How could we forget immunometabolism in SARS-CoV2 infection or COVID-19?
TL;DR: Induction of the immune response against the pathogen also requires metabolic energy that generates through the process of immunometabolism, which may serve as a cell-specific therapeutic approach to target COVID-19.
Abstract: SARS-CoV2 infection or COVID-19 has created panic around the world since its first origin in December 2019 in Wuhan city, China. The COVID-19 pandemic has infected more than 46.4 million people, with 1,199,727 deaths. The immune system plays a crucial role in the severity of COVID-19 and the development of pneumonia-induced acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Along with providing protection, both innate and T cell-based adaptive immune response dysregulate during severe SARS-CoV2 infection. This dysregulation is more pronounced in older population and patients with comorbidities (Diabetes, hypertension, obesity, other pulmonary and autoimmune diseases). However, COVID-19 patients develop protective antibodies (Abs) against SARS-CoV2, but they do not long for last. The induction of the immune response against the pathogen also requires metabolic energy that generates through the process of immunometabolism. The change in the metabolic stage of immune cells from homeostasis to an inflammatory or infectious environment is called immunometabolic reprogramming. The article describes the cellular immunology (macrophages, T cells, B cells, dendritic cells, NK cells and pulmonary epithelial cells (PEC) and vascular endothelial cells) and the associated immune response during COVID-19. Immunometabolism may serve as a cell-specific therapeutic approach to target COVID-19.
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TL;DR: In this paper, the authors highlight how obesity and impaired metabolic health increase complications and mortality in COVID-19 and summarize the consequences of SARS-CoV-2 infection for organ function and risk of NCDs.
Abstract: Obesity and impaired metabolic health are established risk factors for the non-communicable diseases (NCDs) type 2 diabetes mellitus, cardiovascular disease, neurodegenerative diseases, cancer and nonalcoholic fatty liver disease, otherwise known as metabolic associated fatty liver disease (MAFLD). With the worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), obesity and impaired metabolic health also emerged as important determinants of severe coronavirus disease 2019 (COVID-19). Furthermore, novel findings indicate that specifically visceral obesity and characteristics of impaired metabolic health such as hyperglycaemia, hypertension and subclinical inflammation are associated with a high risk of severe COVID-19. In this Review, we highlight how obesity and impaired metabolic health increase complications and mortality in COVID-19. We also summarize the consequences of SARS-CoV-2 infection for organ function and risk of NCDs. In addition, we discuss data indicating that the COVID-19 pandemic could have serious consequences for the obesity epidemic. As obesity and impaired metabolic health are both accelerators and consequences of severe COVID-19, and might adversely influence the efficacy of COVID-19 vaccines, we propose strategies for the prevention and treatment of obesity and impaired metabolic health on a clinical and population level, particularly while the COVID-19 pandemic is present.
264 citations
TL;DR: In this article , the authors discuss the major mechanisms that are involved in the pathogenesis of NAFLD and type 2 diabetes, and discuss whether these mechanisms place NA FLD in an important position to better understand the pathogenic of NCDs and communicable diseases, such as COVID-19.
146 citations
TL;DR: It is proposed that HK2 localization in MAMs of tumor cells is key in sustaining neoplastic progression, as it acts as an intersection node between metabolic and survival pathways.
Abstract: Hexokinases are a family of ubiquitous exose-phosphorylating enzymes that prime glucose for intracellular utilization. Hexokinase 2 (HK2) is the most active isozyme of the family, mainly expressed in insulin-sensitive tissues. HK2 induction in most neoplastic cells contributes to their metabolic rewiring towards aerobic glycolysis, and its genetic ablation inhibits malignant growth in mouse models. HK2 can dock to mitochondria, where it performs additional functions in autophagy regulation and cell death inhibition that are independent of its enzymatic activity. The recent definition of HK2 localization to contact points between mitochondria and endoplasmic reticulum called Mitochondria Associated Membranes (MAMs) has unveiled a novel HK2 role in regulating intracellular Ca2+ fluxes. Here, we propose that HK2 localization in MAMs of tumor cells is key in sustaining neoplastic progression, as it acts as an intersection node between metabolic and survival pathways. Disrupting these functions by targeting HK2 subcellular localization can constitute a promising anti-tumor strategy.
57 citations
Cites background from "How could we forget immunometabolis..."
...Interestingly, displacement of HK2 from mitochondria of dendritic cells was proposed to be involved in their death during SARS-CoV2 infection [47]....
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TL;DR: In this paper, the authors characterized the kinetics and durability of neutralizing antibody (Nab) response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of hyperglycemia.
Abstract: CONTEXT Demonstrating the ability to mount a neutralizing antibody response to SARS-CoV-2 in the presence of diabetes is crucial to understand COVID-19 pathogenesis, reinfection potential, and vaccine development. OBJECTIVE The aim of this study was to characterize the kinetics and durability of neutralizing antibody (Nab) response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of hyperglycemia. METHODS Using a lentiviral vector-based SARS-CoV-2 neutralization assay to measure Nabs, we characterized 150 patients randomly selected from a cohort of 509 patients with confirmed COVID-19 pneumonia. We analyzed Nab response according to the presence of diabetes or hyperglycemia, at the time of hospitalization and during the postdischarge follow-up: 1-, 3-, and 6-month outpatient visits. RESULTS Among 150 randomly selected patients 40 (26.6%) had diabetes. Diabetes (hazard ratio [HR] 8.9, P < .001), glucose levels (HR 1.25 × 1.1 mmol/L, P < .001), and glucose variability (HR 1.17 × 0.6 mmol/L, P < .001) were independently associated with an increased risk of mortality. The neutralizing activity of SARS-CoV-2 antibodies in patients with diabetes was superimposable, as for kinetics and extent, to that of patients without diabetes. It was similar across glucose levels and correlated with the humoral response against the SARS-CoV-2 spike protein. Positivity for Nabs at the time of hospital admission conferred protection on mortality, both in the presence (HR 0.28, P = .046) or absence of diabetes (HR 0.26, P = .030). The longevity of the Nab response was not affected by diabetes. CONCLUSION Diabetes and hyperglycemia do not affect the kinetics and durability of the neutralizing antibody response to SARS-CoV-2. These findings provide the rational to include patients with diabetes in the early phase of the vaccination campaign against SARS-CoV-2.
34 citations
TL;DR: In this article, the authors describe how excessive activation of the innate immune system and the need for viral replication in several cells of the infected organism promote significant alterations in cells' energy metabolism (glucose metabolism), which may underlie the poor prognosis of the disease in severe situations.
Abstract: COVID-19 is an infectious disease caused by Coronavirus 2 (SARS-CoV-2) that may lead to a severe acute respiratory syndrome. Such syndrome is thought to be related, at least in part, to a dysregulation of the immune system which involves three main components: hyperactivity of the innate immune system; decreased production of type 1 Interferons (IFN) by SARS-CoV-2-infected cells, namely respiratory epithelial cells and macrophages; and decreased numbers of both CD4+ and particularly CD8+ T cells. Herein, we describe how excessive activation of the innate immune system and the need for viral replication in several cells of the infected organism promote significant alterations in cells' energy metabolism (glucose metabolism), which may underlie the poor prognosis of the disease in severe situations. When activated, cells of the innate immune system reprogram their metabolism, and increase glucose uptake to ensure secretion of pro-inflammatory cytokines. Changes in glucose metabolism are also observed in pulmonary epithelial cells, contributing to dysregulation of cytokine synthesis and inflammation of the pulmonary epithelium. Controlling hyperglycolysis in critically ill patients may help to reduce the exaggerated production of pro-inflammatory cytokines and optimise the actions of the adaptive immune system. In this review, we suggest that the administration of non-toxic concentrations of 2-deoxy-D-glucose, the use of GLUT 1 inhibitors, of antioxidants such as vitamin C in high doses, as well as the administration of N-acetylcysteine in high doses, may be useful complementary therapeutic strategies for these patients, as suggested by some clinical trials and/ or reports. Overall, understanding changes in the glycolytic pathway associated with COVID-19 infection can help to find new forms of treatment for this disease.
27 citations
References
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TL;DR: Identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China, and it is shown that this virus belongs to the species of SARSr-CoV, indicates that the virus is related to a bat coronav virus.
Abstract: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1–4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV. Characterization of full-length genome sequences from patients infected with a new coronavirus (2019-nCoV) shows that the sequences are nearly identical and indicates that the virus is related to a bat coronavirus.
16,857 citations
TL;DR: It is shown that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets, which are named central memory (TCM) and effector memory (TEM).
Abstract: Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.
5,537 citations
"How could we forget immunometabolis..." refers background in this paper
...The number of T effector memory cells (Tems), including CD8þ T memory cells, increase in severe COVID-19 patients as indicated by CD8þCD69þCD137þ T cells, which highly produce of IFN-c, contain preformed perforin granules for immediate cytotoxic action against invading pathogen and home efficiently to peripheral lymphoid tissues, including lungs [37, 41, 42]....
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TL;DR: The vascular endothelium is an active paracrine, endocrine, and Endothelial cell infection and endotheliitis in COVID-19 and recruitment of immune cells can result in widespread endothelial dysfunction associated with apoptosis.
4,855 citations
TL;DR: The SARS-CoV-2 infection may affect primarily T lymphocytes particularly CD4+T and CD8+ T cells, resulting in decrease in numbers as well as IFN-γ production, which may be of importance due to their correlation with disease severity in COVID-19.
Abstract: BACKGROUNDSince December 2019, an outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, and is now becoming a global threat. We aimed to delineate and compare the immunological features of severe and moderate COVID-19.METHODSIn this retrospective study, the clinical and immunological characteristics of 21 patients (17 male and 4 female) with COVID-19 were analyzed. These patients were classified as severe (11 cases) and moderate (10 cases) according to the guidelines released by the National Health Commission of China.RESULTSThe median age of severe and moderate cases was 61.0 and 52.0 years, respectively. Common clinical manifestations included fever, cough, and fatigue. Compared with moderate cases, severe cases more frequently had dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer as well as markedly higher levels of IL-2R, IL-6, IL-10, and TNF-α. Absolute numbers of T lymphocytes, CD4+ T cells, and CD8+ T cells decreased in nearly all the patients, and were markedly lower in severe cases (294.0, 177.5, and 89.0 × 106/L, respectively) than moderate cases (640.5, 381.5, and 254.0 × 106/L, respectively). The expression of IFN-γ by CD4+ T cells tended to be lower in severe cases (14.1%) than in moderate cases (22.8%).CONCLUSIONThe SARS-CoV-2 infection may affect primarily T lymphocytes, particularly CD4+ and CD8+ T cells, resulting in a decrease in numbers as well as IFN-γ production by CD4+ T cells. These potential immunological markers may be of importance because of their correlation with disease severity in COVID-19.TRIAL REGISTRATIONThis is a retrospective observational study without a trial registration number.FUNDINGThis work is funded by grants from Tongji Hospital for the Pilot Scheme Project, and partly supported by the Chinese National Thirteenth Five Years Project in Science and Technology for Infectious Disease (2017ZX10202201).
3,488 citations
"How could we forget immunometabolis..." refers background in this paper
...The severe COVID-19 patients show a decrease in the absolute number of T cells (along with CD4þ, CD8þ, and IFN-c expressing CD4þ T cells) in the circulation (Figure 2A) [38, 39]....
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...However, central memory T cells (Tcms, CD45RA–CCR7þ) remain unchanged as identified by phenotyping activated CD4þCD69þCD137þ T cells [30, 41] Both, moderate and severe COVID-19 patients show a decrease in CD4þCD25þCD127low and CDR5RATregs, which may suppress the exaggerated inflammatory damage via their immunoregulatory action in a specific antigen (Ag) manner (Figure 2A) [38, 43, 44]....
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...However, still higher serum levels of IL-2R (an indicator of increased T cell activation and exacerbated viral infection), IL-6, IL-10, and TNF-a are present in severe COVID-19 patients than mild or moderate cases [38, 69]....
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Icahn School of Medicine at Mount Sinai1, University of Michigan2, Pasteur Institute3, University of California, San Francisco4, European Bioinformatics Institute5, University of California, San Diego6, University of North Carolina at Chapel Hill7, Fred Hutchinson Cancer Research Center8, Gladstone Institutes9, Buck Institute for Research on Aging10
TL;DR: A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.
Abstract: A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19. A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.
3,319 citations
"How could we forget immunometabolis..." refers background in this paper
...This antiviral immune response can clear the SARS-CoV2 infection, but the virus inhibits the type 1 IFN generation through its nonstructural proteins (Nsp), including Nsp13 and Nsp15, which bind to TBK1 to prevent the IRF3 phosphorylation [9, 165]....
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