Quantitative multi-organ proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation

Abstract

SARS-CoV-2 directly damages lung tissue via its infection and replication process and indirectly due to systemic effects of the host immune system. There are few systems-wide, untargeted studies of these effects on the different tissues of the human body and nearly all of them base their conclusions on the transcriptome. Here we developed a parallelized mass spectrometry (MS)-based proteomics workflow allowing the rapid, quantitative analysis of hundreds of virus-infected and FFPE preserved tissues. The first layer of response in all tissues was dominated by circulating inflammatory molecules. To discriminated between these systemic and true tissue-specific effects, we developed an analysis pipeline revealing that proteome alterations reflect extensive tissue damage, mostly similar to non-COVID diffuse alveolar damage. The next most affected organs were kidney and liver, while the lymph-vessel system was also strongly affected. Finally, secondary inflammatory effects of the brain correlated with receptor rearrangements and the degradation of neuronal myelin. Our results establish MS-based tissue proteomics as a promising strategy to inform organ-specific therapeutic interventions following COVID-19 infections.

Lysis buffer selection guidance for mass spectrometry-based global proteomics including studies on the intersection of signal transduction and metabolism

“…Over the years, advances in mass spectrometry (MS)-based proteomics have transformed our ability to identify and, most importantly, quantify thousands of proteins in a single study [3, 4]. Cell lysis for protein extraction is an indispensable step in proteomic workflows, encompassing the extraction and denaturation of proteins from cells or tissues to enhance sensitivity in downstream detection, ensuring reliable quantification.…”

Innate and Adaptive Immunity during SARS-CoV-2 Infection: Biomolecular Cellular Markers and Mechanisms

“…Categorization of COVID-19 has, therefore, occurred in vascular endothelial cell dysfunction, hyper-inflammatory response, and hypercoagulability, documenting this aspect of SARS-CoV-2 induced pathology with resulting serum elevation in plasma levels of D-dimer, C-reactive protein, P-selectin, and fibrinogen [ 41 ]. More recently, in a yet-to-be-reviewed pre-print, 7315 proteins were investigated specifically in chronic COVID-19 disease, relating to complement protein as key in the coagulation pathways; complement C1q subcomponent subunits A, B, and C (C1QA, C1QB, and C1QC) were mainly enriched in lungs and LNs [ 42 ]. Complement factors C3, C5, C7, and C9, in contrast, were commonly upregulated in LNs and aorta/vessel walls with downregulated SP-C in ATII cells [ 42 ].…”

“…More recently, in a yet-to-be-reviewed pre-print, 7315 proteins were investigated specifically in chronic COVID-19 disease, relating to complement protein as key in the coagulation pathways; complement C1q subcomponent subunits A, B, and C (C1QA, C1QB, and C1QC) were mainly enriched in lungs and LNs [ 42 ]. Complement factors C3, C5, C7, and C9, in contrast, were commonly upregulated in LNs and aorta/vessel walls with downregulated SP-C in ATII cells [ 42 ]. Investigations indicate two other proteins, receptor for advanced glycation end-products (RAGE/AGER) and chloride intracellular channel (CLIC5), also associate with ATI cells, but that an SP-C related protein was downregulated specific to ATII cells, as above [ 42 ].…”

“…Complement factors C3, C5, C7, and C9, in contrast, were commonly upregulated in LNs and aorta/vessel walls with downregulated SP-C in ATII cells [ 42 ]. Investigations indicate two other proteins, receptor for advanced glycation end-products (RAGE/AGER) and chloride intracellular channel (CLIC5), also associate with ATI cells, but that an SP-C related protein was downregulated specific to ATII cells, as above [ 42 ]. Interestingly, the authors noted a significant reduction in IL-12 production in LN that can affect DC maturation, as discussed below.…”