Dynamic modulations of urinary sphingolipid and glycerophospholipid levels in COVID-19 and correlations with COVID-19-associated kidney injuries.

BACKGROUND: Among various complications of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), renal complications, namely COVID-19-associated kidney injuries, are related to the mortality of COVID-19. METHODS: In this retrospective cross-sectional study, we measured the sphingolipids and glycerophospholipids, which have been shown to possess potent biological properties, using liquid chromatography-mass spectrometry in 272 urine samples collected longitudinally from 91 COVID-19 subjects and 95 control subjects without infectious diseases, to elucidate the pathogenesis of COVID-19-associated kidney injuries. RESULTS: The urinary levels of C18:0, C18:1, C22:0, and C24:0 ceramides, sphingosine, dihydrosphingosine, phosphatidylcholine, lysophosphatidylcholine, lysophosphatidic acid, and phosphatidylglycerol decreased, while those of phosphatidylserine, lysophosphatidylserine, phosphatidylethanolamine, and lysophosphatidylethanolamine increased in patients with mild COVID-19, especially during the early phase (day 1-3), suggesting that these modulations might reflect the direct effects of infection with SARS-CoV-2. Generally, the urinary levels of sphingomyelin, ceramides, sphingosine, dihydrosphingosine, dihydrosphingosine L-phosphate, phosphatidylcholine, lysophosphatidic acid, phosphatidylserine, lysophosphatidylserine, phosphatidylethanolamine, lysophosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylglycerol, phosphatidylinositol, and lysophosphatidylinositol increased, especially in patients with severe COVID-19 during the later phase, suggesting that their modulations might result from kidney injuries accompanying severe COVID-19. CONCLUSIONS: Considering the biological properties of sphingolipids and glycerophospholipids, an understanding of their urinary modulations in COVID-19 will help us to understand the mechanisms causing COVID-19-associated kidney injuries as well as general acute kidney injuries and may prompt researchers to develop laboratory tests for predicting maximum severity and/or novel reagents to suppress the renal complications of COVID-19.

Lipidomics Revealed Plasma Phospholipid Profile Differences between Deceased and Recovered COVID-19 Patients.

Thorough understanding of metabolic changes, including lipidome alteration, associated with the development of COVID-19 appears to be crucial, as new types of coronaviruses are still reported. In this study, we analyzed the differences in the plasma phospholipid profiles of the deceased COVID-19 patients, those who recovered and healthy people. Due to identified abnormalities in plasma phospholipid profiles, deceased patients were further divided into two subgroups (D1 and D2). Increased levels of phosphatidylethanolamines (PE), phosphatidylcholines (PC) and phosphatidylserines (PS) were found in the plasma of recovered patients and the majority of deceased patients (first subgroup D1) compared to the control group. However, abundances of all relevant PE, PC and PS species decreased dramatically in the plasma of the second subgroup (D2) of five deceased patients. These patients also had significantly decreased plasma COX-2 activity when compared to the control, in contrast to unchanged and increased COX-2 activity in the plasma of the other deceased patients and recovered patients, respectively. Moreover, these five deceased patients were characterized by abnormally low CRP levels and tremendous increase in LDH levels, which may be the result of other pathophysiological disorders, including disorders of the immune system, liver damage and haemolytic anemia. In addition, an observed trend to decrease the autoantibodies against oxidative modifications of low-density lipoprotein (oLAb) titer in all, especially in deceased patients, indicate systemic oxidative stress and altered immune system that may have prognostic value in COVID-19.

Dynamic modulations of sphingolipids and glycerophospholipids in COVID-19.

BACKGROUND: A heterogeneous clinical phenotype is a characteristic of coronavirus disease 2019 (COVID-19). Therefore, investigating biomarkers associated with disease severity is important for understanding the mechanisms responsible for this heterogeneity and for developing novel agents to prevent critical conditions. This study aimed to elucidate the modulations of sphingolipids and glycerophospholipids, which have been shown to possess potent biological properties. METHODS: We measured the serum sphingolipid and glycerophospholipid levels in a total of 887 samples from 215 COVID-19 subjects, plus 115 control subjects without infectious diseases and 109 subjects with infectious diseases other than COVID-19. RESULTS: We observed the dynamic modulations of sphingolipids and glycerophospholipids in the serum of COVID-19 subjects, depending on the time course and severity. The elevation of C16:0 ceramide and lysophosphatidylinositol and decreases in C18:1 ceramide, dihydrosphingosine, lysophosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol were specific to COVID-19. Regarding the association with maximum severity, phosphatidylinositol and phosphatidylcholine species with long unsaturated acyl chains were negatively associated, while lysophosphatidylethanolamine and phosphatidylethanolamine were positively associated with maximum severity during the early phase. Lysophosphatidylcholine and phosphatidylcholine had strong negative correlations with CRP, while phosphatidylethanolamine had strong positive ones. C16:0 ceramide, lysophosphatidylcholine, phosphatidylcholine and phosphatidylethanolamine species with long unsaturated acyl chains had negative correlations with D-dimer, while phosphatidylethanolamine species with short acyl chains and phosphatidylinositol had positive ones. Several species of phosphatidylcholine, phosphatidylethanolamine and sphingomyelin might serve as better biomarkers for predicting severe COVID-19 during the early phase than CRP and D-dimer. Compared with the lipid modulations seen in mice treated with lipopolysaccharide, tissue factor, or histone, the lipid modulations observed in severe COVID-19 were most akin to those in mice administered lipopolysaccharide. CONCLUSION: A better understanding of the disturbances in sphingolipids and glycerophospholipids observed in this study will prompt further investigation to develop laboratory testing for predicting maximum severity and/or novel agents to suppress the aggravation of COVID-19.

Phosphatidic acid phosphatase 1 impairs SARS-CoV-2 replication by affecting the glycerophospholipid metabolism pathway.

Viruses exploit the host lipid metabolism machinery to achieve efficient replication. We herein characterize the lipids profile reprogramming in vitro and in vivo using liquid chromatography-mass spectrometry-based untargeted lipidomics. The lipidome of SARS-CoV-2-infected Caco-2 cells was markedly different from that of mock-infected samples, with most of the changes involving downregulation of ceramides. In COVID-19 patients' plasma samples, a total of 54 lipids belonging to 12 lipid classes that were significantly perturbed compared to non-infected control subjects' plasma samples were identified. Among these 12 lipid classes, ether-linked phosphatidylcholines, ether-linked phosphatidylethanolamines, phosphatidylcholines, and ceramides were the four most perturbed. Pathway analysis revealed that the glycerophospholipid, sphingolipid, and ether lipid metabolisms pathway were the most significantly perturbed host pathways. Phosphatidic acid phosphatases (PAP) were involved in all three pathways and PAP-1 deficiency significantly suppressed SARS-CoV-2 replication. siRNA knockdown of LPIN2 and LPIN3 resulted in significant reduction of SARS-CoV-2 load. In summary, these findings characterized the host lipidomic changes upon SARS-CoV-2 infection and identified PAP-1 as a potential target for intervention for COVID-19.

A Multifunctional Neutralizing Antibody-Conjugated Nanoparticle Inhibits and Inactivates SARS-CoV-2.

The outbreak of 2019 coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic. Despite intensive research, the current treatment options show limited curative efficacies. Here the authors report a strategy incorporating neutralizing antibodies conjugated to the surface of a photothermal nanoparticle (NP) to capture and inactivate SARS-CoV-2. The NP is comprised of a semiconducting polymer core and a biocompatible polyethylene glycol surface decorated with high-affinity neutralizing antibodies. The multifunctional NP efficiently captures SARS-CoV-2 pseudovirions and completely blocks viral infection to host cells in vitro through the surface neutralizing antibodies. In addition to virus capture and blocking function, the NP also possesses photothermal function to generate heat following irradiation for inactivation of virus. Importantly, the NPs described herein significantly outperform neutralizing antibodies at treating authentic SARS-CoV-2 infection in vivo. This multifunctional NP provides a flexible platform that can be readily adapted to other SARS-CoV-2 antibodies and extended to novel therapeutic proteins, thus it is expected to provide a broad range of protection against original SARS-CoV-2 and its variants.

Secreted Expression of mRNA-Encoded Truncated ACE2 Variants for SARS-CoV-2 via Lipid-Like Nanoassemblies.

The transfer of foreign synthetic messenger RNA (mRNA) into cells is essential for mRNA-based protein-replacement therapies. Prophylactic mRNA COVID-19 vaccines commonly utilize nanotechnology to deliver mRNA encoding SARS-CoV-2 vaccine antigens, thereby triggering the body's immune response and preventing infections. In this study, a new combinatorial library of symmetric lipid-like compounds is constructed, and among which a lead compound is selected to prepare lipid-like nanoassemblies (LLNs) for intracellular delivery of mRNA. After multiround optimization, the mRNA formulated into core-shell-structured LLNs exhibits more than three orders of magnitude higher resistance to serum than the unprotected mRNA, and leads to sustained and high-level protein expression in mammalian cells. A single intravenous injection of LLNs into mice achieves over 95% mRNA translation in the spleen, without causing significant hematological and histological changes. Delivery of in-vitro-transcribed mRNA that encodes high-affinity truncated ACE2 variants (tACE2v mRNA) through LLNs induces elevated expression and secretion of tACE2v decoys, which is able to effectively block the binding of the receptor-binding domain of the SARS-CoV-2 to the human ACE2 receptor. The robust neutralization activity in vitro suggests that intracellular delivery of mRNA encoding ACE2 receptor mimics via LLNs may represent a potential intervention strategy for COVID-19.

Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every continent, registering over 1,250,000 deaths worldwide. The effects of SARS-CoV-2 on host targets remains largely limited, hampering our understanding of Coronavirus Disease 2019 (COVID-19) pathogenesis and the development of therapeutic strategies. The present study used a comprehensive untargeted metabolomic and lipidomic approach to capture the host response to SARS-CoV-2 infection. We found that several circulating lipids acted as potential biomarkers, such as phosphatidylcholine 14:0_22:6 (area under the curve (AUC) = 0.96), phosphatidylcholine 16:1_22:6 (AUC = 0.97), and phosphatidylethanolamine 18:1_20:4 (AUC = 0.94). Furthermore, triglycerides and free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease. An untargeted analysis of non-critical COVID-19 patients identified a strong alteration of lipids and a perturbation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, aminoacyl-tRNA degradation, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. The severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. In addition, our study provided further evidence for considering phospholipase A2 (PLA2) activity as a potential key factor in the pathogenesis of COVID-19 and a possible therapeutic target. To date, the present study provides the largest untargeted metabolomics and lipidomics analysis of plasma from COVID-19 patients and control groups, identifying new mechanisms associated with the host response to COVID-19, potential plasma biomarkers, and therapeutic targets.