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Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19.

ABSTRACT: The biological determinants of the wide spectrum of COVID-19 clinical manifestations are not fully understood. Here, over 1400 plasma proteins and 2600 single-cell immune features comprising cell phenotype, basal signaling activity, and signaling responses to inflammatory ligands were assessed in peripheral blood from patients with mild, moderate, and severe COVID-19, at the time of diagnosis. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identified and independently validated a multivariate model classifying COVID-19 severity (multi-class AUCtraining = 0.799, p-value = 4.2e-6; multi-class AUCvalidation = 0.773, p-value = 7.7e-6). Features of this high-dimensional model recapitulated recent COVID-19 related observations of immune perturbations, and revealed novel biological signatures of severity, including the mobilization of elements of the renin-angiotensin system and primary hemostasis, as well as dysregulation of JAK/STAT, MAPK/mTOR, and NF-?B immune signaling networks. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for the prevention of COVID-19 progression.

SUBMITTER: Feyaerts D

PROVIDER: S-EPMC7885914 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19.

Feyaerts Dorien D Hédou Julien J Gillard Joshua J Chen Han H Tsai Eileen S ES Peterson Laura S LS Ando Kazuo K Manohar Monali M Do Evan E Dhondalay Gopal K R GKR Fitzpatrick Jessica J Artandi Maja M Chang Iris I Snow Theo T TT Chinthrajah R Sharon RS Warren Christopher M CM Wittman Rich R Meyerowitz Justin G JG Ganio Edward A EA Stelzer Ina A IA Han Xiaoyuan X Verdonk Franck F Gaudillière Dyani K DK Mukherjee Nilanjan N Tsai Amy S AS Rumer Kristen K KK Jiang Sizun S Valdés Ferrer Sergio Iván SI Kelly J Daniel JD Furman David D Aghaeepour Nima N Angst Martin S MS Boyd Scott D SD Pinsky Benjamin A BA Nolan Garry P GP Nadeau Kari C KC Gaudillière Brice B McIlwain David R DR

bioRxiv : the preprint server for biology 20210210

The biological determinants of the wide spectrum of COVID-19 clinical manifestations are not fully understood. Here, over 1400 plasma proteins and 2600 single-cell immune features comprising cell phenotype, basal signaling activity, and signaling responses to inflammatory ligands were assessed in peripheral blood from patients with mild, moderate, and severe COVID-19, at the time of diagnosis. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic dat ...[more]

PMID: 33594362

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Project description:BACKGROUND:Reactive oxygen species (ROS) plays a major role in the pathology of male infertility. It is an independent biomarker of sperm function. Seminal plasma is a natural reservoir of antioxidants responsible for the nourishment, protection, capacitation, and motility of sperm within the female reproductive tract resulting in successful fertilization and implantation of the embryo. A comparative proteomic analysis of seminal plasma proteins from fertile men and infertile men with varying levels of ROS was carried out to identify signature proteins involved in ROS-mediated reproductive dysfunction. METHODS:A total of 42 infertile men presenting with infertility and 17 proven fertile donors were enrolled in the study. ROS levels were measured in the seminal ejaculates by chemiluminescence assay. Infertile men were subdivided into Low ROS (0-<93 RLU/s/10(6) sperm; n = 11), Medium ROS (>93-500 RLU/s/10(6) sperm; n = 17) and High ROS (>500 RLU/s/10(6) sperm; n = 14) groups and compared with fertile men (4-50 RLU/s/10(6) sperm). 4 subjects from fertile group and 4 each from the Low, Medium and High ROS were pooled. 1D gel electrophoresis followed by in-gel digestion and LC/MS-MS in a LTQ-Orbitrap Elite hybrid mass spectrometer system was used for proteome analysis. Identification of differentially expressed proteins (DEPs), their cellular localization and involvement in different pathways were examined utilizing bioinformatics tools. RESULTS:The results indicate that proteins involved in biomolecule metabolism, protein folding and protein degradation are differentially modulated in all three infertile patient groups in comparison to fertile controls. Membrane metallo-endopeptidase (MME) was uniformly overexpressed (>2 fold) in all infertile groups. Pathway involving 35 focus proteins in post-translational modification of proteins, protein folding (heat shock proteins, molecular chaperones) and developmental disorder was overexpressed in the High ROS group compared with fertile control group. MME was one of the key proteins in the pathway. FAM3D was uniquely expressed in fertile group. CONCLUSION:We have for the first time demonstrated the presence of 35 DEPs of a single pathway that may lead to impairment of sperm function in men with Low, Medium or High ROS levels by altering protein turn over. MME and FAM3D along with ROS levels in the seminal plasma may serve as good markers for diagnosis of male infertility.

Dataset Information

Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19.

Publications

Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19.

Similar Datasets

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