Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS

Abstract

Background: Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions.

Methods and findings: In this study, we compared COVID-19 ARDS (n = 43) and bacterial sepsis-induced (non-COVID-19) ARDS (n = 24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within- ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation.

Conclusion: We present a first comprehensive molecular characterization of differences between two ARDS etiologies-COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions.

Fig 1. Study overview.

This study was based on 67 ARDS patients, 43 with COVID-19 and 24 with bacterial sepsis group. Profiling of plasma samples resulted in 1,906 measured molecules, including 663 metabolites, 1,051 lipids, and 266 proteins. For inter-ARDS comparison, we identified molecules and pathways differently regulated between the two ARDS groups. In addition, focusing on several selected pathways with therapeutic relevance, we constructed a cascade of biological processes starting from sphingosine metabolism. For intra-ARDS comparison, we identified molecules associated with clinical manifestations, including acute kidney injury (AKI), thrombocytosis (platelet count), PaO2/FiO2 ratio, and mortality, within each ARDS group. Further, we constructed a data-driven multi-omic network based on the Gaussian graphical model (GGM). This network was used to generate subnetworks associated with clinical manifestations.

Fig 2. Multi-omic comparison between COVID-19 ARDS and bacterial sepsis-induced ARDS.

a. Metabolomic, lipidomic, and proteomic analyses between the two ARDS groups. 706 molecules were differently abundant in the two ARDS groups. b. Functional annotations of significant molecules. Pathways and classes with at least 4 significant molecules were included in these plots. FDR–false discovery rate. Lipid class abbreviations: TAG–Triacylglycerol, PC–Phosphatidylcholine, DAG–Diacylglycerol, CE–Cholesteryl ester, HCER–Hexosylceramides, Total–total lipids, SM–Sphingomyelin, LPC–Lysophosphatidylcholine, LCER—Lactosylceramides, DCER–Dihydroceramides, CER–Ceramides, PE–Phosphatidylethanolamine, MAG–Monoacylglycerol, LPE—Lysophosphatidylethanolamine, PI—Phosphatidylinositol.

Fig 3. Multi-omic interplay of selected, therapeutically relevant ARDS-associated pathways.

We selected several pathways that are of pharmaceutical interest in inflammatory or infectious diseases and built the cascade using literature-based knowledge of their interactions. This cascade begins with sphingosine metabolism, which is a target of interest to improve inflammatory conditions [28, 29]. Sphingosine-1 phosphate (S1P) and its receptors (S1PRs) activate MAPK, RAS, and PI3K-AKT signaling pathways downstream [32]. These signaling pathways are central to various biological functions, including viral replication and propagation in host cells [–36]. Inhibition of these pathways has been discussed as a potential therapeutic approach for treating ARDS [37, 39]. Further down in this cascade, arginine metabolism can be activated by PI3K-AKT and JAK-STAT signaling pathways [41]. These pathways activate the nitric oxide synthase enzymes, which catalyze the conversion of arginine to nitric oxide. Arginine depletion strategies have been discussed in the context of controlling viral infections [43, 44], and JAK inhibition was found to be effective in improving the outcome of COVID-19 [47, 48].

Fig 4. Overview of intra-ARDS multi-omic signatures within each ARDS.

a. Molecules associated with each of the two clinical manifestations that could be compared across ARDS groups (AKI and platelet count) for each omics layer. 249 molecules were associated with AKI and 111 with platelet count in the ARDS groups. b. Gaussian graphical model (GGM) of metabolites, lipids, and proteins. Shapes and colors of the molecules in the network are based on the omics type.

Fig 5. Subnetwork-based signatures of two clinical manifestations across ARDS groups.

a. AKI-associated subnetwork enriched in amino acids and acylcarnitines, indicating mitochondrial dysfunction. b. Thrombocytosis-associated subnetwork enriched in IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. These are prothrombotic processes that may lead to hypercoagulative complications in COVID-19.