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Hypertension is one of the most common risk factors for COVID-19 clinical progression. The identification of plasma biomarkers for anticipating worse clinical outcomes and to better understand the shared mechanisms between hypertension and COVID-19 are needed. A hypothesis-generating study was designed to compare plasma proteomics and metabolomics between 22 hypertensives (HT) and 41 non-hypertensives (nHT) patients with the most unfavorable COVID-19 progression. A total of 43 molecules were significantly differed between HT (n = 22) and nHT (n = 41). Random Forest (RF) analysis identified myo-inositol, gelsolin and phosphatidylcholine (PC) 32:1 as the top molecules for distinguishing between HT and nHT. Plasma myo-inositol and gelsolin were higher ( P  = 0.03 and P  = 0.02, respectively) and plasma PC 32:1 was lower ( P  = 0.03) in HT compared to nHT. Biological processes like stress response and blood coagulation, along with KEGG pathways including ascorbate and aldarate metabolism ( P  = 0.021) and linoleic acid metabolism ( P  = 0.028), were altered in hypertensive patients with the most unfavorable COVID-19 progression. There is a clear link between hypertension and severe COVID-19. Key biological pathways to consider for improving the prognosis and quality of life of hypertensive patients who become infected with SARS-CoV-2 include oxidative stress, ascorbate and aldarate metabolism, lipid metabolism, immune system and inflammation.

[This corrects the article DOI: 10.1371/journal.pone.0269875.].

Antiretroviral therapy (ART) induces persistent suppression of HIV-1 replication and gradual recovery of T-cell counts, and consequently, morbidity and mortality from HIV-related illnesses have been significantly reduced. However, in approximately 30% of people living with HIV (PLHIV) on ART, CD4 + T-cell counts fail to normalize despite ART and complete suppression of HIV viral load, resulting in severe immune dysfunction, which may represent an increased risk of clinical progression to AIDS and non-AIDS events as well as increased mortality. These patients are referred to as “immune inadequate responders”, “immunodiscordant responders” or “immune nonresponders (INR)”. The molecular mechanisms underlying poor CD4 + T-cell recovery are still unclear. In this sense, the use of omics sciences has shed light on possible factors involved in the activity and metabolic dysregulation of immune cells during the failure of CD4 + T-cell recovery in INR. Moreover, identification of key molecules by omics approaches allows for the proposal of potential biomarkers or therapeutic targets to improve CD4 + T-cell recovery and the quality of life of these patients. Hence, this review aimed to summarize the information obtained through different omics concerning the molecular factors and pathways associated with the INR phenotype to better understand the complexity of this immunological status in HIV infection.

The pathological mechanisms of SARS-CoV-2 in humans remain unclear and the unpredictability of COVID-19 progression may be attributed to the absence of biomarkers that contribute to the prognosis of this disease. Therefore, the discovery of biomarkers is needed for reliable risk stratification and to identify patients who are more likely to progress to a critical stage. Aiming to identify new biomarkers we analysed N-glycan traits in plasma from 196 patients with COVID-19. Samples were classified into three groups according to their severity (mild, severe and critical) and obtained at diagnosis (baseline) and at 4 weeks of follow-up (postdiagnosis), to evaluate their behaviour through disease progression. N-glycans were released with PNGase F and labelled with Rapifluor-MS, followed by their analysis by LC-MS/MS. The Simglycan structural identification tool and Glycostore database were employed to predict the structure of glycans. We determined that plasma from SARS-CoV-2-infected patients display different N-glycosylation profiles depending on the disease severity. Specifically, levels of fucosylation and galactosylation decreased with increasing severity and Fuc1Hex5HexNAc5 was identified as the most suitable biomarker to stratify patients at diagnosis and distinguish mild from critical outcomes. In this study we explored the global plasma glycosignature, reflecting the inflammatory state of the organs during the infectious disease. Our findings show the promising potential of glycans as biomarkers of COVID-19 severity.

Coronavirus-19 (COVID-19) disease is driven by an unchecked immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus which alters host mitochondrial-associated mechanisms. Compromised mitochondrial health results in abnormal reprogramming of glucose metabolism, which can disrupt extracellular signalling. We hypothesized that examining mitochondrial energy-related signalling metabolites implicated in host immune response to SARS-CoV-2 infection would provide potential biomarkers for predicting the risk of severe COVID-19 illness. We used a semi-targeted serum metabolomics approach in 273 patients with different severity grades of COVID-19 recruited at the acute phase of the infection to determine the relative abundance of tricarboxylic acid (Krebs) cycle-related metabolites with known extracellular signaling properties (pyruvate, lactate, succinate and α-ketoglutarate). Abundance levels of energy-related metabolites were evaluated in a validation cohort (n=398) using quantitative fluorimetric assays. Increased levels of four energy-related metabolites (pyruvate, lactate, a-ketoglutarate and succinate) were found in critically ill COVID-19 patients using semi-targeted and targeted approaches (p<0.05). The combined strategy proposed herein enabled us to establish that circulating pyruvate levels (p<0.001) together with body mass index (p=0.025), C-reactive protein (p=0.039), D-Dimer (p<0.001) and creatinine (p=0.043) levels, are independent predictors of critical COVID-19. Furthermore, classification and regression tree (CART) analysis provided a cut-off value of pyruvate in serum (24.54 µM; p<0.001) as an early criterion to accurately classify patients with critical outcomes. Our findings support the link between COVID-19 pathogenesis and immunometabolic dysregulation, and show that fluorometric quantification of circulating pyruvate is a cost-effective clinical decision support tool to improve patient stratification and prognosis prediction.

People living with chronic HIV (PLWH) show immune dysfunction, despite viral suppression and normal CD4 recovery, particularly those with low CD4/CD8 ratios. Subjacent cellular alterations of such a reliable marker of clinical progression remain elusive. Categorization by CD4/CD8 ratio after three year of therapy (R < 0.8/R > 1.2, = 28/ = 24) and reclassification by nadir-CD4 ( ≤ 350/ > 350) were performed in PLWH achieving viral suppression and CD4 ≥ 500. CD4 T cell-associated viral reservoir, as well as metabolism-related gene expression, glucose uptake ability, relative telomere length (RTL), and thymic output for CD4 and CD8 T cells, were determined. Patients with a CD4/CD8 ratio < 0.8 exhibited reduced CD8 T-cell glucose uptake ability after stimulation ( = 0.007) and trends to shorter RTL ( = 0.093) and to larger CD4-associated viral reservoir ( = 0.068) than > 1.2. Differently, patients with nadir ≤350 exhibited altered CD4 and CD8 T-cell expression of metabolism-related genes, although no differences in glucose uptake ability, and shorter RTL in both cell subsets, but similar viral reservoir to patients with nadir >350. Remarkably, viral reservoir and both CD4 and CD8 thymic output showed inverse associations ( = -0.623, = 0.01 and = -0.661,  = 0.038, respectively). A low CD4/CD8 ratio in chronic PLWH stands on a larger viral reservoir in CD4 T cells and metabolic alterations in CD8 T cells, probably related to its exhaustion and compromised effector functionality, and thymic output could contribute to such alterations. Patients with lower nadir-CD4 showed a resting-like CD4 phenotype and a metabolically active CD8 subset, without further viral reservoir extension. Persistence of low CD4/CD8 ratio and low nadir-CD4 counts seems to rely on different immune damage.

Background COVID-19 pneumonia causes hyperinflammatory response that culminates in acute respiratory syndrome (ARDS) related to increased multiorgan dysfunction and mortality risk. Antiviral-neutralizing immunoglobulins production reflect the host humoral status and illness severity, and thus, immunoglobulin (Ig) circulating levels could be evidence of COVID-19 prognosis. Methods The relationship among circulating immunoglobulins (IgA, IgG, IgM) and COVID-19 pneumonia was evaluated using clinical information and blood samples in a COVID-19 cohort composed by 320 individuals recruited during the acute phase and followed up to 4 to 8 weeks (n = 252) from the Spanish first to fourth waves. Results COVID-19 pneumonia development depended on baseline Ig concentrations. Circulating IgA levels together with clinical features at acute phase was highly associated with COVID-19 pneumonia development. IgM was positively correlated with obesity (ρb = 0.156, P = 0.020), dyslipemia (ρb = 0.140, P = 0.029), COPD (ρb = 0.133, P = 0.037), cancer (ρb = 0.173, P = 0.007) and hypertension (ρb = 0.148, P = 0.020). Ig concentrations at recovery phase were related to COVID-19 treatments. Conclusions Our results provide valuable information on the dynamics of immunoglobulins upon SARS-CoV-2 infection or other similar viruses.

Background Paraoxonase-1 (PON1) is an antioxidant enzyme synthesized by the liver. It protects against liver impairment and attenuates the production of the pro-inflammatory monocyte chemoattractant protein-1 (MCP-1). We investigated the relationships between hepatic PON1 and MCP-1 expression in rats with liver disease and explored the possible molecular mechanisms involved. Methods CCl 4 was administered for up to 12 weeks to induce liver damage. Serum and hepatic levels of PON1 and MCP-1, their gene and protein expression, nuclear transcription factors, and histological and biochemical markers of liver impairment were measured. Results High levels of PON1 and MCP-1 expression were observed at 12 th week in the hepatocytes surrounding the fibrous septa and inflammatory areas. CCl 4 -administered rats had an increased hepatic PON1 concentration that was related to decreased gene transcription and inhibited protein degradation. Decreased PON1 gene transcription was associated with PPARδ expression. These changes were accompanied by increased hepatic MCP-1 concentration and gene expression. There were significant direct relationships between hepatic PON1 and MCP-1 concentrations (P = 0.005) and between PON1 and the amount of activated stellate cells (P = 0.001). Conclusion Our results from this experimental model suggest a hepato-protective role for PON1 against inflammation, fibrosis and liver disease mediated by MCP-1.

Long-term elite controllers (LTECs) are a fascinating small subset of HIV individuals with viral and immunological HIV control in the long term that have been designated as models of an HIV functional cure. However, data on the LTEC phenotype are still scarce, and hence, the metabolomics and lipidomics signatures in the LTEC-extreme phenotype, LTECs with more than 10 years of viral and immunological HIV control, could be pivotal to finding the keys for functional HIV remission. Metabolomics and lipidomics analyses were performed using high-resolution mass spectrometry (ultra-high-performance liquid chromatography–electrospray ionization–quadrupole time of flight [UHPLC-(ESI) qTOF] in plasma samples of 13 patients defined as LTEC-extreme, a group of 20 LTECs that lost viral and/or immunological control during the follow-up study (LTEC-losing) and 9 EC patients with short-term viral and immunological control (less than 5 years; no-LTEC patients). Long-term viral and immunological HIV-1 control was found to be strongly associated with elevated tricarboxylic acid (TCA) cycle function. Interestingly, of the nine metabolites identified in the TCA cycle, α-ketoglutaric acid (p = 0.004), a metabolite implicated in the activation of the mTOR complex, a modulator of HIV latency and regulator of several biological processes, was found to be a key metabolite in the persistent control. On the other hand, a lipidomics panel combining 45 lipid species showed an optimal percentage of separation and an ability to differentiate LTEC-extreme from LTEC-losing, revealing that an elevated lipidomics plasma profile could be a predictive factor for the reignition of viral replication in LTEC individuals.

Background: In adults living with HIV, non-invasive biomarkers have been described for the early identification of metabolic dysfunction-associated steatotic liver diseases (MASLD). However, this issue remains unexplored in children and young people with vertical HIV (YWVH), among whom MASLD prevalence is around 30%. Methods: To identify biomarkers associated with MASLD in YWVH under sustained viral suppression with antiretroviral therapy, we analysed plasma lipid species, plasma bile acid profile, and gut microbiome composition in a cross-sectional cohort of 10 YWVH with MASLD and 19 YWVH without clinical evidence of MASLD (control). Results: Here we show that YWVH with MASLD have significantly increased circulating levels of eight specific lipid molecules and one bile acid, ursodeoxycholic acid (UDCA). UDCA and two triglycerides (TG54:5 and TG56:7) are identified as key biomolecules with strong discriminatory potential. The regression model incorporating these markers, along with hepatic steatosis index (HSI) and triglycerides-glucose index (TyG), demonstrates the highest predictive accuracy for MASLD (AUC of 0.932). UDCA correlates positively with Blautia and Collinsella genus ( p  = 0.040 and p  = 0.021, respectively), and negatively with Faecalibacterium ( p  = 0.030). Notably, principal component analysis based on bile acid levels reveals two possible subpopulations within the control group, one potentially at higher risk for MASLD. Conclusions: Combining UDCA, TG54:5 and TG56:7 with the validated HSI score provides a potential model with high specificity and sensitivity for predicting MASLD in YWVH. Moreover, early alterations in the bile acid profile may help identify YWVH at risk of developing MASLD. Plain Language Summary Children and young people who acquired HIV at birth are increasingly developing liver problems, such as metabolic dysfunction-associated steatotic liver disease (MASLD), a condition caused by fat accumulation in the liver. While there are non-invasive tools for early detection in adults, no biomarkers are currently available for children and youth. This preliminary study aims to identify simple, blood-based markers that could support early detection of MASLD in this population. Blood and stool samples from 29 participants were analysed to examine circulating fats, bile acids, and gut bacteria. The results indicate that one bile acid and two triglycerides were higher in those with MASLD and, when combined with clinical scores, could predict the disease. These findings may support earlier diagnosis and help prevent liver damage. Chafino et al. investigate plasma biomarkers to identify metabolic dysfunction-associated steatotic liver disease (MASLD) in youth with vertically acquired HIV. Plasma metabolomics and gut microbiome analyses reveal ursodeoxycholic acid and specific triglycerides as key molecules in a predictive model for MASLD.