infection and the inflammatory state of obese patients, offering a more accurate explanation as to why obese patients are at increased risk of poor COVID outcomes. These commonalities encompass macrophage phenotype switching, genetic expression switching, and overexpression of the pro-inflammatory cytokines, depletion of the regulatory cytokines, in situ T cell proliferation, and T cell exhaustion. These findings demonstrate the necessity of single cell sequencing as a rapid means to identify and treat those who are most likely to need hospital admission and intensive care, in the hopes of precision medicine. Furthermore, this study underlines the use of immune modulators such as Leptin sensitizers, rather than immune suppressors as anti-inflammation therapies to switch the inflammatory response from a drastic immunological type 1 response to a beneficial type 2 effective one. Highlights • ScRNA-seq focuses on the analysis of individual cells, instead of bulk cell populations, and can lead to a more insightful characterization of local microenvironments.• ScRNA-seq unleashed that tissue tropism in COVID-19 is not solely determinant by ACE2 distribution but rather by Furin.• ScRNA-seq in COVID-19 revealed two distinct types of immunologic reactions, deleterious type 1 characterized by inefficient antigen presentation, decreased memory B cells, imbalance between M1 and M2 macrophages and T cell exhaustion, and beneficial type 2 reaction which exactly the reverse of the type 1.• The immunotype 1 reaction is intriguingly similar to the immune landscape seen in obese individuals when leptin resistance sets in.• This might indicate that the use of leptin sensitizers to induce an immunologic switch from immunotype 1 to immunotype 2 can greatly improve the outcome of COVID-19 cases.• ScRNA-seq was also able to unveil the disparity between aggressive and milder strains of SARS-CoV-2, which are mainly related to their affinity to cellular activation by Furin.• The applications of ScRNA-seq may help to anticipate cases at higher risk of severe COVID-19 at their earliest encounter.

SUBMITTER: AbdelMassih A

PROVIDER: S-EPMC7513689 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Project description:In this study, we aimed to comprehensively characterize the proteomic landscapes of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in patients with severe obesity, to establish their associations with clinical characteristics, and to identify potential serum protein biomarkers indicative of tissue-specific alterations or metabolic states. We conducted a cross-sectional analysis of 32 patients with severe obesity (16 males and 16 females) of Central European descent who underwent bariatric surgery. Clinical parameters and body composition were assessed using dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance, with 15 patients diagnosed with type 2 diabetes (T2D) and 17 with hypertension. Paired SAT and VAT samples, along with serum samples, were subjected to state-of-the-art proteomics liquid chromatography-mass spectrometry (LC-MS). Our analysis identified 7,284 proteins across SAT and VAT, with 1,249 differentially expressed proteins between the tissues and 1,206 proteins identified in serum. Correlation analyses between differential protein expression and clinical traits suggest a significant role of SAT in the pathogenesis of obesity and related metabolic complications. Specifically, the SAT proteomic profile revealed marked alterations in metabolic pathways and processes contributing to tissue fibrosis and inflammation. Although we do not establish a definitive causal relationship, it appears that VAT might respond to SAT metabolic dysfunction by potentially enhancing mitochondrial activity and expanding its capacity. However, when this adaptive response is exceeded, it could possibly contribute to insulin resistance (IR) and in some cases, it may be associated with the progression to T2D. Our findings provide critical insights into the molecular foundations of SAT and VAT in obesity and may inform the development of targeted therapeutic strategies.NEW & NOTEWORTHY This study provides insights into distinct proteomic profiles of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and serum in patients with severe obesity and their associations with clinical traits and body composition. It underscores SAT's crucial role in obesity development and related complications, such as insulin resistance (IR) and type 2 diabetes (T2D). Our findings emphasize the importance of understanding the SAT and VAT balance in energy homeostasis, proteostasis, and the potential role of SAT capacity in the development of metabolic disorders.

Project description:Memory B cells play a fundamental role in host defences against viruses. This dataset aimed at understanding their maturation and stability in the context of SARS-CoV-2 infection and consist of a longitudinal single-cell and repertoire profiling of the B cell response up to six months in four severe COVID-19 patients. All four patients were recruited at Henri Mondor University Hospital (AP-HP, Paris France), between March and May 2020, and required oxygen as treatment. Clinical and biological characteristics of these patients are summarized in the Patient_information.csv file. Peripheral (CD3-CD14-CD15-CD56-CD19+IgD-) B cells were FACS-sorted (MA900, Sony) in PBS/0.08% FCS from 4 patients (S-CoV) at baseline (M0) and 6 months (M6). 5x104 to 10x105 cells were obtained for each subset and 20000 were loaded in the 10x Chromium Controller to generate single-cell gel-beads in emulsion. The scRNA-seq libraries were generated using the Chromium Next GEM Single Cell V(D)J Reagent Kit v.1.1 with Feature Barcoding (10x Genomics) according to the manufacturer’s protocol. PBMCs were initially isolated from venous blood samples via standard density gradient centrifugation and used after cryopreservation at -150°C. Cells were thawed using RPMI-1640 (Gibco) 10% FBS, washed twice and incubated with 10µg of the SARS-CoV-2 his tagged spike protein in 100µL of PBS (Gibco) 2% FBS during 20 minutes on ice. Cells were washed and resuspended in the same conditions, then fluorochrome-conjugated antibody cocktail including the 2 anti-His was added at pre-titrated concentrations for 20 min at 4°C and viable cells were identified using a LIVE/DEAD Fixable Aqua Dead Cell Stain Kit (Thermo Fisher Scientific) incubated with conjugated antibodies used for cell sorting (CD3/CD14/CD15/CD56/CD19/IgD) as well as a panel of barcoded TotalSeqC® and homemade anti-His antibodies (see feature_reference.csv.gz files). Three distinct sorts were performed for each donor: two at the M0 time-point (M0_Sort1 and M0_Sort2) and one at the M6 time-point (M6_Sort1). His-tagged-Spike + barcoded-anti-his staining was only included in the last two sorts (M0_Sort2 and M6_Sort1). For these two sorts it should additionally be noted that 5’-transcriptomic and ADT libraries were sequenced in two separate runs (Run1 and Run2) to achieve sufficient sequencing depth for both libraries. Both runs were pooled at the Cell Ranger analysis step.

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Single cell sequencing unraveling genetic basis of shared immunologic switch between Severe COVID19 and Obesity

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