MicroRNAs and Mammarenaviruses: Modulating Cellular Metabolism

Mammarenaviruses are a diverse genus of emerging viruses that include several causative agents of severe viral hemorrhagic fevers with high mortality in humans. Although these viruses share many similarities, important differences with regard to pathogenicity, type of immune response, and molecular mechanisms during virus infection are different between and within New World and Old World viral infections. Viruses rely exclusively on the host cellular machinery to translate their genome, and therefore to replicate and propagate. miRNAs are the crucial factor in diverse biological processes such as antiviral defense, oncogenesis, and cell development. The viral infection can exert a profound impact on the cellular miRNA expression profile, and numerous RNA viruses have been reported to interact directly with cellular miRNAs and/or to use these miRNAs to augment their replication potential. Our present study indicates that mammarenavirus infection induces metabolic reprogramming of host cells, probably manipulating cellular microRNAs. A number of metabolic pathways, including valine, leucine, and isoleucine biosynthesis, d-Glutamine and d-glutamate metabolism, thiamine metabolism, and pools of several amino acids were impacted by the predicted miRNAs that would no longer regulate these pathways. A deeper understanding of mechanisms by which mammarenaviruses handle these signaling pathways is critical for understanding the virus/host interactions and potential diagnostic and therapeutic targets, through the inhibition of specific pathologic metabolic pathways.

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Molecular mechanisms of human herpes viruses inferring with host immune surveillance

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000841 ◽

2020 ◽

Vol 8 (2) ◽

pp. e000841

Author(s):

Simon Jasinski-Bergner ◽

Ofer Mandelboim ◽

Barbara Seliger

Keyword(s):

Immune Evasion ◽

Antigen Processing ◽

Molecular Mechanisms ◽

Viral Infections ◽

Immune Surveillance ◽

Host Cells ◽

Herpes Viruses ◽

Molecular Processes ◽

Human Herpes ◽

Human Herpes Viruses

Several human herpes viruses (HHVs) exert oncogenic potential leading to malignant transformation of infected cells and/or tissues. The molecular processes induced by viral-encoded molecules including microRNAs, peptides, and proteins contributing to immune evasion of the infected host cells are equal to the molecular processes of immune evasion mediated by tumor cells independently of viral infections. Such major immune evasion strategies include (1) the downregulation of proinflammatory cytokines/chemokines as well as the induction of anti-inflammatory cytokines/chemokines, (2) the downregulation of major histocompatibility complex (MHC) class Ia directly as well as indirectly by downregulation of the components involved in the antigen processing, and (3) the downregulation of stress-induced ligands for activating receptors on immune effector cells with NKG2D leading the way. Furthermore, (4) immune modulatory molecules like MHC class Ib molecules and programmed cell death1 ligand 1 can be upregulated on infections with certain herpes viruses. This review article focuses on the known molecular mechanisms of HHVs modulating the above-mentioned possibilities for immune surveillance and even postulates a temporal order linking regular tumor immunology with basic virology and offering putatively novel insights for targeting HHVs.

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Untargeted Metabolomics Reveal Defensome-Related Metabolic Reprogramming in Sorghum bicolor against Infection by Burkholderia andropogonis

Metabolites ◽

10.3390/metabo9010008 ◽

2019 ◽

Vol 9 (1) ◽

pp. 8 ◽

Cited By ~ 16

Author(s):

Charity R. Mareya ◽

Fidele Tugizimana ◽

Lizelle A. Piater ◽

Ntakadzeni E. Madala ◽

Paul A. Steenkamp ◽

...

Keyword(s):

Sorghum Bicolor ◽

Metabolic Pathways ◽

Molecular Mechanisms ◽

Shikimic Acid ◽

Dynamic Network ◽

Metabolic Reprogramming ◽

Disease Suppression ◽

Untargeted Metabolomics ◽

Wide Range ◽

Burkholderia Andropogonis

Burkholderia andropogonis is the causal agent of bacterial leaf stripe, one of the three major bacterial diseases affecting Sorghum bicolor. However, the biochemical aspects of the pathophysiological host responses are not well understood. An untargeted metabolomics approach was designed to understand molecular mechanisms underlying S. bicolor–B. andropogonis interactions. At the 4-leaf stage, two sorghum cultivars (NS 5511 and NS 5655) differing in disease tolerance, were infected with B. andropogonis and the metabolic changes monitored over time. The NS 5511 cultivar displayed delayed signs of wilting and lesion progression compared to the NS 5655 cultivar, indicative of enhanced resistance. The metabolomics results identified statistically significant metabolites as biomarkers associated with the sorghum defence. These include the phytohormones salicylic acid, jasmonic acid, and zeatin. Moreover, metabolic reprogramming in an array of chemically diverse metabolites that span a wide range of metabolic pathways was associated with the defence response. Signatory biomarkers included aromatic amino acids, shikimic acid, metabolites from the phenylpropanoid and flavonoid pathways, as well as fatty acids. Enhanced synthesis and accumulation of apigenin and derivatives thereof was a prominent feature of the altered metabolomes. The analyses revealed an intricate and dynamic network of the sorghum defence arsenal towards B. andropogonis in establishing an enhanced defensive capacity in support of resistance and disease suppression. The results pave the way for future analysis of the biosynthesis of signatory biomarkers and regulation of relevant metabolic pathways in sorghum.

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Cellular Electron Cryo-Tomography to Study Virus-Host Interactions

Annual Review of Virology ◽

10.1146/annurev-virology-021920-115935 ◽

2020 ◽

Vol 7 (1) ◽

pp. 239-262

Author(s):

Emmanuelle R.J. Quemin ◽

Emily A. Machala ◽

Benjamin Vollmer ◽

Vojtěch Pražák ◽

Daven Vasishtan ◽

...

Keyword(s):

Viral Entry ◽

Cell Biology ◽

Molecular Mechanisms ◽

Virus Assembly ◽

Three Dimensional ◽

Surface Proteins ◽

Host Cells ◽

Phase Plate ◽

Structural Cell ◽

Host Interactions

Viruses are obligatory intracellular parasites that reprogram host cells upon infection to produce viral progeny. Here, we review recent structural insights into virus-host interactions in bacteria, archaea, and eukaryotes unveiled by cellular electron cryo-tomography (cryoET). This advanced three-dimensional imaging technique of vitreous samples in near-native state has matured over the past two decades and proven powerful in revealing molecular mechanisms underlying viral replication. Initial studies were restricted to cell peripheries and typically focused on early infection steps, analyzing surface proteins and viral entry. Recent developments including cryo-thinning techniques, phase-plate imaging, and correlative approaches have been instrumental in also targeting rare events inside infected cells. When combined with advances in dedicated image analyses and processing methods, details of virus assembly and egress at (sub)nanometer resolution were uncovered. Altogether, we provide a historical and technical perspective and discuss future directions and impacts of cryoET for integrative structural cell biology analyses of viruses.

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SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered Pathogenesis via Metabolic Reprograming of Glutamine in Host Cells

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.627842 ◽

2021 ◽

Vol 7 ◽

Author(s):

Shiv Bharadwaj ◽

Mahendra Singh ◽

Nikhil Kirtipal ◽

Sang Gu Kang

Keyword(s):

Cancer Metabolism ◽

Viral Infections ◽

Mammalian Target Of Rapamycin ◽

Metabolic Reprogramming ◽

Host Cells ◽

Glutamine Metabolism ◽

Altered Glucose

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as coronavirus disease 2019 (COVID-19) pandemic, has killed more than a million people worldwide, and researchers are constantly working to develop therapeutics in the treatment and prevention of this new viral infection. To infect and induced pathogenesis as observed in other viral infections, we postulated that SARS-CoV-2 may also require an escalation in the anabolic metabolism, such as glucose and glutamine, to support its energy and biosynthetic requirements during the infection cycle. Recently, the requirement of altered glucose metabolism in SARS-CoV-2 pathogenesis was demonstrated, but the role of dysregulated glutamine metabolism is not yet mentioned for its infection. In this perspective, we have attempted to provide a summary of possible biochemical events on putative metabolic reprograming of glutamine in host cells upon SARS-CoV-2 infection by comparison to other viral infections/cancer metabolism and available clinical data or research on SARS-CoV-2 pathogenesis. This systematic hypothesis concluded the vital role of glutaminase-1 (GLS1), phosphoserine aminotransferase (PSAT1), hypoxia-inducible factor-1 alpha (HIF-1α), mammalian target of rapamycin complex 1 (mTORC1), glutamine-fructose amidotransferase 1/2 (GFAT1/2), and transcription factor Myc as key cellular factors to mediate and promote the glutamine metabolic reprogramming in SARS-CoV-2 infected cells. In absence of concrete data available for SARS-CoV-2 induced metabolic reprogramming of glutamine, this study efforts to connect the gaps with available clinical shreds of evidence in SARS-CoV-2 infection with altered glutamine metabolism and hopefully could be beneficial in the designing of strategic methods for therapeutic development with elucidation using in vitro or in vivo approaches.

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Mitochondrial Retrograde Signalling and Metabolic Alterations in the Tumour Microenvironment

Cells ◽

10.3390/cells8030275 ◽

2019 ◽

Vol 8 (3) ◽

pp. 275 ◽

Cited By ~ 14

Author(s):

Dongki Yang ◽

Jaehong Kim

Keyword(s):

Molecular Mechanisms ◽

Tumour Microenvironment ◽

Metabolic Reprogramming ◽

Host Cells ◽

Metabolic Alterations ◽

Retrograde Signalling ◽

Functional Modulation

This review explores the molecular mechanisms that may be responsible for mitochondrial retrograde signalling related metabolic reprogramming in cancer and host cells in the tumour microenvironment and provides a summary of recent updates with regard to the functional modulation of diverse cells in the tumour microenvironment.

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A Message from the Human Placenta: Structural and Immunomodulatory Defense against SARS-CoV-2

Cells ◽

10.3390/cells9081777 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1777 ◽

Cited By ~ 3

Author(s):

Nina-Naomi Kreis ◽

Andreas Ritter ◽

Frank Louwen ◽

Juping Yuan

Keyword(s):

Vertical Transmission ◽

Molecular Mechanisms ◽

Viral Infections ◽

Preterm Births ◽

Nuclear Factor Κb ◽

Immune Defense ◽

Global Public Health ◽

Health Crisis ◽

Host Interactions ◽

Tissue Damages

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic has caused a global public health crisis. Viral infections may predispose pregnant women to a higher rate of pregnancy complications, including preterm births, miscarriage and stillbirth. Despite reports of neonatal COVID-19, definitive proof of vertical transmission is still lacking. In this review, we summarize studies regarding the potential evidence for transplacental transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterize the expression of its receptors and proteases, describe the placental pathology and analyze virus-host interactions at the maternal-fetal interface. We focus on the syncytium, the barrier between mother and fetus, and describe in detail its physical and structural defense against viral infections. We further discuss the potential molecular mechanisms, whereby the placenta serves as a defense front against pathogens by regulating the interferon type III signaling, microRNA-triggered autophagy and the nuclear factor-κB pathway. Based on these data, we conclude that vertical transmission may occur but rare, ascribed to the potent physical barrier, the fine-regulated placental immune defense and modulation strategies. Particularly, immunomodulatory mechanisms employed by the placenta may mitigate violent immune response, maybe soften cytokine storm tightly associated with severely ill COVID-19 patients, possibly minimizing cell and tissue damages, and potentially reducing SARS-CoV-2 transmission.

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Deep-Sea Hydrothermal Vent Viruses Compensate for Microbial Metabolism in Virus-Host Interactions

mBio ◽

10.1128/mbio.00893-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 20

Author(s):

Tianliang He ◽

Hongyun Li ◽

Xiaobo Zhang

Keyword(s):

Deep Sea ◽

Metabolic Pathways ◽

Extreme Environments ◽

Host Cells ◽

Host Interactions ◽

Metabolic Compensation ◽

Viral Genes ◽

Population Sizes ◽

Biological Entities ◽

The Relationship

ABSTRACT Viruses are believed to be responsible for the mortality of host organisms. However, some recent investigations reveal that viruses may be essential for host survival. To date, it remains unclear whether viruses are beneficial or harmful to their hosts. To reveal the roles of viruses in the virus-host interactions, viromes and microbiomes of sediment samples from three deep-sea hydrothermal vents were explored in this study. To exclude the influence of exogenous DNAs on viromes, the virus particles were purified with nuclease (DNase I and RNase A) treatments and cesium chloride density gradient centrifugation. The metagenomic analysis of viromes without exogenous DNA contamination and microbiomes of vent samples indicated that viruses had compensation effects on the metabolisms of their host microorganisms. Viral genes not only participated in most of the microbial metabolic pathways but also formed branched pathways in microbial metabolisms, including pyrimidine metabolism; alanine, aspartate, and glutamate metabolism; nitrogen metabolism and assimilation pathways of the two-component system; selenocompound metabolism; aminoacyl-tRNA biosynthesis; and amino sugar and nucleotide sugar metabolism. As is well known, deep-sea hydrothermal vent ecosystems exist in relatively isolated environments which are barely influenced by other ecosystems. The metabolic compensation of hosts mediated by viruses might represent a very important aspect of virus-host interactions. IMPORTANCE Viruses are the most abundant biological entities in the oceans and have very important roles in regulating microbial community structure and biogeochemical cycles. The relationship between virus and host microbes is broadly thought to be that of predator and prey. Viruses can lyse host cells to control microbial population sizes and affect community structures of hosts by killing specific microbes. However, viruses also influence their hosts through manipulation of bacterial metabolism. We found that viral genes not only participated in most microbial metabolic pathways but also formed branched pathways in microbial metabolisms. The metabolic compensation of hosts mediated by viruses may help hosts to adapt to extreme environments and may be essential for host survival. IMPORTANCE Viruses are the most abundant biological entities in the oceans and have very important roles in regulating microbial community structure and biogeochemical cycles. The relationship between virus and host microbes is broadly thought to be that of predator and prey. Viruses can lyse host cells to control microbial population sizes and affect community structures of hosts by killing specific microbes. However, viruses also influence their hosts through manipulation of bacterial metabolism. We found that viral genes not only participated in most microbial metabolic pathways but also formed branched pathways in microbial metabolisms. The metabolic compensation of hosts mediated by viruses may help hosts to adapt to extreme environments and may be essential for host survival.

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VDAC1 Silencing in Cancer Cells Leads to Metabolic Reprogramming That Modulates Tumor Microenvironment

Cancers ◽

10.3390/cancers13112850 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2850

Author(s):

Erez Zerbib ◽

Tasleem Arif ◽

Anna Shteinfer-Kuzmine ◽

Vered Chalifa-Caspi ◽

Varda Shoshan-Barmatz

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Cancer Progression ◽

Therapeutic Potential ◽

Tumor Regression ◽

Metabolic Reprogramming ◽

Host Cells ◽

Migration And Invasion ◽

Altered Expression ◽

Host Interactions

The tumor microenvironment (TME) plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Thus, better insight into tumor–host interactions is required. Most of these processes involve the metabolic reprogramming of cells. Here, we focused on this reprogramming in cancerous cells and its effect on the TME. A major limitation in the study of tumor–host interactions is the difficulty in separating cancerous from non-cancerous signaling pathways within a tumor. Our strategy involved specifically silencing the expression of VDAC1 in the mitochondria of human-derived A549 lung cancer xenografts in mice, but not in the mouse-derived cells of the TME. Next-generation sequencing (NGS) analysis allows distinguishing the human or mouse origin of genes, thus enabling the separation of the bidirectional cross-talk between the TME and malignant cells. We demonstrate that depleting VDAC1 in cancer cells led to metabolic reprogramming, tumor regression, and the disruption of tumor–host interactions. This was reflected in the altered expression of a battery of genes associated with TME, including those involved in extracellular matrix organization and structure, matrix-related peptidases, angiogenesis, intercellular interacting proteins, integrins, and growth factors associated with stromal activities. We show that metabolic rewiring upon mitochondrial VDAC1 silencing in cancer cells affected several components of the TME, such as structural protein matrix metalloproteinases and Lox, and elicited a stromal response resembling the reaction to a foreign body in wound healing. As tumor progression requires a cooperative interplay between the host and cancer cells, and the ECM is intensively remodeled during cancer progression, VDAC1 depletion induced metabolic reprogramming that targeted both tumor cells and resulted in the alteration of the whole spectrum of TME-related genes, affecting the reciprocal feedback between ECM molecules, host cells, and cancer cells. Thus, VDAC1 depletion using si-VDAC1 represents therapeutic potential, inhibiting cancer cell proliferation and also inducing the modulation of TME components, which influences cancer progression, migration, and invasion.

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Apoptosis: Molecular Mechanisms, Regulation and Role in Pathogenesis

Canadian Journal of Infectious Diseases ◽

10.1155/1997/131305 ◽

1997 ◽

Vol 8 (2) ◽

pp. 103-109 ◽

Cited By ~ 9

Author(s):

Ryan Wei Yan Hung ◽

Anthony W Chow

Keyword(s):

Infectious Diseases ◽

Molecular Mechanisms ◽

Biochemical Characterization ◽

Viral Infections ◽

Data Extraction ◽

Relevant Information ◽

Host Cells ◽

Novel Treatments ◽

University Of British Columbia ◽

Cell Death Pathway

OBJECTIVE: To review the current state of knowledge of apoptosis, with an emphasis on identifying potential and established roles for apoptosis in the pathogenesis of infectious diseases.DATA SOURCES: MEDLINE and the University of British Columbia library system were searched using the search subject, “apoptosis”, for the years 1992 to 1996. Further search terms (eg, “pathogenesis”) were used to narrow the results. These review articles and reference books were used as the basis for locating original articles on particular studies.DATA SELECTION: Approximately 40 studies were reviewed, with the criterion for selection being the relevance to either the molecular mechanisms behind apoptosis or roles for apoptosis in the pathogenesis of infectious diseases.DATA EXTRACTION: Relevant information from each study was collated into categories specific to morphological and biochemical characterization, and the regulation and molecular mechanisms of apoptosis and its role in the pathogenesis of infectious diseases.DATA SYNTHESIS AND CONCLUSIONS: Apoptosis is characterized by distinct morphological and biochemical changes that distinguish it from cell necrosis. Different signal transduction events and transcription factors can promote or inhibit apoptosis, although where and how these tie into the cell death pathway is still poorly understood. Apoptosis has been implicated in the pathogenesis of infectious diseases in two distinct ways: first, multicellular organisms use apoptosis to combat viral infections; and second, pathogens can alter the normal process of apoptosis in host cells by abnormal upregulation or downregulation. Many diseases have been shown to implicate apoptosis in their pathogenesis, raising the possibility of novel treatments for some disorders by therapeutically altering the occurrence and course of apoptosis. Therefore, further study of apoptosis in both health and disease needs to be rigorously pursued.

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Autocrine and paracrine interferon signalling as ‘ring vaccination’ and ‘contact tracing’ strategies to suppress virus infection in a host

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2020.3002 ◽

2021 ◽

Vol 288 (1945) ◽

pp. 20203002

Author(s):

G. Michael Lavigne ◽

Hayley Russell ◽

Barbara Sherry ◽

Ruian Ke

Keyword(s):

Molecular Mechanisms ◽

Viral Infections ◽

Population Level ◽

Host Cells ◽

Contact Tracing ◽

Interferon Response ◽

Paracrine Signalling ◽

Viral Spread ◽

Ring Vaccination ◽

Spread Of Infection

The innate immune response, particularly the interferon response, represents a first line of defence against viral infections. The interferon molecules produced from infected cells act through autocrine and paracrine signalling to turn host cells into an antiviral state. Although the molecular mechanisms of IFN signalling have been well characterized, how the interferon response collectively contribute to the regulation of host cells to stop or suppress viral infection during early infection remain unclear. Here, we use mathematical models to delineate the roles of the autocrine and the paracrine signalling, and show that their impacts on viral spread are dependent on how infection proceeds. In particular, we found that when infection is well-mixed, the paracrine signalling is not as effective; by contrast, when infection spreads in a spatial manner, a likely scenario during initial infection in tissue, the paracrine signalling can impede the spread of infection by decreasing the number of susceptible cells close to the site of infection. Furthermore, we argue that the interferon response can be seen as a parallel to population-level epidemic prevention strategies such as ‘contact tracing’ or ‘ring vaccination’. Thus, our results here may have implications for the outbreak control at the population scale more broadly.

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