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Simplified outline for snRNA-seq data analysis. snRNA-seq data from COVID-19 and control lung tissue were downloaded from the GEO database. “AddModuleScore” was used to score the metabolism-related KEGG pathways and Gene Ontology Terms associated with cellular functions. Then corr.test function was used to perform correlation analysis between metabolism-related pathways and cellular functions. “FindMarkers” was used to identify the Differential Expression Genes (DEGs) between the two groups. A circos plot and a heat map were used to visualize the DEGs associated with metabolic pathways of certain cell types to reveal the metabolic alterations relevant to innate or adaptive immunity
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Metabolic pathways drive cellular behavior. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes lung tissue damage directly by targeting cells or indirectly by producing inflammatory cytokines. However, whether functional alterations are related to metabolic changes in lung cells after SARS-CoV-2 infection remains unknown....
Citations
... The super pathway of Inositol Phosphate Compounds involves genes responsible for inositol production, which is essential to generate the phosphatidylinositol (PtdIns) needed to preserve the signaling pathways. A prior study has found that SARS-CoV-2 also affects metabolic pathways like the inositol phosphate metabolism, glycolysis, and oxidative phosphorylation [50]. The dysregulation of those pathways blocks surfactant secretion and alveolar epithelial differentiation. ...
... The dysregulation of those pathways blocks surfactant secretion and alveolar epithelial differentiation. In addition, disrupting the inositol phosphate metabolism may induce neutrophil infiltration and disrupt the lung barrier [50]. ...
The premise for this study emanated from the need to understand SARS-CoV-2 infections at the molecular level and to develop predictive tools for managing COVID-19 severity. With the varied clinical outcomes observed among infected individuals, creating a reliable machine learning (ML) model for predicting the severity of COVID-19 became paramount. Despite the availability of large-scale genomic and clinical data, previous studies have not effectively utilized multi-modality data for disease severity prediction using data-driven approaches. Our primary goal is to predict COVID-19 severity using a machine-learning model trained on a combination of patients' gene expression, clinical features, and co-morbidity data. Employing various ML algorithms, including Logistic Regression (LR), XGBoost (XG), Naïve Bayes (NB), and Support Vector Machine (SVM), alongside feature selection methods, we sought to identify the best-performing model for disease severity prediction. The results highlighted XG as the superior classifier, with 95% accuracy and a 0.99 AUC (Area Under the Curve), for distinguishing severity groups. Additionally, the SHAP analysis revealed vital features contributing to prediction, including several genes such as COX14, LAMB2, DOLK, SDCBP2, RHBDL1, and IER3-AS1. Notably, two clinical features, the absolute neutrophil count and Viremia Categories, emerged as top contributors. Integrating multiple data modalities has significantly improved the accuracy of disease severity prediction compared to using any single modality. The identified features could serve as biomarkers for COVID-19 prognosis and patient care, allowing clinicians to optimize treatment strategies and refine clinical decision-making processes for enhanced patient outcomes.
... Polysaccharides from the plant as a food/feed additive were suggested that they could have potential activities against SARS-CoV-2 and highly contagious viruses of animals including feline coronavirus, feline herpesvirus 1, feline influenza viruses, feline panleukopenia virus and feline calicivirus of domestic cats [13,15,16,17,18]. Myo-inositol is a natural polysaccharide synthesized by both animal and plant cells and presented in all tissues as an essential component of biological membranes and lung surfactant [19,20]. Besides its polysaccharide structure, myo-inositol is described as a nutritional additive as vitamins, pro-vitamins and chemically well-defined substances having a similar effect in fish, dog and cat nutrition by authorities [20,21,22]. ...
The study was carried to investigate the effect of myo–inositol supplementation on feed physicochemical structure and viral load of dry cat food contaminated with inactive SARS–CoV–2 by simulating sneezing. The most natural infection of severe acute respiratory syndrome coronavirus 2 (SARS–CoV–2) in animals is related to close contact with their owners with COVID–19 which is handling, taking care and feeding them. SARS–CoV–2 can survive on food, fomites and surfaces for extended periods related to environmental conditions. Many natural feed additives and supplements have been a candidate in recent antiviral treatment strategies against COVID–19. In this study, myo–inositol which is permitted in animal nutrition was used at different concentrations (0, 12.5, 25 and 50 mg·100 g-1 cat food) and conditions (22°C at room temperature and 4°C in the refrigerator) to investigate its effects on feed physicochemical structure and viral load of dry cat food contaminated with inactive SARS–CoV–2 by simulating sneezing. For the interactions between myo–inositol, feed structure and viral load, dry matter, moisture, water absorption index (WAI), water solubility index (WSI), pH and virus gene copy (GC) by RT–qPCR were measured. As only storage temperature affected both WAI and WSI as expected, myo–inostol supplementation dose–dependently decreased gene copy in dry cat food (IC50:366.4–581.5 mg·100 g-1 cat food) at 22°C storage temperature. Virus GC did not correlate with the dry matter, moisture content, pH and WAI after the 30 min contact time (except WSI). In conclusion, myo–inositol as a feed additive might have the potential to control serious viral infections such as COVID–19 for human–animal interactions in a One–Health context.
... The metagenome of the upper respiratory tract microbiota comprises of an extensive array of functionally distinct genes that are involved in a plethora of host cellular metabolic processes. Microbial infection in the upper respiratory tract has been shown to dysregulate these functional processes (72). In the case of SARS-CoV-2 infection, perturbation of cellular metabolic pathways has been demonstrated to alter host immunity with respect to disease severity and viral replication (73). ...
Background: Microbiome dysbiosis is associated with various diseases, including COVID-19. The association of the oral microbiome with SARS-CoV-2 infections and disease progression has been documented in European, Asian, and American populations but not in Africa.
Methods: We conducted a study in Ghana to evaluate and compare the naso-oropharyngeal microbiome in SARS-CoV-2-infected and noninfected persons before and after vaccination. 16S rDNA was sequenced and analysed from DNA extracted from the naso-oropharyngeal swabs of consenting participants.
Results: Alpha diversity was high among pre-vaccinated virus-positive individuals (Shannon: p< 0.0001) but reduced among vaccinated persons. Contrary to other reports, differences in viral loads did not significantly affect alpha diversity. Pre-vaccinated SARS-CoV-2-positive and -negative individuals had little yet significant microbial compositional dissimilarity (PERMANOVA: R²=0.14, p= 0.001) but not when some individuals were vaccinated (PERMANOVA: R²=0.013, p= 0.49). Consistent with other studies, Prevotella and Atopobium were abundant in pre-vaccinated virus-positive persons (adjusted p value <0.05). Butyrate-producing microbes, including members of Lachnospiraceae and Fusobacterium sp., were in relatively high abundances in infected individuals. As biomarkers associated with the infection (log10LDA> 4.0), they suggest probable protective pathophysiological processes that would prevent severe disease outcomes in this population. Anaerovoracaceae was increased in infected vaccinated persons, further implicating Firmicutes in protective immunity against COVID-19.
Conclusion: Our results necessitate further studies to confirm the integral role of Firmicutes in immune responses and disease progression. We also recommend expansion of microbiome–disease association studies across Africa to identify possible bacterial-mediated therapeutics for emerging infections.
... SARS-CoV-2 infection may lead to viral myocarditis, which may be associated with the expression of PLCG2. The expression of PLCG2 transcripts is upregulated in club cells after SARS-CoV-2 infection [109], and PLCG2 is highly expressed in the kidneys of patients with COVID-19 [108]. Cardiac injury due to COVID-19-induced differential expression of PLCG2 in cardiomyocytes may be associated with myocarditis. ...
Corona Virus Disease 2019 (COVID-19) not only causes respiratory system damage, but also imposes strain on the cardiovascular system. Vascular endothelial cells and cardiomyocytes play an important role in cardiac function. The aberrant expression of genes in vascular endothelial cells and cardiomyocytes can lead to cardiovascular diseases. In this study, we sought to explain the influence of respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the gene expression levels of vascular endothelial cells and cardiomyocytes. We designed an advanced machine learning-based workflow to analyze the gene expression profile data of vascular endothelial cells and cardiomyocytes from patients with COVID-19 and healthy controls. An incremental feature selection method with a decision tree was used in building efficient classifiers and summarizing quantitative classification genes and rules. Some key genes, such as MALAT1, MT-CO1, and CD36, were extracted, which exert important effects on cardiac function, from the gene expression matrix of 104,182 cardiomyocytes, including 12,007 cells from patients with COVID-19 and 92,175 cells from healthy controls, and 22,438 vascular endothelial cells, including 10,812 cells from patients with COVID-19 and 11,626 cells from healthy controls. The findings reported in this study may provide insights into the effect of COVID-19 on cardiac cells and further explain the pathogenesis of COVID-19, and they may facilitate the identification of potential therapeutic targets.
... In patients with COVID-19,thescores of NK cell chemotaxis, activation, proliferation, and degranulation are significantly elevated. The level of inositol phosphate metabolism, glycolysis,and glycerolipid metabolism in NK cells are upregulated during COVID-19 [66]. During inflammation and viral infection,the glycolyticrate of NK cells obviously increases. ...
... Additionally, during COVID-19, the expression level of PLCG2 in NK cells significantly increases, which boosts its cytotoxicity. And the two enzymes participating glycerolipid metabolism including LPIN1 and LPIN2 are also upregulated in NK cells upon SARS-CoV-2 infection, which are very important for the dephosphorylation of phosphatidic acid, thus increasing the level of intracellular calcium andfacilitating NK cell cytotoxicity [66]. ...
... Meanwhile, arginine as well as its metabolites display a pronounced reduction, which may possibly impede normal Tmem or Teff responses [85]. The cytotoxicity of CD8+ T cells is enhanced by inositol phosphate and glycerolipid metabolism in lung tissue from patients with COVID-19 [66].As one of the products of neutral fat metabolism, free fatty acids also trigger T cell differentiation by inducing NETs during ALI. But the above process is mediated by DCs but not the direct effect of NETs on T cells [86].Hospitalized COVID-19 patients with pulmonary disease displayed enhanced glycosaminoglycan metabolism, which is associated with an accumulation of effector-like CD8+ T cell populations and decreased CD8+ Tmem as well as memory B cells [87].During exudative phase of ALI, a large number of T cellsmigrate toward infectious foci ininjured lung, giving rise to the progression or resolution of ALI [88].Experimental and clinical studies have demonstrated a vital relationship between the infiltration of resident CD8+ T cells and ALI [88].Additionally, a two-photon study have also disclosed that lung-infiltrating T cells exhibit obvious interstitial migration during infection [89,90]. ...
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions triggered by multiple intra- and extra-pulmonary injury factors, characterized by complicated molecular mechanisms and high mortality. Great strides have been made in the field of immunometabolism to clarify the interplay between intracellular metabolism and immune function in the past few years. Emerging evidence unveils the crucial roles of immunometabolism in inflammatory response and ALI. During ALI, both macrophages and lymphocytes undergo robust metabolic reprogramming and discrete epigenetic changes after activated. Apart from providing ATP and biosynthetic precursors, these metabolic cellular reactions and processes in lung also regulate inflammation and immunity.In fact, metabolic reprogramming involving glucose metabolism and fatty acidoxidation (FAO) acts as a double-edged sword in inflammatory response, which not only drives inflammasome activation but also elicits anti-inflammatory response. Additionally, the features and roles of metabolic reprogramming in different immune cells are not exactly the same. Here, we outline the evidence implicating how adverse factors shape immunometabolism in differentiation types of immune cells during ALI and summarize key proteins associated with energy expenditure and metabolic reprogramming. Finally, novel therapeutic targets in metabolic intermediates and enzymes together with current challenges in immunometabolism against ALI were discussed.
... The inflammatory microenvironment may induce metabolic reprogramming of neutrophils associated with severe outcomes of respiratory virus diseases [184,[204][205][206][207][208]. The respiratory syncytial virus is associated with the production by neutrophils of oxygen radicals through arachidonic acid metabolism responsible for tissue damage and bronchoconstriction during pathogenesis [209,210]. ...
... Salomon and colleagues [222] demonstrate that a robust metabolic response occurs at the peak of the NK response, involving elevated rates of glycolysis and OXPHOS. NK cells enhance glycerolipid and inositol phosphate metabolism to enhance cytotoxicity during SARS-CoV-2 infection [206]. ...
RNA viruses are known to induce a wide variety of respiratory tract illnesses, from simple colds to the latest coronavirus pandemic, causing effects on public health and the economy worldwide. Influenza virus (IV), parainfluenza virus (PIV), metapneumovirus (MPV), respiratory syncytial virus (RSV), rhinovirus (RhV), and coronavirus (CoV) are some of the most notable RNA viruses. Despite efforts, due to the high mutation rate, there are still no effective and scalable treatments that accompany the rapid emergence of new diseases associated with respiratory RNA viruses. Host-directed therapies have been applied to combat RNA virus infections by interfering with host cell factors that enhance the ability of immune cells to respond against those pathogens. The reprogramming of immune cell metabolism has recently emerged as a central mechanism in orchestrated immunity against respiratory viruses. Therefore, understanding the metabolic signature of immune cells during virus infection may be a promising tool for developing host-directed therapies. In this review, we revisit recent findings on the immunometabolic modulation in response to infection and discuss how these metabolic pathways may be used as targets for new therapies to combat illnesses caused by respiratory RNA viruses.
... In this study, high levels of some metabolic pathways (glycolysis, inositol phosphate and glycerolipid metabolism) and two enzymes in glycerolipid metabolism pathway (lipin 1 and lipin 2) were found. These metabolic changes may contribute to enhance NK cell functions, such as chemotaxis, degranulation and cytotoxicity (94). ...
Cellular metabolism is essential for the correct function of immune system cells, including Natural Killer cells (NK). These cells depend on energy to carry out their effector functions, especially in the early stages of viral infection. NK cells participate in the innate immune response against viruses and tumors. Their main functions are cytotoxicity and cytokine production. Metabolic changes can impact intracellular signals, molecule production, secretion, and cell activation which is essential as the first line of immune defense. Metabolic variations in different immune cells in response to a tumor or pathogen infection have been described; however, little is known about NK cell metabolism in the context of viral infection. This review summarizes the activation-specific metabolic changes in NK cells, the immunometabolism of NK cells during early, late, and chronic antiviral responses, and the metabolic alterations in NK cells in SARS-CoV2 infection. The modulation points of these metabolic routes are also discussed to explore potential new immunotherapies against viral infections.
... Reducing the levels of proinflammatory molecules like mCRP and nnCRP (331,332) will further reduce the detrimental effects of inflammaging. Reestablishing the cellular metabolic homeostasis in inflammatory diseases as well as SARS-CoV-2 infection and COVID-19 disease especially in the lungs and cardiovascular system, could become paramount to balance altered innate and adaptive immunity and cell function and reduce morbimortality (333)(334)(335). Treatment of chronic inflammatory diseases and now COVID-19 appears to be complex and may resist finding a single silver bullet intervention (247) supporting the use of combination therapies (170); especially in COVID-19 bearing in mind that "no one is safe until everyone is safe" (336). ...
Many local and systemic diseases especially diseases that are leading causes of death globally like chronic obstructive pulmonary disease, atherosclerosis with ischemic heart disease and stroke, cancer and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 19 (COVID-19), involve both, (1) oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels, and (2) inflammation. The GSH tripeptide (γ- L-glutamyl-L-cysteinyl-glycine), the most abundant water-soluble non-protein thiol in the cell (1–10 mM) is fundamental for life by (a) sustaining the adequate redox cell signaling needed to maintain physiologic levels of oxidative stress fundamental to control life processes, and (b) limiting excessive oxidative stress that causes cell and tissue damage. GSH activity is facilitated by activation of the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 that regulates expression of genes controlling antioxidant, inflammatory and immune system responses. GSH exists in the thiol-reduced (>98% of total GSH) and disulfide-oxidized (GSSG) forms, and the concentrations of GSH and GSSG and their molar ratio are indicators of the functionality of the cell. GSH depletion may play a central role in inflammatory diseases and COVID-19 pathophysiology, host immune response and disease severity and mortality. Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of inflammatory diseases and COVID-19 and increasing GSH levels may prevent and subdue these diseases. The life value of GSH makes for a paramount research field in biology and medicine and may be key against systemic inflammation and SARS-CoV-2 infection and COVID-19 disease. In this review, we emphasize on (1) GSH depletion as a fundamental risk factor for diseases like chronic obstructive pulmonary disease and atherosclerosis (ischemic heart disease and stroke), (2) importance of oxidative stress and antioxidants in SARS-CoV-2 infection and COVID-19 disease, (3) significance of GSH to counteract persistent damaging inflammation, inflammaging and early (premature) inflammaging associated with cell and tissue damage caused by excessive oxidative stress and lack of adequate antioxidant defenses in younger individuals, and (4) new therapies that include antioxidant defenses restoration.
... The value of GSH and nutritional strategies like amino acids, vitamins, minerals, phytochemicals, sulforaphane to enhance cellular Nrf2, and other supplements used to restore GSH levels (Minich and Brown, 2019;Hermel et al., 2021) as adjunct treatments for SARS-CoV-2 infection needs to be further emphasized. Reestablishing the cellular metabolic homeostasis in SARS-CoV-2 infection and COVID-19 disease especially in the lungs, could become paramount to balance altered innate and adaptive immunity and cell function and reduce morbimortality (Hsu et al., 2022;Li S. et al., 2022). COVID-19 of the respiratory system appears to be a complex disease that may resist finding a single silver bullet intervention (Brosnahan et al., 2020). ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 19 (COVID-19) has numerous risk factors leading to severe disease with high mortality rate. Oxidative stress with excessive production of reactive oxygen species (ROS) that lower glutathione (GSH) levels seems to be a common pathway associated with the high COVID-19 mortality. GSH is a unique small but powerful molecule paramount for life. It sustains adequate redox cell signaling since a physiologic level of oxidative stress is fundamental for controlling life processes via redox signaling, but excessive oxidation causes cell and tissue damage. The water-soluble GSH tripeptide (γ-L-glutamyl-L-cysteinyl-glycine) is present in the cytoplasm of all cells. GSH is at 1–10 mM concentrations in all mammalian tissues (highest concentration in liver) as the most abundant non-protein thiol that protects against excessive oxidative stress. Oxidative stress also activates the Kelch-like ECH-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) redox regulator pathway, releasing Nrf2 to regulate the expression of genes that control antioxidant, inflammatory and immune system responses, facilitating GSH activity. GSH exists in the thiol-reduced and disulfide-oxidized (GSSG) forms. Reduced GSH is the prevailing form accounting for >98% of total GSH. The concentrations of GSH and GSSG and their molar ratio are indicators of the functionality of the cell and its alteration is related to various human pathological processes including COVID-19. Oxidative stress plays a prominent role in SARS-CoV-2 infection following recognition of the viral S-protein by angiotensin converting enzyme-2 receptor and pattern recognition receptors like toll-like receptors 2 and 4, and activation of transcription factors like nuclear factor kappa B, that subsequently activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) expression succeeded by ROS production. GSH depletion may have a fundamental role in COVID-19 pathophysiology, host immune response and disease severity and mortality. Therapies enhancing GSH could become a cornerstone to reduce severity and fatal outcomes of COVID-19 disease and increasing GSH levels may prevent and subdue the disease. The life value of GSH makes for a paramount research field in biology and medicine and may be key against SARS-CoV-2 infection and COVID-19 disease.
... Previous studies have found that healthy AEC II cells are highly oxidative and preferentially utilize lactate as a metabolic substrate for mitochondrial ATP production [69]; moreover, LDH enzyme activity can affect lactate oxidation and promote the formation of pulmonary fibrosis [70]. A recent study explored that in serious deceased COVID-19 patients, an upregulated glycolysis and oxidative phosphorylation are observed in AEC II cells, which may suppress alveolar epithelial differentiation and surfactant production; furthermore, increased glycolysis, oxidative phosphorylation, and inositol phosphate metabolism may also promote macrophages activation and contribute to lung injury [71]. Above all, metabolites can serve as an energy source for the cell survival as well as vital Fig. 2 The M1 macrophages interact with the AEC I to induce the cell death and the same way contribute to the AEC II expansion, M2 macrophages primary promote the AEC II proliferation as well as induce fibrosis, and the AEC II to AEC I differentiation is an important checkpoint for driving the alveoli structure reconstruction, which is a crucial step for returning structural and functional homeostasis. ...
Acute lung injury (ALI) usually causes acute respiratory distress syndrome (ARDS), or even death in critical ill patients. Immune cell infiltration in inflamed lungs is an important hallmark of ARDS. Macrophages are a type of immune cell that participate in the entire pathogenic trajectory of ARDS and most prominently via their interactions with lung alveolar epithelial cells (AECs). In the early stage of ARDS, classically activated macrophages secrete pro-inflammatory cytokines to clearance of the pathogens which may damage alveolar AECs cell structure and result in cell death. Paradoxically, in late stage of ARDS, anti-inflammatory cytokines secreted by alternatively activated macrophages dampen the inflammation response and promote epithelial regeneration and alveolar structure remodeling. In this review, we discuss the important role of macrophages and AECs in the progression of ARDS.
