can autophagy cure herpes

BCL-2, B cell lymphoma-2; BIF, BAX-interacting factor; LAMP2, lysosome-associated membrane glycoprotein 2; PAS, pre-autophagosomal structure. Zhong, Z., Sanchez-Lopez, E. & Karin, M. Autophagy, inflammation, and immunity: a troika governing cancer and its treatment. 21, 719726 (2010). The role of Atg proteins in autophagosome formation. (b) Quantification of the number of LC3 punctae per cells, from confocal microscopy experiments performed as in (a). This result indicated that HSV-2, similarly to HSV-1, prevents autophagy induction in response to infection, but meanwhile maintains the basal autophagy activity of the host mostly unhampered. Lee, M. S. & Min, Y. J. 15, 745759 (2015). Autophagy is involved in anti-viral activity of pentagalloylglucose This leads to the detection of permeated endosomes and marks them for autophagic degradation. 87, 58205830 (2013). Microbe. Immunity. Nondegradative role of Atg5-Atg12/ Atg16L1 autophagy protein complex in antiviral activity of interferon gamma. (a) ARPE19 cells were infected with HSV-2-GFP for 2hrs and then replenished with medium with or without BFN. 2b,c). Cell Rep. 15, 10761087 (2016). Nat. Influenza A virus infection of human primary dendritic cells impairs their ability to cross-present antigen to CD8 T cells. Google Scholar. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Here, we found that HSV-2 does not allow induction of an autophagic response to infection, but maintains basal autophagy levels mostly unchanged during productive infection. Viruses that are associated with cancer development, including EBV, hepatitis B virus (HBV), HCV and KSHV, have evolved multiple strategies to avoid autophagy-mediated elimination, which can facilitate tumour progression. (f) qPCR HSV-2 genome quantification from HSV-2-infected, mock-treated or BFN-treated, HCE cells at 16 hpi. Lipid droplets were initially identified as a lipid reservoir that contributes to both energy metabolism and membrane biogenesis. PubMed Central Autophagy and immunity - insights from human herpesviruses ICP34.5 also counteracts the antiviral role of PKR by recruiting host phosphatase PP1 to dephosphorylate eIF265 (Fig. Int. Lei, Y. et al. Importantly, this study draws a sharp distinction between induced and basal autophagy, where the former acts as a viral clearance mechanism abrogating infection, while the latter supports infection. The .gov means its official. Hepatitis C virus induces the localization of lipid rafts to autophagosomes for its RNA replication. 3). Curr. USA 114, E6371E6380 (2017). Hosokawa, N. et al. 9, 13981403 (2003). The autophagosome: origins unknown, biogenesis complex. Moreover, the possibility of cell death upon BFN treatment was ruled out (Fig. Inflammasomes induce maturation and secretion of proinflammatory cytokines50, which represent powerful antiviral effectors51,52,53. Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8alpha(+) dendritic cells. Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Free Radic. During reactivation in neurons, HSV-1 can relocate to the central nervous system, and, there, the expression of the autophagy inhibitor ICP34.5 is involved in causing fatal encephalitis129,130. These results indicate that basal autophagy plays an indispensable role required for a productive infection. Similar to their use of autophagic membranes, viruses can hijack the secretion machinery for exocytosis. To investigate such a role of autophagy in HSV-2 infection, we used pharmacological means to suppress cellular autophagy levels. Herpesviruses and Autophagy: Catch Me If You Can! - MDPI Historical landmarks of autophagy research. Hutchins, M. U., Veenhuis, M. & Klionsky, D. J. Peroxisome degradation in Saccharomyces cerevisiae is dependent on machinery of macroautophagy and the Cvt pathway. 1). 2016 Apr 14;90(9):4706-4719. doi: 10.1128/JVI.02908-15. Although reports suggested that HSV-1 may inhibit autophagy via ICP34.5-mediated beclin1 binding while HSV-2 ICP34.5 was not tested for its ability to bind beclin1, our results may suggest that HSV-2 ICP34.5 also binds beclin1 to a certain extent; however this hypothesis remains to be experimentally investigated. We monitored basal autophagosomal levels in normal feeding conditions and induced autophagosomal levels under nutrient loss (starvation). Back to the Future: The Role of Infections in Psychopathology. Sahu, R. et al. Cell Host Microbe 15, 564577 (2014). JUN N-terminal kinase (JNK) phosphorylates BCL-2 to initiate Beclin 1-mediated autophagy. HPIV3 phosphoprotein (P) directly binds to the SNARE domains of SNAP29 and inhibits the interaction between STX17 and SNAP29 (Fig. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Ravindran, R. et al. HIV Res. Numerous medically infectious pathogens are degraded by autophagy, such as group A Streptococcus, herpes simplex virus type I (HSV-1), Listeria monocytogenes, . 14hrs later, infection was monitored using fluorescence microscopy. This work is licensed under a Creative Commons Attribution 4.0 International License. The role of autophagy in Herpes simplex virus-2 (HSV-2) infection is unknown. Double-membrane vesicles, termed autophagosomes, deliver trapped viral cargo to the lysosome for degradation.. A ubiquitin-like system mediates protein lipidation. PLoS Biol. Biol. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Rev Microbiol 16, 341354 (2018). IAV also triggers the accumulation of autophagosomes for viral replication103. PMC Biol. Nature 288, 288290 (1980). Autophagy 4, 276279 (2008). In a mouse model of murine norovirus (MNV) infection, IFN-mediated antiviral defence requires the ATG5ATG12ATG16L1 complex that functions in autophagosome formation47. ADS Funct. Kanai, R. et al. government site. Autophagy 7, 260265 (2011). Pharmacological inhibition of autophagy suppresses HSV-2 infection. J. Virol. Int. 151, 263276 (2000). Unauthorized use of these marks is strictly prohibited. Cell 157, 6575 (2014). The https:// ensures that you are connecting to the Ge, L., Melville, D., Zhang, M. & Schekman, R. The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. As lysosomes and/or endosomes fuse, many factors contribute to the formation of the autolysosome, enabling degradation of contents by hydrolytic enzymes. Ribeiro, C. M. et al. & Roizman, B. Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture. Autophagy protects against Sindbis virus infection of the central nervous system. Nat. 89, 615625 (2015). FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. Foot-and-mouth disease virus induces autophagosomes during cell entry via a class III phosphatidylinositol 3-kinase-independent pathway. The broad mechanisms that viruses use to interfere with autophagy are striking. As discussed above, picornaviruses accumulate autophagic membranes to support their viral replication and release. Cell 160, 619630 (2015). It's a natural process of cellular repair and cleaning. 88, 1271512726 (2014). Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Before using the ATG5/ cells in our virus assays, we wanted to validate their autophagy deficiency. and D.S. The absence of induced autophagy in HSV-1 and HSV-2 infection and persistence of basal autophagy suggest a role for this basal autophagy that supports infection (as we show here for HSV-2). ZIKV-infected primary fibroblasts contained multi-membrane structures that resembled autophagic vesicles93. Herpes can hide in the nerve cells for a long time before activating, which makes finding a cure challenging. Article Hepatitis C virus (HCV) also induces the formation of autophagosome-containing lipid cargos. Invest. Furthermore, plasmacytoid dendritic cells (pDCs) that are deficient for autophagy protein 5 (ATG5) showed reduced TLR7-dependent production of IFNs during infection with vesicular stomatitis virus (VSV) or Sendai virus (SeV)18. and D.S. How To Get Rid Herpes Virus with Autophagy Fasting? Virology. In host cells, various pattern-recognition receptors (PRRs) recognize viral pathogen-associated molecular patterns (PAMPs), which leads to the activation of transcription factors and the induction of the interferon (IFN) response. Science 333, 228233 (2011). Herpes sores usually appear as one or more blisters on or around the genitals, rectum or mouth. 3). Google Scholar. Inflammation Pharmacology Volume 12 - 2021 | https://doi.org/10.3389/fphar.2021.775521 JieZe-1 Alleviates HSV-2 Infection-Induced Genital Herpes in Balb/c Mice by Inhibiting Cell Apoptosis via Inducing Autophagy 13, 416426 (2007). Chen, Y. H. et al. Nakai, A. et al. Cell. Infection was monitored microscopically at 16 hpi. 87, 50055018 (2013). Cadwell, K. et al. 1). Thus, we decided to confirm the chloroquine preliminary finding with a more specific autophagy inhibitor, BFN. Staring, J. et al. The Chinese herbal prescription JZ-1 induces autophagy to protect The Atg5-Atg12 conjugate associates with innate antiviral immune responses. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. (c) Viral DNA was isolated from HSV-2-infected WT or ATG5/ MEFs at 14 hpi and quantified using qPCR. 13, 722737 (2013). Influenza A virus (IAV) M2 binds to and relocalizes LC3 to the plasma membrane. Viruses also hijack the exocytosis pathway for the secretion of viral particles. . Autophagy - a cure for many present-day diseases? - Diet Doctor PKR-mediated phosphorylation of the eukaryotic translation initiation factor 2 subunit 1 (EIF2S1; also known as eIF2) also induces autophagy23 (Fig. 49, 383391 (2010). Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. 91, 20402048 (2010). Johnson, D. C. & Baines, J. D. Herpesviruses remodel host membranes for virus egress. In response to HSV-1 infection, we previously found that autophagy levels may be slightly inhibited, or in most cases remain unchanged, during productive HSV-1 infection29. Chaumorcel, M. et al. 128, 207217 (2015). Napoletani G, Protto V, Marcocci ME, Nencioni L, Palamara AT, De Chiara G. Int J Mol Sci. Cell. 1. Accordingly, as improved autophagy correlates with tumour-suppression, its downregulation by viral infection may facilitate cancer development. Current therapies can relieve symptoms in patients but do not cure or prevent the spread of the virus. Screaton, G., Mongkolsapaya, J., Yacoub, S. & Roberts, C. New insights into the immunopathology and control of dengue virus infection. Buckingham, E. M., Jarosinski, K. W., Jackson, W., Carpenter, J. E. & Grose, C. Exocytosis of varicella-zoster virus virions involves a convergence of endosomal and autophagy pathways. Viruses are under high pressure to block autophagosomelysosome fusion; however, the mechanisms for achieving this vary considerably among viruses. HSV-2 ICP34.5 shares some common features with HSV-1 ICP34.5 and also shows differences26,27,28. Jaishankar, D., Yakoub, A. M., Bogdanov, A., Valyi-Nagy, T. & Shukla, D. Characterization of a proteolytically stable D-peptide that suppresses herpes simplex virus 1 infection: implications for the development of entry-based antiviral therapy. Dash, S. et al. Autophagosomes constitutively form in MHC class II-positive dendritic cells, B cells and epithelial cells and fuse with multivesicular MIICs to deliver cytoplasmic proteins for MHC class II presentation and antiviral immunity50. 4). These studies suggest that HCV dynamically modulates autophagy to coordinate viral replication. Valera, M. S. et al. Recently, the CD8+ T cell-specific antigens of HCMV 65kDa phosphoprotein (pp65) were shown to be cross-presented by human B cells through a pathway involving autophagosomes rather than the TAP-dependent conventional secretory pathway60 (Fig. Article Zika virus NS4A and NS4B proteins deregulate Akt-mTOR signaling in human fetal neural stem cells to inhibit neurogenesis and induce autophagy. During viral infection, the host uses autophagy for optimal antigen processing for MHC class II presentation and, when TAP is inhibited, MHC class I presentation. A hallmark of xenophagy is its coordination by the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). Chen, B. J., Leser, G. P., Jackson, D. & Lamb, R. A. Although there is no cure, HSL is of little clinical risk and usually spontaneously goes away within 10 d. . Proc. A key component of the cellular membrane fusion machinery that mediates vesicular fusion events in autophagosomelysosome fusion. Munz, C. The autophagic machinery in viral exocytosis. Department of Microbiology and Immunology, University of Illinois, Chicago, 60612, IL, USA, Department of Ophthalmology and Visual Sciences, University of Illinois Medical Center, Chicago, 60612, IL, USA, You can also search for this author in Cruz, F. M., Colbert, J. D., Merino, E., Kriegsman, B. Another type of autophagy, termed lipophagy, is a degradation pathway for lipid droplets in cells, and viruses can also hijack this process15. J. Biol. ICP34.5 also engages TBK1 to inhibit TBK1-mediated antiviral signaling, and may also prevent autophagic cargo recruitment through TBK1-mediated SQSTM1 phosphorylation. 35, 149176 (2017). (MVBs). Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Moreover, ATG5 deficiency results in delayed SINV clearance and accumulation of the autophagy receptor p62 (also called sequestosome 1 (SQSTM1)). Autophagy-deficient mice develop multiple liver tumors. For example, HSV-1 blocks NALP3 (or NLRP3) inflammasome activity during the course of infection49. 16, 24652478 (2002). Two host factors, E3 ubiquitin-protein ligase SMURF1 and Fanconi anaemia group C protein (FANCC), are involved in the virophagy of SINV and herpes simplex virus type 1 (HSV-1). 24, 5868 (2014). Opin. Sci. Harris, J. et al. Selective degradation of mitochondria by mitophagy. Proc. Thurston, T. L., Ryzhakov, G., Bloor, S., von Muhlinen, N. & Randow, F. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. and J.U.J. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Inhibition of herpes simplex virus infection by oligomeric stilbenoids through ROS generation. & Shukla, D. Herpes simplex virus infects most cell types in vitro: clues to its success. Natl. 1ad). ADS Chem. Abstract. 2). Additionally, in order to rule out the possibility that autophagy deficiency may interfere with virus entry into cells, we assessed internalized virus levels in WT or ATG5/ cells. Here, pathogen specificity is mediated by xenophagy signalling receptors, such as p62 (sequestosome 1), next to of BRCA1 gene 1 protein (NBR1), calcium-binding and coiled-coil domain-containing protein 2 (NDP52; also known as CALCOCO2) and optineurin, which are a subset of PRRs called p62/SQSTM1-like receptors (SLRs)169,170,171,172. An antiviral protein that is produced in the host and blocks viral replication. Bird, S. W., Maynard, N. D., Covert, M. W. & Kirkegaard, K. Nonlytic viral spread enhanced by autophagy components. After 24hr, the supernatants of infected cells were collected and titered using plaque assay. Hara, T. et al. Komatsu, M., Ueno, T., Waguri, S., Uchiyama, Y., Kominami, E. & Tanaka, K. Constitutive autophagy: vital role in clearance of unfavorable proteins in neurons. Article Transfection was performed using Lipofectamine 2000 (Invuitrogen) according to the manufacturers guidelines. Cell Host Microbe 12, 334345 (2012). In this Review, we provide an overview of the function of autophagy as an antiviral defence mechanism and then focus on how viruses subvert and exploit multiple steps of the autophagic pathway to evade immune responses and facilitate viral replication. Virology. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Moreover, DENV infection induces lipophagy, which depletes stored triglycerides and increases -oxidation and energy production for viral replication (Fig. We treated human corneal epithelial (HCE) cells, known to be targeted by both HSV-1 and HSV-2 in vivo and in vitro9,10, with BFN.

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