Viruses Run: The Evasion Mechanisms of the Antiviral Innate Immunity by Hantavirus

Hantavirus can cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome (HPS) in America, with high mortality and unknown mechanisms. Innate immunity is the host’s first-line defense to bridge the acquired immunity against viral infections. However, hantavirus has evolved various strategies in both molecular and cellular aspects to evade the host’s natural immune surveillance. The Interferon-I (IFN-I) signaling pathway, a central link of host defense, induces various antiviral proteins to control the infection. This paper summarizes the molecular mechanisms of hantavirus evasion mechanisms of the IFN signaling pathway and cellular processes such as regulated cell death and cell stress. Besides, hantavirus could also evade immune surveillance evasion through cellular mechanisms, such as upregulating immune checkpoint molecules interfering with viral infections. Understanding hantavirus’s antiviral immune evasion mechanisms will deepen our understanding of its pathogenesis and help us develop more effective methods to control and eliminate hantavirus.

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When human guanylate-binding proteins meet viral infections

Journal of Biomedical Science ◽

10.1186/s12929-021-00716-8 ◽

2021 ◽

Vol 28 (1) ◽

Author(s):

Rongzhao Zhang ◽

Zhixin Li ◽

Yan-Dong Tang ◽

Chenhe Su ◽

Chunfu Zheng

Keyword(s):

Innate Immunity ◽

Viral Infection ◽

Binding Proteins ◽

Molecular Mechanisms ◽

Viral Infections ◽

Innate Immune ◽

Type I Interferons ◽

Type I ◽

Downstream Signaling ◽

Antiviral Innate Immunity

AbstractInnate immunity is the first line of host defense against viral infection. After invading into the cells, pathogen-associated-molecular-patterns derived from viruses are recognized by pattern recognition receptors to activate the downstream signaling pathways to induce the production of type I interferons (IFN-I) and inflammatory cytokines, which play critical functions in the host antiviral innate immune responses. Guanylate-binding proteins (GBPs) are IFN-inducible antiviral effectors belonging to the guanosine triphosphatases family. In addition to exerting direct antiviral functions against certain viruses, a few GBPs also exhibit regulatory roles on the host antiviral innate immunity. However, our understanding of the underlying molecular mechanisms of GBPs' roles in viral infection and host antiviral innate immune signaling is still very limited. Therefore, here we present an updated overview of the functions of GBPs during viral infection and in antiviral innate immunity, and highlight discrepancies in reported findings and current challenges for future studies, which will advance our understanding of the functions of GBPs and provide a scientific and theoretical basis for the regulation of antiviral innate immunity.

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β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein

Journal of Virology ◽

10.1128/jvi.01847-19 ◽

2019 ◽

Vol 94 (5) ◽

Cited By ~ 4

Author(s):

Hongjuan You ◽

Yingying Lin ◽

Feng Lin ◽

Mingyue Yang ◽

Jiahui Li ◽

...

Keyword(s):

Innate Immunity ◽

Herpes Simplex ◽

Immune Responses ◽

Signaling Pathway ◽

Kinase Activity ◽

Dna Virus ◽

Host Immune Responses ◽

Simplex Virus ◽

Antiviral Innate Immunity ◽

Hsv 1

ABSTRACT The cGAS/STING-mediated DNA-sensing signaling pathway is crucial for interferon (IFN) production and host antiviral responses. Herpes simplex virus I (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. Here, we demonstrate that the highly conserved β-catenin protein in the Wnt signaling pathway is an important factor to enhance the transcription of type I interferon (IFN-I) in the cGAS/STING signaling pathway, and the production of IFN-I mediated by β-catenin was antagonized by HSV-1 US3 protein via its kinase activity. Infection by US3-deficienct HSV-1 and its kinase-dead variants failed to downregulate IFN-I and IFN-stimulated gene (ISG) production induced by β-catenin. Consistent with this, absence of β-catenin enhanced the replication of US3-deficienct HSV-1, but not wild-type HSV-1. The underlying mechanism was the interaction of US3 with β-catenin and its hyperphosphorylation of β-catenin at Thr556 to block its nuclear translocation. For the first time, HSV-1 US3 has been shown to inhibit IFN-I production through hyperphosphorylation of β-catenin and to subvert host antiviral innate immunity. IMPORTANCE Although increasing evidence has demonstrated that HSV-1 subverts host immune responses and establishes lifelong latent infection, the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity, especially the cGAS/STING-mediated cellular DNA-sensing signaling pathway, have not been fully explored. Here, we show that β-catenin promotes cGAS/STING-mediated activation of the IFN pathway, which is important for cellular innate immune responses and intrinsic resistance to DNA virus infection. The protein kinase US3 antagonizes the production of IFN by targeting β-catenin via its kinase activity. The findings in this study reveal a novel mechanism for HSV-1 to evade host antiviral immunity and add new knowledge to help in understanding the interaction between the host and HSV-1 infection.

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Abstract 497: Cholesterol and Toll-like Receptor Signaling Are Important Regulators of Macrophage Interactions with Atherosclerotic Lipoprotein Aggregates

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a497 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Harvey F Chin ◽

Abigail Haka ◽

Frederick R Maxfield

Keyword(s):

Molecular Mechanisms ◽

Atherosclerotic Plaques ◽

Cholesteryl Esters ◽

Cellular Mechanisms ◽

Downstream Signaling ◽

Cellular Processes ◽

Atherosclerotic Plaque Formation ◽

Subendothelial Space ◽

Morphological Responses ◽

Cytoskeletal Rearrangements

Macrophages encounter deposits of aggregated low-density lipoproteins (agLDL) in the subendothelial space of blood vessels during the first stages of atherosclerotic plaque formation. Notably, current models for the mechanism of macrophage internalization of cholesterol in early atherosclerotic plaques are incomplete due to the lack of attention paid to the unique cellular mechanisms that are required for macrophages to degrade aggregates of LDL in particular, which can comprise >90% of the LDL in atherosclerotic plaques. In fact, internalization of cholesterol from cholesteryl esters in agLDL involves the development of intriguing cellular processes in which extracellular acidic compartments, lysosomal synapses (LSs), are formed whereby agLDL is partially degraded prior to internalization. This process requires extensive cytoskeletal rearrangements and secretion of lysosomal enzymes responsible for hydrolysis of cholesteryl esters from the agLDL. Subsequent delivery of free cholesterol from agLDL to the macrophage plasma membrane is central for development of the LS. Nonetheless, the molecular mechanism underlying initiation and propagation of the LS are currently largely unknown. This research proposal aims to elucidate the molecular mechanisms of LS formation and the role that cholesterol plays in eliciting these morphological responses to agLDL. Fluorescence microscopy assays were used to identify activation of TLR4 and downstream signaling involving PI3K and Akt as important events leading to LS formation. Furthermore, morphological responses of macrophages to cholesterol overloading require overlapping signaling pathways, indicating the role of interplay of cholesterol and TLR4 signaling in development of this novel macrophage interaction with aggregated LDL found in plaques. Identification of specific molecular pathways involved in this process will not only contribute to the basic understanding of one of the primary cellular processes contributing to atherosclerosis, one of the primary causes of heart disease, but also provide tangible molecular targets for the ultimate development of therapies.

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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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The Interaction between microRNAs and the Wnt/β-catenin Signaling Pathway in Osteoarthritis

International Journal of Molecular Sciences ◽

10.3390/ijms22189887 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9887

Author(s):

Xiaobin Shang ◽

Kai Oliver Böker ◽

Shahed Taheri ◽

Thelonius Hawellek ◽

Wolfgang Lehmann ◽

...

Keyword(s):

Chronic Disease ◽

Signaling Pathway ◽

Metabolic Activity ◽

Molecular Mechanisms ◽

Microrna Regulation ◽

Cellular Processes ◽

Disease Modifying ◽

Disease Modifying Treatment ◽

And Cartilage

Osteoarthritis (OA) is a chronic disease affecting the whole joint, which still lacks a disease-modifying treatment. This suggests an incomplete understanding of underlying molecular mechanisms. The Wnt/β-catenin pathway is involved in different pathophysiological processes of OA. Interestingly, both excessive stimulation and suppression of this pathway can contribute to the pathogenesis of OA. microRNAs have been shown to regulate different cellular processes in different diseases, including the metabolic activity of chondrocytes and osteocytes. To bridge these findings, here we attempt to give a conclusive overview of microRNA regulation of the Wnt/β-catenin pathway in bone and cartilage, which may provide insights to advance the development of miRNA-based therapeutics for OA treatment.

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Understanding the molecular mechanisms of NETs and their role in antiviral innate immunity

Virus Research ◽

10.1016/j.virusres.2016.11.033 ◽

2017 ◽

Vol 228 ◽

pp. 124-133 ◽

Cited By ~ 12

Author(s):

Juan Manuel Agraz-Cibrian ◽

Diana M. Giraldo ◽

Fafutis-Morris Mary ◽

Silvio Urcuqui-Inchima

Keyword(s):

Innate Immunity ◽

Molecular Mechanisms ◽

Antiviral Innate Immunity

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Glial Bridge Ecology: Cellular Mechanisms that Drive Spinal Cord Regeneration in Zebrafish

10.20944/preprints201805.0303.v1 ◽

2018 ◽

Author(s):

Corbin J. Schuster ◽

Robert M. Kao

Keyword(s):

Spinal Cord ◽

Molecular Mechanisms ◽

Cell Injury ◽

Model Organism ◽

Spinal Cord Regeneration ◽

Cellular Mechanisms ◽

Bridge Formation ◽

Cellular Processes ◽

Cord Injury ◽

One Step

Zebrafish have been found to be the premier model organism in biological and biomedical research, specifically offering many advantages in developmental biology and genetics. This unique aquatic species has been found to have the capacity to regenerate their spinal cord after injury. However, the complete molecular and cellular mechanisms behind glial bridge formation in the central and peripheral nervous systems upon glial cell injury remains unclear. This review paper focuses on the molecular mechanisms and cellular processes that underlie spinal cord regeneration in four initial phases: proliferation and initial migration; migration and differentiation; glial bridge formation; and remodeling. We propose that within these four phases the cellular mechanisms that underlie spinal cord regeneration each express a terminating signal that aborts one step of the process and initiates the next. Specifically, future studies would be devoted to investigate transmitting signals in the spinal cord injury micro-environment in hope to contribute to the understanding of underlying cellular mechanisms by connecting each process of spinal cord regeneration in zebrafish.

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The transmembrane serine protease hepsin suppresses type I interferon induction by cleaving STING

Science Signaling ◽

10.1126/scisignal.abb4752 ◽

2021 ◽

Vol 14 (687) ◽

pp. eabb4752

Author(s):

Fu Hsin ◽

Yu-Chen Hsu ◽

Yu-Fei Tsai ◽

Shu-Wha Lin ◽

Helene Minyi Liu

Keyword(s):

Innate Immunity ◽

Viral Infections ◽

Ectopic Expression ◽

Type I ◽

Adapter Proteins ◽

Type I Ifn ◽

Chronic Viral Infections ◽

Viral Proteases ◽

Transmembrane Serine Protease ◽

Antiviral Innate Immunity

Many viral proteases mediate the evasion of antiviral innate immunity by cleaving adapter proteins in the interferon (IFN) induction pathway. Host proteases are also involved in innate immunity and inflammation. Here, we report that the transmembrane protease hepsin (also known as TMPRSS1), which is predominantly present in hepatocytes, inhibited the induction of type I IFN during viral infections. Knocking out hepsin in mouse embryonic fibroblasts (MEFs) increased the viral infection–induced expression of Ifnb1, an Ifnb1 promoter reporter, and an IFN-sensitive response element promoter reporter. Ectopic expression of hepsin in cultured human hepatocytes and HEK293T cells suppressed the induction of IFNβ during viral infections by reducing the abundance of STING. These effects depended on the protease activity of hepsin. We identified a putative hepsin target site in STING and showed that mutating this site protected STING from hepsin-mediated cleavage. In addition to hepatocytes, several hepsin-producing prostate cancer cell lines showed reduced STING-mediated type I IFN induction and responses. These results reveal a role for hepsin in suppressing STING-mediated type I IFN induction, which may contribute to the vulnerability of hepatocytes to chronic viral infections.

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Yeast Cells Exposed to Exogenous Palmitoleic Acid Either Adapt to Stress and Survive or Commit to Regulated Liponecrosis and Die

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/3074769 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Karamat Mohammad ◽

Paméla Dakik ◽

Younes Medkour ◽

Mélissa McAuley ◽

Darya Mitrofanova ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Lipid Metabolism ◽

Lipid Droplets ◽

Palmitoleic Acid ◽

Molecular Mechanisms ◽

Neutral Lipids ◽

Yeast Cells ◽

Cellular Processes ◽

Regulated Cell Death

A disturbed homeostasis of cellular lipids and the resulting lipotoxicity are considered to be key contributors to many human pathologies, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases, and cancer. The yeast Saccharomyces cerevisiae has been successfully used for uncovering molecular mechanisms through which impaired lipid metabolism causes lipotoxicity and elicits different forms of regulated cell death. Here, we discuss mechanisms of the “liponecrotic” mode of regulated cell death in S. cerevisiae. This mode of regulated cell death can be initiated in response to a brief treatment of yeast with exogenous palmitoleic acid. Such treatment prompts the incorporation of exogenously added palmitoleic acid into phospholipids and neutral lipids. This orchestrates a global remodeling of lipid metabolism and transfer in the endoplasmic reticulum, mitochondria, lipid droplets, and the plasma membrane. Certain features of such remodeling play essential roles either in committing yeast to liponecrosis or in executing this mode of regulated cell death. We also outline four processes through which yeast cells actively resist liponecrosis by adapting to the cellular stress imposed by palmitoleic acid and maintaining viability. These prosurvival cellular processes are confined in the endoplasmic reticulum, lipid droplets, peroxisomes, autophagosomes, vacuoles, and the cytosol.

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