SARS-Coronavirus 2, A Metabolic Reprogrammer: A Review in the Context of the Possible Therapeutic Strategies

2021 ◽  
Vol 22 ◽  
Author(s):  
Poornima Gopi ◽  
TR Anju ◽  
Vinod Soman Pillai ◽  
Mohanan Veettil

: Novel coronavirus, SARS-CoV-2 is advancing at a staggering pace to devastate the health care system and foster the concerns over public health. In contrast to the past outbreaks, coronaviruses aren’t clinging themselves as a strict respiratory virus. Rather, becoming a multifaceted virus, it affects multiple organs by interrupting a number of metabolic pathways leading to significant rates of morbidity and mortality. Following infection they rigorously reprogram multiple metabolic pathways of glucose, lipid, protein, nucleic acid and their metabolites to extract adequate energy and carbon skeletons required for their existence and further molecular constructions inside a host cell. Although the mechanism of these alterations are yet to be known, the impact of these reprogramming is reflected in the hyper inflammatory responses, so called cytokine storm and the hindrance of host immune defence system. The metabolic reprogramming during SARS-CoV-2 infection needs to be considered while devising therapeutic strategies to combat the disease and its further complication. The inhibitors of cholesterol and phospholipids synthesis and cell membrane lipid raft of the host cell can, to a great extent, control the viral load and further infection. Depletion of energy source by inhibiting the activation of glycolytic and hexoseamine biosynthetic pathway can also augment the antiviral therapy. The cross talk between these pathways also necessitates the inhibition of amino acid catabolism and tryptophan metabolism. A combinatorial strategy which can address the cross talks between the metabolic pathways might be more effective than a single approach and the infection stage and timing of therapy will also influence the effectiveness of the antiviral approach. We herein focus on the different metabolic alterations during the course of virus infection that help to exploit the cellular machinery and devise a therapeutic strategy which promotes resistance to viral infection and can augment body’s antivirulence mechanisms. This review may cast the light into the possibilities of targeting altered metabolic pathways to defend virus infection in a new perspective.

2020 ◽  
Vol 32 (7) ◽  
pp. 485-491 ◽  
Author(s):  
Michael P Plebanek ◽  
Michael Sturdivant ◽  
Nicholas C DeVito ◽  
Brent A Hanks

Abstract The dendritic cell (DC) is recognized as a vital mediator of anti-tumor immunity. More recent studies have also demonstrated the important role of DCs in the generation of effective responses to checkpoint inhibitor immunotherapy. Metabolic programming of DCs dictates their functionality and can determine which DCs become immunostimulatory versus those that develop a tolerized phenotype capable of actively suppressing effector T-cell responses to cancers. As a result, there is great interest in understanding what mechanisms have evolved in cancers to alter these metabolic pathways, thereby allowing for their continued progression and metastasis. The therapeutic strategies developed to reverse these processes of DC tolerization in the tumor microenvironment represent promising candidates for future testing in combination immunotherapy clinical trials.


mSphere ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Anaïs Burgain ◽  
Faiza Tebbji ◽  
Inès Khemiri ◽  
Adnane Sellam

ABSTRACT Hypoxia is the predominant condition that the human opportunistic fungus Candida albicans encounters in the majority of the colonized niches within the host. So far, the impact of such a condition on the overall metabolism of this important human-pathogenic yeast has not been investigated. Here, we have undertaken a time-resolved metabolomics analysis to uncover the metabolic landscape of fungal cells experiencing hypoxia. Our data showed a dynamic reprogramming of many fundamental metabolic pathways, such as glycolysis, the pentose phosphate pathway, and different metabolic routes related to fungal cell wall biogenesis. The C. albicans lipidome was highly affected by oxygen depletion, with an increased level of free fatty acids and biochemical intermediates of membrane lipids, including phospholipids, lysophospholipids, sphingolipids, and mevalonate. The depletion of oxygen-dependent lipids such as ergosterol or phosphatidylcholine with longer and polyunsaturated lateral fatty acid chains was observed only at the later hypoxic time point (180 min). Transcriptomics data supported the main metabolic response to hypoxia when matched to our metabolomic profiles. The hypoxic metabolome reflected different physiological alterations of the cell wall and plasma membrane of C. albicans under an oxygen-limiting environment that were confirmed by different approaches. This study provided a framework for future in vivo investigations to examine relevant hypoxic metabolic trajectories in fungal virulence and fitness within the host. IMPORTANCE A critical aspect of cell fitness is the ability to sense and adapt to variations in oxygen levels in their local environment. Candida albicans is an opportunistic yeast that is the most prevalent human fungal pathogen. While hypoxia is the predominant condition that C. albicans encounters in most of its niches, its impact on fungal metabolism remains unexplored so far. Here, we provided a detailed landscape of the C. albicans metabolome that emphasized the importance of many metabolic routes for the adaptation of this yeast to oxygen depletion. The fungal hypoxic metabolome identified in this work provides a framework for future investigations to assess the contribution of relevant metabolic pathways in the fitness of C. albicans and other human eukaryotic pathogens with similar colonized human niches. As hypoxia is present at most of the fungal infection foci in the host, hypoxic metabolic pathways are thus an attractive target for antifungal therapy.


Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 74
Author(s):  
Erika S. Guimarães ◽  
Fabio V. Marinho ◽  
Nina M. G. P. de Queiroz ◽  
Maísa M. Antunes ◽  
Sergio C. Oliveira

The early detection of bacterial pathogens through immune sensors is an essential step in innate immunity. STING (Stimulator of Interferon Genes) has emerged as a key mediator of inflammation in the setting of infection by connecting pathogen cytosolic recognition with immune responses. STING detects bacteria by directly recognizing cyclic dinucleotides or indirectly by bacterial genomic DNA sensing through the cyclic GMP-AMP synthase (cGAS). Upon activation, STING triggers a plethora of powerful signaling pathways, including the production of type I interferons and proinflammatory cytokines. STING activation has also been associated with the induction of endoplasmic reticulum (ER) stress and the associated inflammatory responses. Recent reports indicate that STING-dependent pathways participate in the metabolic reprogramming of macrophages and contribute to the establishment and maintenance of a robust inflammatory profile. The induction of this inflammatory state is typically antimicrobial and related to pathogen clearance. However, depending on the infection, STING-mediated immune responses can be detrimental to the host, facilitating bacterial survival, indicating an intricate balance between immune signaling and inflammation during bacterial infections. In this paper, we review recent insights regarding the role of STING in inducing an inflammatory profile upon intracellular bacterial entry in host cells and discuss the impact of STING signaling on the outcome of infection. Unraveling the STING-mediated inflammatory responses can enable a better understanding of the pathogenesis of certain bacterial diseases and reveal the potential of new antimicrobial therapy.


Viruses ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 2
Author(s):  
Eric Mai ◽  
Caroline M. Percopo ◽  
Ajinkya R. Limkar ◽  
Albert C. Sek ◽  
Michelle Ma ◽  
...  

Virus-induced inflammation plays a critical role in determining the clinical outcome of an acute respiratory virus infection. We have shown previously that the administration of immunobiotic Lactobacillus plantarum (Lp) directly to the respiratory tract prevents lethal inflammatory responses to subsequent infection with a mouse respiratory virus pathogen. While Lp-mediated protective responses involve non-redundant contributions of both Toll-like receptor 2 (TLR2) and NOD2, the cellular basis of these findings remains unclear. Here, we address the impact of Lp and its capacity to suppress inflammation in virus-infected respiratory epithelial cells in two cell culture models. We found that both MLE-12 cells and polarized mouse tracheal epithelial cells (mTECs) were susceptible to infection with Influenza A and released proinflammatory cytokines, including CCL2, CCL5, CXCL1, and CXCL10, in response to replicating virus. MLE-12 cells express NOD2 (81 ± 6.3%) and TLR2 (19 ± 4%), respond to Lp, and are TLR2-specific, but not NOD2-specific, biochemical agonists. By contrast, we found that mTECs express NOD2 (81 ± 17%) but minimal TLR2 (0.93 ± 0.58%); nonetheless, mTECs respond to Lp and the TLR2 agonist, Pam2CSK4, but not NOD2 agonists or the bifunctional TLR2-NOD2 agonist, CL-429. Although MLE-12 cells and mTECS were both activated by Lp, little to no cytokine suppression was observed in response to Lp followed by virus infection via a protocol that replicated experimental conditions that were effective in vivo. Further study and a more complex approach may be required to reveal critical factors that suppress virus-induced inflammatory responses.


Author(s):  
Wei-Chun Chou ◽  
Elena Rampanelli ◽  
Xin Li ◽  
Jenny P.-Y. Ting

AbstractImmunometabolism, which is the metabolic reprogramming of anaerobic glycolysis, oxidative phosphorylation, and metabolite synthesis upon immune cell activation, has gained importance as a regulator of the homeostasis, activation, proliferation, and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity. Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection, inflammation, cancer, autoimmune diseases, and metabolic disorders. The crosstalk between the PI3K–AKT–mTOR and LKB1–AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism. The bidirectional interaction between immune cells and metabolism is a topic of intense study. Toll-like receptors (TLRs), cytokine receptors, and T and B cell receptors have been shown to activate multiple downstream metabolic pathways. However, how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood. The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors, such as nucleotide-binding and leucine-rich repeat-containing receptors (NLRs, or NOD-like receptors), absent in melanoma 2 (AIM2)-like receptors (ALRs), and the cyclic dinucleotide receptor stimulator of interferon genes (STING). We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways. Whenever appropriate, this review will provide a brief contextual connection to pathogenic infections, autoimmune diseases, cancers, metabolic disorders, and/or inflammatory bowel diseases.


2021 ◽  
Vol 5 (1) ◽  
pp. 156-166
Author(s):  
Caroline Lo Presti ◽  
Florence Fauvelle ◽  
Marie-Christine Jacob ◽  
Julie Mondet ◽  
Pascal Mossuz

Abstract Leukemic cells display some alterations in metabolic pathways, which play a role in leukemogenesis and in patients’ prognosis. To evaluate the characteristics and the impact of this metabolic reprogramming, we explore the bone marrow samples from 54 de novo acute myeloid leukemia (AML) patients, using an untargeted metabolomics approach based on proton high-resolution magic angle spinning-nuclear magnetic resonance. The spectra obtained were subjected to multivariate statistical analysis to find specific metabolome alterations and biomarkers correlated to clinical features. We found that patients display a large diversity of metabolic profiles, according to the different AML cytologic subtypes and molecular statuses. The link between metabolism and molecular status was particularly strong for the oncometabolite 2-hydroxyglutarate (2-HG), whose intracellular production is directly linked to the presence of isocitrate dehydrogenase mutations. Moreover, patients’ prognosis was strongly impacted by several metabolites, such as 2-HG that appeared as a good prognostic biomarker in our cohort. Conversely, deregulations in phospholipid metabolism had a negative impact on prognosis through 2 main metabolites (phosphocholine and phosphoethanolamine), which could be potential aggressiveness biomarkers. Finally, we highlighted an overexpression of glutathione and alanine in chemoresistant patients. Overall, our results demonstrate that different metabolic pathways could be activated in leukemic cells according to their phenotype and maturation levels. This confirms that metabolic reprogramming strongly influences prognosis of patients and underscores a particular role of certain metabolites and associated pathways in AML prognosis, suggesting common mechanisms developed by leukemic cells to maintain their aggressiveness even after well-conducted induction chemotherapy.


2020 ◽  
Author(s):  
Laura Lafon-Hughes

BACKGROUND COVID-19 pandemic prompts the study of coronavirus biology and search of putative therapeutic strategies. OBJECTIVE To compare SARS-CoV-2 genome-wide structure and proteins with other coronaviruses, focusing on putative coronavirus-specific or SARS-CoV-2 specific therapeutic designs. METHODS The genome-wide structure of SARS-CoV-2 was compared to that of SARS and other coronaviruses in order to gain insights, doing a literature review through Google searches. RESULTS There are promising therapeutic alternatives. Host cell targets could be modulated to hamper viral replication, but targeting viral proteins directly would be a better therapeutic design, since fewer adverse side effects would be expected. CONCLUSIONS Therapeutic strategies (Figure 1) could include the modulation of host targets (PARPs, kinases) , competition with G-quadruplexes or nucleoside analogs to hamper RDRP. The nicest anti-CoV options include inhibitors of the conserved essential viral proteases and drugs that interfere ribosome slippage at the -1 PRF site.


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