ABSTRACT
We present compelling evidence for the existence of an evolutionary adaptive response to viral agents such as SARS-CoV-2, that results in the human in vivo biosynthesis of a family of compounds with potential antiviral activity. Using nuclear magnetic resonance (NMR) spectroscopy, we detected a characteristic spin-system motif indicative of the presence of an extended panel of urinary and serum metabolites during the acute viral phase. The structure of eight of nucleoside analogues was elucidated (six of which have not previously been reported in human urine), and subsequently confirmed by total-synthesis and matrix spiking. The molecular structures of the nucleoside analogues and their correlation with an array of serum cytokines, including IFN-2, IFN-{gamma} and IL-10, suggest an association with the viperin enzyme contributing to an endogenous innate immune defense mechanism against viral infection.
Subject(s)
Virus Diseases , COVID-19ABSTRACT
Deep metabolomic, proteomic and immunologic phenotyping of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients have matched a wide diversity of clinical symptoms with potential biomarkers for coronavirus disease 2019 (COVID-19). Within here, several studies described the role of metabolites, lipoproteins and inflammation markers during infection and in recovered patients. In fact, after SARS-CoV-2 viral infection almost 20-30% of patients experience persistent symptoms even after 12 weeks of recovery which has been defined as long-term COVID-19 syndrome (LTCS). Emerging evidence revealed that a dysregulated immune system and persisting inflammation could be one of the key drivers of LTCS. However, how these small biomolecules such as metabolites, lipoprotein, cytokines and chemokines altogether govern pathophysiology is largely underexplored. Thus, a clear understanding of how these parameters in an integrated fashion could predict the disease course may help to stratify LTCS patients from acute COVID-19 or recovered specimens and would help to elucidate a potential mechanistic role of these biomolecules during the disease course. Here, we report an integrated analysis of blood serum and plasma by in vitro diagnostics research NMR spectroscopy and flow cytometry-based cytokine quantification in a total of 125 individuals (healthy controls (HC; n=73), recovered (n=12), acute (n=7) and LTCS (n=33)). We identified that in LTCS patients lactate and pyruvate were significantly different from either healthy controls or acute COVID-19 patients. Further correlational analysis of cytokines and metabolites indicated that creatine, glutamine, and high-density lipoprotein (HDL) phospholipids were distributed differentially amongst patients or individuals. Of note, triglycerides and several lipoproteins (apolipoproteins Apo-A1 and A2) in LTCS patients demonstrate COVID-19-like alterations compared to HC. Interestingly, LTCS and acute COVID-19 samples were distinguished mostly by their creatinine, phenylalanine, succinate, 3-hydroxybutyrate (3-HB) and glucose concentrations, illustrating an imbalanced energy metabolism. Most of the cytokines and chemokines were present at low levels in LTCS patients compared with HC except IL-18 chemokine, which tended to be higher in LTCS patients and correlated positively with several amino acids (creatine, histidine, leucine, and valine), metabolites (lactate and 3-HB) and lipoproteins. The identification of these persisting plasma metabolites, lipoprotein and inflammation alterations will help to better stratify LTCS patients from other diseases and could help to predict the ongoing severity of LTCS patients.
Subject(s)
Coronavirus Infections , Severe Acute Respiratory Syndrome , Disruptive, Impulse Control, and Conduct Disorders , COVID-19 , InflammationABSTRACT
Background: The exact pathophysiology of humans suffering from the multifaceted SARS-CoV-2 infection is not yet conclusively understood and risk stratification is needed. Novel diagnostic approaches like the nuclear magnetic resonance spectroscopy (NMR) based quantification of metabolites, lipoproteins, and inflammation markers has helped to identify typical alterations in the blood serum of COVID-19 patients. However, important confounders such as age, sex, and comorbidities, which strongly influence the metabolome, were often not considered. Therefore, the aim of this NMR study was to consider gender, as well as arterial hypertension (AHT) which affects more than 1.2 billion people worldwide, when investigating COVID-19-positive serum samples in a large age-matched cohort. As AHT is a risk factor for severe COVID-19 disease, this study focuses on comparing metabolomic characteristics of COVID-19 patients with and without AHT. Methods and Findings: NMR serum data from 329 COVID-19 patients were compared with 305 individuals from a healthy age and sex-matched control cohort. 134 of the 329 COVID-19 patients were affected by AHT. These were analyzed together with NMR data from 58 hypertensives without COVID-19. In addition to metabolite, lipoprotein, and glycoprotein data from NMR, common laboratory parameters were considered. Statistical comparison of the COVID-19 cohort with the control cohort reproduced results of previous studies. However, several differences emerged when AHT was considered. Especially, the previously described triglyceride-rich lipoprotein profile was no longer observed in COVID-19 patients, nor was an increase in ketone bodies. Typical metabolic changes that were apparent in COVID-19 patients in both sexes and with AHT were an increase in C- reactive protein (CRP) and the ratio of total glycoprotein (Glyc) to supramolecular phospholipids composite (SPC) which is an inflammatory NMR parameter. Further alterations were a decrease in glutamine, leucine, isoleucine, and lysine, citric acid, HDL-4 particles, and total cholesterol. Typical metabolic cardiovascular risk markers could be detected in hypertensive COVID-19 patients, as well as higher inflammatory NMR parameters than in normotensive COVID-19 patients. Conclusion: We could show that a more precise picture of COVID-19 blood serum parameters emerge when AHT is considered which accordingly should be included in future studies and would help for a refined patient stratification.
Subject(s)
Hypertension , COVID-19 , InflammationABSTRACT
The SARS-CoV-2 virus is the causative agent of the global COVID-19 infectious disease outbreak, which can lead to acute respiratory distress syndrome (ARDS). However, it is still unclear how the virus interferes with immune cell and metabolic functions in the human body. In this study, we investigated the immune response in acute or convalescent COVID19 patients. We characterized the peripheral blood mononuclear cells (PBMCs) using flow cytometry and found that CD8+ T cells were significantly subsided in moderate COVID-19 and convalescent patients. Furthermore, characterization of CD8+ T cells suggested that patients with a mild and moderate course of the COVID-19 disease and convalescent patients have significantly diminished expression of both perforin and granzyme A in CD8+ T cells. Using 1H-NMR spectroscopy, we characterized the metabolic status of their autologous PBMCs. We found that fructose, lactate and taurine levels were elevated in infected (mild and moderate) patients compared with control and convalescent patients. Glucose, glutamate, formate and acetate levels were attenuated in COVID-19 (mild and moderate) patients. In summary, our report suggests that SARS-CoV-2 infection leads to disrupted CD8+ T cytotoxic functions and changes the overall metabolic functions of immune cells.