Identification of Robust Protein Associations With COVID-19 Disease Based on Five Clinical Studies

Abstract

Multiple studies have investigated the role of blood circulating proteins in COVID-19 disease using the Olink affinity proteomics platform. However, study inclusion criteria and sample collection conditions varied between studies, leading to sometimes incongruent associations. To identify the most robust protein markers of the disease and the underlying pathways that are relevant under all conditions, it is essential to identify proteins that replicate most widely. Here we combined the Olink proteomics profiles of two newly recruited COVID-19 studies (N=68 and N=98) with those of three previously published COVID-19 studies (N=383, N=83, N=57). For these studies, three Olink panels (Inflammation and Cardiovascular II & III) with 253 unique proteins were compared. Case/control analysis revealed thirteen proteins (CCL16, CCL7, CXCL10, CCL8, LGALS9, CXCL11, IL1RN, CCL2, CD274, IL6, IL18, MERTK, IFNγ, and IL18R1) that were differentially expressed in COVID-19 patients in all five studies. Except CCL16, which was higher in controls, all proteins were overexpressed in COVID-19 patients. Pathway analysis revealed concordant trends across all studies with pathways related to cytokine-cytokine interaction, IL18 signaling, fluid shear stress and rheumatoid arthritis. Our results reaffirm previous findings related to a COVID-19 cytokine storm syndrome. Cross-study robustness of COVID-19 specific protein expression profiles support the utility of affinity proteomics as a tool and for the identification of potential therapeutic targets.

Proteomic Approaches to Unravel Mechanisms of Antibiotic Resistance and Immune Evasion of Bacterial Pathogens

“…Using combinations such as protein cross-linking with MS and computational modeling or affinity purification strategies with SWATH-MS, all integrated in the system biology frame are useful to unravel the networks formed during these host-pathogen interactions too. Recently, multiple proteomic studies identified 13 proteins reproducibly differentially expressed in patients with COVID-19, which were related to cytokine-cytokine interaction, IL18 signaling, fluid shear stress and rheumatoid arthritis, which together validated prior indications of the involvement of cytokine storms in COVID-19 cases ( 88 ).…”

Structure and Dynamics of Human Chemokine CCL16—Implications for Biological Activity

“…These samples may reflect cases with more significant local inflammation, possibly leading to CCL16 induction in non-hepatocytes, or with overproduction by the tumour cells themselves; our HBV-related tumour cohort featuring a lower number of specimens with a single outlier ( Figure 2 ) may actually be sampling the same underlying distribution. Remarkably, a recent survey of five independent proteomics studies in COVID-19 patients revealed a consistent reduction in CCL16 in blood samples [ 71 ]. While the underlying mechanisms have not been investigated, the systemic nature of the disease, potentially involving significant damage to liver tissue [ 72 ], would appear consistent both with reduced synthesis in hepatocytes and with enhanced turnover in the periphery.…”

Increased mRNA Levels of ADAM17, IFITM3, and IFNE in Peripheral Blood Cells Are Present in Patients with Obesity and May Predict Severe COVID-19 Evolution

“…Among the proinflammatory interleukins and chemokines genes analyzed in the present work, IL6 , CXCL10 and CXCL11 showed a differential expression (upregulation) in PBCs of COVID-19 patients on hospital admission relative to controls, the upregulation being proportional to the severity of the disease course for CXCL11 . IL-6, CXCL10 and CXCL11 are among the blood circulating proteins found to be robustly associated with COVID-19 disease through a non-biased proteomics approach based on five clinical case-control studies [ 56 ]. Upregulations of IL-6 [ 43 ] and chemokine CXCL10 [ 55 , 57 ] signaling are key components of the SARS-CoV-2 induced cytokine storm.…”