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Marnezi M, Tsiakalos A, Akinosoglou K. Correlation Between West Nile Virus and Pregnancy: A Systematic Review. Pathogens 2024; 13:1129. [PMID: 39770388 PMCID: PMC11676914 DOI: 10.3390/pathogens13121129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 12/14/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND West Nile Virus [WNV] is a mosquito-borne flavivirus. It has spread globally, causing asymptomatic to severe neurological diseases in humans, with an increased risk in older adults and those with underlying conditions. This review examines WNV's impact on pregnancy, focusing on maternal and neonatal symptoms and risks. METHODS This systematic review included primary studies from "PUBMED" and "SCOPUS" databases, as well as Google and Google Scholar, conducted in July 2024 using the appropriate keywords. This review adhered to PRISMA guidelines and utilized the Newcastle-Ottawa scale for bias assessment. RESULTS Seven primary studies were included in the systematic review. Fever was the predominating symptom, including neurological manifestations, respiratory symptoms, myalgia, weakness, nausea, vomiting, and rashes. Delivery, in most cases, progressed without any complications, while no infection was noted. Most of the neonates had a normal Apgar score, and their developmental functions did not seem to be affected. Even though, antibodies against WNV were detected in breast milk, no association with transmission to the neonate was observed. CONCLUSIONS WNV infection is mostly associated with favorable outcomes during pregnancy. However, larger cohorts are needed to confirm our conclusions. Prompt diagnosis and public health surveillance are pivotal to eliminate disease transmission.
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Affiliation(s)
| | | | - Karolina Akinosoglou
- Department of Medicine, School of Health Sciences, University of Patras, 26504 Rio, Greece;
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2
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Lin SC, Zhao FR, Janova H, Gervais A, Rucknagel S, Murray KO, Casanova JL, Diamond MS. Blockade of interferon signaling decreases gut barrier integrity and promotes severe West Nile virus disease. Nat Commun 2023; 14:5973. [PMID: 37749080 PMCID: PMC10520062 DOI: 10.1038/s41467-023-41600-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 08/29/2023] [Indexed: 09/27/2023] Open
Abstract
The determinants of severe disease caused by West Nile virus (WNV) and why only ~1% of individuals progress to encephalitis remain poorly understood. Here, we use human and mouse enteroids, and a mouse model of pathogenesis, to explore the capacity of WNV to directly infect gastrointestinal (GI) tract cells and contribute to disease severity. At baseline, WNV poorly infects human and mouse enteroid cultures and enterocytes in mice. However, when STAT1 or type I interferon (IFN) responses are absent, GI tract cells become infected, and this is associated with augmented GI tract and blood-brain barrier (BBB) permeability, accumulation of gut-derived molecules in the brain, and more severe WNV disease. The increased gut permeability requires TNF-α signaling, and is absent in WNV-infected IFN-deficient germ-free mice. To link these findings to human disease, we measured auto-antibodies against type I IFNs in serum from WNV-infected human cohorts. A greater frequency of auto- and neutralizing antibodies against IFN-α2 or IFN-ω is present in patients with severe WNV infection, whereas virtually no asymptomatic WNV-infected subjects have such antibodies (odds ratio 24 [95% confidence interval: 3.0 - 192.5; P = 0.003]). Overall, our experiments establish that blockade of type I IFN signaling extends WNV tropism to enterocytes, which correlates with increased gut and BBB permeability, and more severe disease.
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Affiliation(s)
- Shih-Ching Lin
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Fang R Zhao
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Hana Janova
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Adrian Gervais
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, EU, 75015, France
- Paris Cité University, Imagine Institute, Paris, EU, 75015, France
| | - Summer Rucknagel
- Gnotobiotic Research, Education, and Transgenic Center, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Kristy O Murray
- Department of Pediatrics, Section of Pediatric Tropical Medicine, William T. Shearer Center for Human Immunobiology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Necker Hospital for Sick Children, Paris, EU, 75015, France
- Paris Cité University, Imagine Institute, Paris, EU, 75015, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA
- Howard Hughes Medical Institute, New York, NY, 10065, USA
- Department of Paediatrics, Necker Hospital for Sick Children, Paris, EU, 75015, France
| | - Michael S Diamond
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
- Andrew M. and Jane M. Bursky the Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, 63110, USA.
- Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, St. Louis, MO, 63110, USA.
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3
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Lu ZG, Shen J, Yang J, Wang JW, Zhao RC, Zhang TL, Guo J, Zhang X. Nucleic acid drug vectors for diagnosis and treatment of brain diseases. Signal Transduct Target Ther 2023; 8:39. [PMID: 36650130 PMCID: PMC9844208 DOI: 10.1038/s41392-022-01298-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/08/2022] [Accepted: 12/21/2022] [Indexed: 01/18/2023] Open
Abstract
Nucleic acid drugs have the advantages of rich target selection, simple in design, good and enduring effect. They have been demonstrated to have irreplaceable superiority in brain disease treatment, while vectors are a decisive factor in therapeutic efficacy. Strict physiological barriers, such as degradation and clearance in circulation, blood-brain barrier, cellular uptake, endosome/lysosome barriers, release, obstruct the delivery of nucleic acid drugs to the brain by the vectors. Nucleic acid drugs against a single target are inefficient in treating brain diseases of complex pathogenesis. Differences between individual patients lead to severe uncertainties in brain disease treatment with nucleic acid drugs. In this Review, we briefly summarize the classification of nucleic acid drugs. Next, we discuss physiological barriers during drug delivery and universal coping strategies and introduce the application methods of these universal strategies to nucleic acid drug vectors. Subsequently, we explore nucleic acid drug-based multidrug regimens for the combination treatment of brain diseases and the construction of the corresponding vectors. In the following, we address the feasibility of patient stratification and personalized therapy through diagnostic information from medical imaging and the manner of introducing contrast agents into vectors. Finally, we take a perspective on the future feasibility and remaining challenges of vector-based integrated diagnosis and gene therapy for brain diseases.
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Affiliation(s)
- Zhi-Guo Lu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
| | - Jie Shen
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Jun Yang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Jing-Wen Wang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
| | - Rui-Chen Zhao
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Tian-Lu Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
| | - Jing Guo
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China
| | - Xin Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
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4
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Sultana H, Neelakanta G. Isolation of Exosomes or Extracellular Vesicles from West Nile Virus-Infected N2a Cells, Primary Cortical Neurons, and Brain Tissues. Methods Mol Biol 2023; 2585:79-95. [PMID: 36331767 DOI: 10.1007/978-1-0716-2760-0_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Several flaviviruses compromise the blood-brain barrier integrity, infect the central nervous system, and elicit neuroinvasion to successfully cause neuropathogenesis in the vertebrate host. Therefore, understanding the pathway(s) and mechanism(s) to block the transmission and/or dissemination of flaviviruses and perhaps other neuroinvasive viruses is considered as an important area of research. Moreover, studies that address mechanism(s) of neuroinvasion by flaviviruses are limited. In this chapter, we discuss detailed methods to isolate exosomes or extracellular vesicles (EVs) from mouse and human N2a cells, primary cultures of murine cortical neurons, and mouse brain tissue. Two different methods including differential ultracentrifugation and density gradient exosome (DG-Exo) isolation are described for the preparation of exosomes/EVs from N2a cells and cortical neurons. In addition, we discuss the detailed DG-Exo method for the isolation of exosomes from murine brain tissue. Studies on neuronal exosomes will perhaps enhance our understanding of the mechanism of neuroinvasion by these deadly viruses.
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Affiliation(s)
- Hameeda Sultana
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA.
| | - Girish Neelakanta
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA
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5
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Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies. ENDOCRINES 2022. [DOI: 10.3390/endocrines3040058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Similar to previous pandemics, COVID-19 has been succeeded by well-documented post-infectious sequelae, including chronic fatigue, cough, shortness of breath, myalgia, and concentration difficulties, which may last 5 to 12 weeks or longer after the acute phase of illness. Both the psychological stress of SARS-CoV-2 infection and being diagnosed with COVID-19 can upregulate cortisol, a stress hormone that disrupts the efferocytosis effectors, macrophages, and natural killer cells, leading to the excessive accumulation of senescent cells and disruption of biological barriers. This has been well-established in cancer patients who often experience unrelenting fatigue as well as gut and blood–brain barrier dysfunction upon treatment with senescence-inducing radiation or chemotherapy. In our previous research from 2020 and 2021, we linked COVID-19 to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via angiotensin II upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. In 2021 and 2022, these hypotheses were validated and SARS-CoV-2-induced cellular senescence as well as microbial translocation were documented in both acute SARS-CoV-2 infection, long COVID, and ME/CFS, connecting intestinal barrier dysfunction to disabling fatigue and specific infectious events. The purpose of this narrative review is to summarize what is currently known about host immune responses to translocated gut microbes and how these responses relate to fatiguing illnesses, including long COVID. To accomplish this goal, we examine the role of intestinal and blood–brain barriers in long COVID and other illnesses typified by chronic fatigue, with a special emphasis on commensal microbes functioning as viral reservoirs. Furthermore, we discuss the role of SARS-CoV-2/Mycoplasma coinfection in dysfunctional efferocytosis, emphasizing some potential novel treatment strategies, including the use of senotherapeutic drugs, HMGB1 inhibitors, Toll-like receptor 4 (TLR4) blockers, and membrane lipid replacement.
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6
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Cheng Y, Medina A, Yao Z, Basu M, Natekar JP, Lang J, Sanchez E, Nkembo MB, Xu C, Qian X, Nguyen PTT, Wen Z, Song H, Ming GL, Kumar M, Brinton MA, Li MMH, Tang H. Intrinsic antiviral immunity of barrier cells revealed by an iPSC-derived blood-brain barrier cellular model. Cell Rep 2022; 39:110885. [PMID: 35649379 PMCID: PMC9230077 DOI: 10.1016/j.celrep.2022.110885] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 03/27/2022] [Accepted: 05/05/2022] [Indexed: 11/25/2022] Open
Abstract
Physiological blood-tissue barriers play a critical role in separating the circulation from immune-privileged sites and denying access to blood-borne viruses. The mechanism of virus restriction by these barriers is poorly understood. We utilize induced pluripotent stem cell (iPSC)-derived human brain microvascular endothelial cells (iBMECs) to study virus-blood-brain barrier (BBB) interactions. These iPSC-derived cells faithfully recapitulate a striking difference in in vivo neuroinvasion by two alphavirus isolates and are selectively permissive to neurotropic flaviviruses. A model of cocultured iBMECs and astrocytes exhibits high transendothelial electrical resistance and blocks non-neurotropic flaviviruses from getting across the barrier. We find that iBMECs constitutively express an interferon-induced gene, IFITM1, which preferentially restricts the replication of non-neurotropic flaviviruses. Barrier cells from blood-testis and blood-retinal barriers also constitutively express IFITMs that contribute to the viral resistance. Our application of a renewable human iPSC-based model for studying virus-BBB interactions reveals that intrinsic immunity at the barriers contributes to virus exclusion.
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Affiliation(s)
- Yichen Cheng
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Angelica Medina
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Zhenlan Yao
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Mausumi Basu
- Department of Biology, Georgia State University, Atlanta, GA, USA
| | | | - Jianshe Lang
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Egan Sanchez
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Mezindia B Nkembo
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Chongchong Xu
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Xuyu Qian
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Phuong T T Nguyen
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Zhexing Wen
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Hongjun Song
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Guo-Li Ming
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mukesh Kumar
- Department of Biology, Georgia State University, Atlanta, GA, USA
| | - Margo A Brinton
- Department of Biology, Georgia State University, Atlanta, GA, USA
| | - Melody M H Li
- Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Hengli Tang
- Department of Biological Science, Florida State University, Tallahassee, FL, USA.
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7
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Constant O, Maarifi G, Blanchet FP, Van de Perre P, Simonin Y, Salinas S. Role of Dendritic Cells in Viral Brain Infections. Front Immunol 2022; 13:862053. [PMID: 35529884 PMCID: PMC9072653 DOI: 10.3389/fimmu.2022.862053] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/22/2022] [Indexed: 11/13/2022] Open
Abstract
To gain access to the brain, a so-called immune-privileged organ due to its physical separation from the blood stream, pathogens and particularly viruses have been selected throughout evolution for their use of specific mechanisms. They can enter the central nervous system through direct infection of nerves or cerebral barriers or through cell-mediated transport. Indeed, peripheral lymphoid and myeloid immune cells can interact with the blood-brain and the blood-cerebrospinal fluid barriers and allow viral brain access using the "Trojan horse" mechanism. Among immune cells, at the frontier between innate and adaptive immune responses, dendritic cells (DCs) can be pathogen carriers, regulate or exacerbate antiviral responses and neuroinflammation, and therefore be involved in viral transmission and spread. In this review, we highlight an important contribution of DCs in the development and the consequences of viral brain infections.
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Affiliation(s)
- Orianne Constant
- Pathogenesis and Control of Chronic and Emerging Infections, Institut national de la santé et de la recherche médicale (INSERM), University of Montpellier, Etablissement Français du Sang, Montpellier, France
| | - Ghizlane Maarifi
- Institut de Recherche en Infectiologie de Montpellier, Centre national de la recherche scientifique (CNRS), Université de Montpellier, Montpellier, France
| | - Fabien P. Blanchet
- Institut de Recherche en Infectiologie de Montpellier, Centre national de la recherche scientifique (CNRS), Université de Montpellier, Montpellier, France
| | - Philippe Van de Perre
- Pathogenesis and Control of Chronic and Emerging Infections, Institut national de la santé et de la recherche médicale (INSERM), University of Montpellier, Etablissement Français du Sang, Montpellier, France
| | - Yannick Simonin
- Pathogenesis and Control of Chronic and Emerging Infections, Institut national de la santé et de la recherche médicale (INSERM), University of Montpellier, Etablissement Français du Sang, Montpellier, France
| | - Sara Salinas
- Pathogenesis and Control of Chronic and Emerging Infections, Institut national de la santé et de la recherche médicale (INSERM), University of Montpellier, Etablissement Français du Sang, Montpellier, France
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Ji W, Li Y, Peng H, Zhao R, Shen J, Wu Y, Wang J, Hao Q, Lu Z, Yang J, Zhang X. Self-Catalytic Small Interfering RNA Nanocarriers for Synergistic Treatment of Neurodegenerative Diseases. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2105711. [PMID: 34601753 DOI: 10.1002/adma.202105711] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/14/2021] [Indexed: 06/13/2023]
Abstract
Gene therapy has shown great potential for neurodegenerative diseases with complex pathology. However, its therapeutic effect is limited due to the delivery barriers and its own single function. Herein, self-catalytic small interfering RNA (siRNA) nanocarriers (S/Ce-PABMS) are developed to catalyze delivery process and treatment process for synergistic treatment of neurodegenerative diseases. On the one hand, the rough surface of the S/Ce-PABMS mediated by ceria (CeO2 ) nanozymes can catalyze cellular uptake in the delivery process, so that S/Ce-PABMS with acetylcholine analogs penetrate the blood-brain barrier and enter neurons more effectively. On the other hand, the CeO2 nanozymes can catalyze the treatment process by scavenging excess reactive oxygen species, and cooperate with siRNA-targeting SNCA to decrease the α-synuclein (α-syn) aggregation and alleviate the Parkinsonian pathology. Moreover, the S/Ce-PABMS treatment reduces the number of activated microglia and regulates the release of inflammatory cytokine, thereby relieving neuroinflammation. After treatment with S/Ce-PABMS, dyskinesia in Parkinson's disease model mice is significantly alleviated. The finding shows that the self-catalytic nanocarriers, S/Ce-PABMS, have great potential in the treatment of neurodegenerative diseases.
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Affiliation(s)
- Weihong Ji
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Yan Li
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, 100083, P. R. China
| | - Huan Peng
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Ruichen Zhao
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Jie Shen
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Yanyue Wu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Jianze Wang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
| | - Qiulian Hao
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
| | - Zhiguo Lu
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
| | - Jun Yang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
| | - Xin Zhang
- State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, P. R. China
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
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9
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Uversky VN, Elrashdy F, Aljadawi A, Ali SM, Khan RH, Redwan EM. Severe acute respiratory syndrome coronavirus 2 infection reaches the human nervous system: How? J Neurosci Res 2021; 99:750-777. [PMID: 33217763 PMCID: PMC7753416 DOI: 10.1002/jnr.24752] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/19/2020] [Accepted: 10/21/2020] [Indexed: 02/06/2023]
Abstract
Without protective and/or therapeutic agents the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection known as coronavirus disease 2019 is quickly spreading worldwide. It has surprising transmissibility potential, since it could infect all ages, gender, and human sectors. It attacks respiratory, gastrointestinal, urinary, hepatic, and endovascular systems and can reach the peripheral nervous system (PNS) and central nervous system (CNS) through known and unknown mechanisms. The reports on the neurological manifestations and complications of the SARS-CoV-2 infection are increasing exponentially. Herein, we enumerate seven candidate routes, which the mature or immature SARS-CoV-2 components could use to reach the CNS and PNS, utilizing the within-body cross talk between organs. The majority of SARS-CoV-2-infected patients suffer from some neurological manifestations (e.g., confusion, anosmia, and ageusia). It seems that although the mature virus did not reach the CNS or PNS of the majority of patients, its unassembled components and/or the accompanying immune-mediated responses may be responsible for the observed neurological symptoms. The viral particles and/or its components have been specifically documented in endothelial cells of lung, kidney, skin, and CNS. This means that the blood-endothelial barrier may be considered as the main route for SARS-CoV-2 entry into the nervous system, with the barrier disruption being more logical than barrier permeability, as evidenced by postmortem analyses.
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Affiliation(s)
- Vladimir N. Uversky
- Biological Science DepartmentFaculty of ScienceKing Abdulaziz UniversityJeddahSaudi Arabia
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of MedicineUniversity of South FloridaTampaFLUSA
- Institute for Biological Instrumentation of the Russian Academy of SciencesFederal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”PushchinoRussia
| | - Fatma Elrashdy
- Department of Endemic Medicine and HepatogastroenterologyKasr Alainy School of MedicineCairo UniversityCairoEgypt
| | - Abdullah Aljadawi
- Biological Science DepartmentFaculty of ScienceKing Abdulaziz UniversityJeddahSaudi Arabia
| | - Syed Moasfar Ali
- Interdisciplinary Biotechnology UnitAligarh Muslim UniversityAligarhIndia
| | - Rizwan Hasan Khan
- Interdisciplinary Biotechnology UnitAligarh Muslim UniversityAligarhIndia
| | - Elrashdy M. Redwan
- Biological Science DepartmentFaculty of ScienceKing Abdulaziz UniversityJeddahSaudi Arabia
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10
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The Roles of Osteopontin in the Pathogenesis of West Nile Encephalitis. Vaccines (Basel) 2020; 8:vaccines8040748. [PMID: 33317005 PMCID: PMC7768535 DOI: 10.3390/vaccines8040748] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/03/2020] [Accepted: 12/06/2020] [Indexed: 12/18/2022] Open
Abstract
Osteopontin (OPN), a multifunctional protein encoded by the secreted phosphoprotein-1 (Spp-1) gene in humans, plays important roles in a variety of physiological conditions, such as biomineralization, bone remodeling and immune functions. OPN also has significant roles in the pathogenesis of autoimmune, allergy and inflammatory diseases, as well as bacterial, fungal and viral infections. West Nile virus (WNV), a mosquito-transmitted flavivirus, is the leading agent for viral encephalitis in North America. Recent progress has been made in understanding both the biological functions of OPN and the pathogenesis of WNV. In this review article, we have summarized the current understanding of the biology of OPN and its vital roles in the pathogenesis of WNV encephalitis.
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11
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Huang Y, Li X, Pan C, Cheng W, Wang X, Yang Z, Zheng L. The intervention mechanism of emodin on TLR3 pathway in the process of central nervous system injury caused by herpes virus infection. Neurol Res 2020; 43:307-313. [PMID: 33274693 DOI: 10.1080/01616412.2020.1853989] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background and purpose: To investigate the effect of Emodin on the inflammatory response of brain tissue and the expression of the TLR3 pathway in mice with herpes virus encephalitis.Method: Twenty male BALB/c mice were randomly divided into the NS group, HSV-1 group, HSV-1 + Emodin group and HSV-1 + ACV group. The histopathological features and the effect of TLR3 expression were observed by staining and immunohistochemistry (IHC) respectively. The gene expression of TLR3, trif, TRADD, TRAF6, traf3, p38, Nemo and IRF3 was detected by polymerase chain reaction (PCR). The protein production of TLR3 and its downstream molecules was detected by Western blot. The expression of IL-6, TNF-α and IFN-β in the brain tissues was detected by ELISA.Result: Compared to the HSV-1 group, the pathological changes (inflammatory cell infiltration, necrotic temporal lobe and massive hemorrhage) were not as obvious as those in the HSV-1+emodin and HSV-1+ACV groups. The TLR3 staining increased significantly in the HSV-1 groups and decreased in the HSV-1 + emodin group. Compared with the NS group, the mRNA expression of TLR3, TRIF, TRADD, TRAF6, traf3, p38, NEMO and IRF3 decreased by 20%-60% in the HSV-1 + emodin group and 30% in the HSV-1 + ACV group, respectively. The expression of IL-6, TNF-α and IFN-β decreased by 30%-50% in the HSV-1 + emodin group and showed no significant change in the HSV-1 + ACV group, respectively.Conclusion: Emodin could inhibit the inflammatory response in the brain of mice with herpes virus encephalitis. The inhibition of TLR3 expression may play an important role in this process.
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Affiliation(s)
- Yongqian Huang
- Department of Neurology, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
| | - Xing Li
- Department of Neurology, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
| | - Chunlian Pan
- Department of Neurology, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
| | - Wei Cheng
- Department of Neurology, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
| | - Xijia Wang
- Department of Neurology, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
| | - Zhigang Yang
- Department of Neurology, Puren Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
| | - Lifang Zheng
- Department of Neurology, Yantian Hospital of Southern University of Science and Technology, Shenzhen, China
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12
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Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, Bullock TA, McGary HM, Khan JA, Razmpour R, Hale JF, Galie PA, Potula R, Andrews AM, Ramirez SH. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Neurobiol Dis 2020; 146:105131. [PMID: 33053430 PMCID: PMC7547916 DOI: 10.1016/j.nbd.2020.105131] [Citation(s) in RCA: 329] [Impact Index Per Article: 65.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 09/07/2020] [Accepted: 10/06/2020] [Indexed: 01/08/2023] Open
Abstract
As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system include neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-CoV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. The spike protein, which plays a key role in receptor recognition, is formed by the S1 subunit containing a receptor binding domain (RBD) and the S2 subunit. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is ubiquitously expressed throughout various vessel calibers in the frontal cortex. Moreover, ACE2 expression was upregulated in cases of hypertension and dementia. ACE2 was also detectable in primary hBMVECs maintained under cell culture conditions. Analysis of cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48 h exposure window. Introduction of spike proteins to invitro models of the blood-brain barrier (BBB) showed significant changes to barrier properties. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluidic model of the human BBB, a platform that more closely resembles the physiological conditions at this CNS interface. Evidence provided suggests that the SARS-CoV-2 spike proteins trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients.
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Affiliation(s)
- Tetyana P Buzhdygan
- Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America; Center for Substance Abuse Research, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America
| | - Brandon J DeOre
- Department of Biomedical Engineering, Rowan University, Glassboro, NJ 08028, United States of America
| | - Abigail Baldwin-Leclair
- Department of Biomedical Engineering, Rowan University, Glassboro, NJ 08028, United States of America
| | - Trent A Bullock
- Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America; Center for Substance Abuse Research, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America
| | - Hannah M McGary
- Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America
| | - Jana A Khan
- Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America
| | - Roshanak Razmpour
- Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America
| | - Jonathan F Hale
- Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America
| | - Peter A Galie
- Department of Biomedical Engineering, Rowan University, Glassboro, NJ 08028, United States of America
| | - Raghava Potula
- Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America; Center for Substance Abuse Research, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America
| | - Allison M Andrews
- Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America; Center for Substance Abuse Research, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America
| | - Servio H Ramirez
- Department of Pathology and Laboratory Medicine, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America; Center for Substance Abuse Research, The Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, United States of America; The Shriners Hospitals Pediatric Research Center, Philadelphia, PA 19140, United States of America.
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13
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Alam SB, Willows S, Kulka M, Sandhu JK. Severe acute respiratory syndrome coronavirus 2 may be an underappreciated pathogen of the central nervous system. Eur J Neurol 2020; 27:2348-2360. [PMID: 32668062 PMCID: PMC7405269 DOI: 10.1111/ene.14442] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 07/10/2020] [Indexed: 02/06/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a highly contagious respiratory disease referred to as COVID-19. However, emerging evidence indicates that a small but growing number of COVID-19 patients also manifest neurological symptoms, suggesting that SARS-CoV-2 may infect the nervous system under some circumstances. SARS-CoV-2 primarily enters the body through the epithelial lining of the respiratory and gastrointestinal tracts, but under certain conditions this pleiotropic virus may also infect peripheral nerves and gain entry into the central nervous system (CNS). The brain is shielded by various anatomical and physiological barriers, most notably the blood-brain barrier (BBB) which functions to prevent harmful substances, including pathogens and pro-inflammatory mediators, from entering the brain. The BBB is composed of highly specialized endothelial cells, pericytes, mast cells and astrocytes that form the neurovascular unit, which regulates BBB permeability and maintains the integrity of the CNS. In this review, potential routes of viral entry and the possible mechanisms utilized by SARS-CoV-2 to penetrate the CNS, either by disrupting the BBB or infecting the peripheral nerves and using the neuronal network to initiate neuroinflammation, are briefly discussed. Furthermore, the long-term effects of SARS-CoV-2 infection on the brain and in the progression of neurodegenerative diseases known to be associated with other human coronaviruses are considered. Although the mechanisms of SARS-CoV-2 entry into the CNS and neurovirulence are currently unknown, the potential pathways described here might pave the way for future research in this area and enable the development of better therapeutic strategies.
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Affiliation(s)
- S. B. Alam
- Nanotechnology Research CentreNational Research Council CanadaEdmontonAlbertaCanada
- Department of Medical Microbiology and ImmunologyUniversity of AlbertaEdmontonAlbertaCanada
| | - S. Willows
- Nanotechnology Research CentreNational Research Council CanadaEdmontonAlbertaCanada
- Department of Medical Microbiology and ImmunologyUniversity of AlbertaEdmontonAlbertaCanada
| | - M. Kulka
- Nanotechnology Research CentreNational Research Council CanadaEdmontonAlbertaCanada
- Department of Medical Microbiology and ImmunologyUniversity of AlbertaEdmontonAlbertaCanada
| | - J. K. Sandhu
- Human Health Therapeutics Research CentreNational Research Council CanadaOttawaOntarioCanada
- Department of Biochemistry, Microbiology and ImmunologyUniversity of OttawaOttawaOntarioCanada
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14
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Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, McGary H, Razmpour R, Galie PA, Potula R, Andrews AM, Ramirez SH. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in vitro models of the human blood-brain barrier. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2020. [PMID: 32587958 DOI: 10.1101/2020.06.15.150912] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system includes neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-COV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is expressed throughout various caliber vessels in the frontal cortex. Additionally, ACE2 was also detectable in primary human brain microvascular endothelial (hBMVEC) maintained under cell culture conditions. Analysis for cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48hr exposure window. However, when the viral spike proteins were introduced into model systems that recapitulate the essential features of the Blood-Brain Barrier (BBB), breach to the barrier was evident in various degrees depending on the spike protein subunit tested. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluid model of the human BBB, a platform that most closely resembles the human physiological conditions at this CNS interface. Subsequent analysis also showed the ability for SARS-CoV-2 spike proteins to trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients.
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15
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Kobayashi S, Kaneko C, Kawakami R, Hasebe R, Sawa H, Yoshii K, Kariwa H. Amino acid 159 of the envelope protein affects viral replication and T-cell infiltration by West Nile virus in intracranial infection. Sci Rep 2020; 10:7168. [PMID: 32346055 PMCID: PMC7189269 DOI: 10.1038/s41598-020-64199-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 04/13/2020] [Indexed: 12/15/2022] Open
Abstract
West Nile virus (WNV) is an important cause of viral encephalitis in birds and animals, including humans. Amino acid 159 of the envelope (E) protein is reportedly implicated in the different levels of neurovirulence in mice infected with WNV NY99 or Eg101. We investigated the role of amino acid 159 of the E protein in the pathogenesis of WNV infection. We produced recombinant WNV with the structural proteins of the NY99 or Eg101 strain (NY-WT or EgCME-WT) and mutant viruses with substitutions of amino acid 159 of the E protein (NY-E-V159I or EgCME-E-I159V). The NY-WT and NY-E-V159I or EgCME-WT and EgCME-E-I159V titers in culture supernatant were similar. The mortality rate and viral titer in the brains of mice inoculated intraperitoneally with NY-WT or NY-E-V159I were also similar. In contrast, the mortality rate and viral titer in the brains of mice inoculated intracranially with EgCME-E-I159V were significantly higher than those of mice inoculated with EgCME-WT. The numbers of CD3-positive and CD8-positive T cells were greater in brains inoculated with EgCME-E-I159V than in those inoculated with EgCME-WT. Therefore, amino acid 159 of the E protein modulates the pathogenicity of WNV by affecting viral replication and T-cell infiltration in the brain.
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Affiliation(s)
- Shintaro Kobayashi
- Laboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, N18, W9, Kita-ku, Sapporo, 060-0818, Japan.
| | - Chisato Kaneko
- Laboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, N18, W9, Kita-ku, Sapporo, 060-0818, Japan
| | - Ryoko Kawakami
- Laboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, N18, W9, Kita-ku, Sapporo, 060-0818, Japan
| | - Rie Hasebe
- Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, N15, W7, Kita-ku, Sapporo, 060-0815, Japan
| | - Hirofumi Sawa
- Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, N20, W10, Kita-ku, Sapporo, 001-0020, Japan.,Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.,Global Virus Network, Baltimore, MD, USA
| | - Kentaro Yoshii
- Laboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, N18, W9, Kita-ku, Sapporo, 060-0818, Japan
| | - Hiroaki Kariwa
- Laboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, N18, W9, Kita-ku, Sapporo, 060-0818, Japan
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16
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Puerta-Guardo H, Glasner DR, Espinosa DA, Biering SB, Patana M, Ratnasiri K, Wang C, Beatty PR, Harris E. Flavivirus NS1 Triggers Tissue-Specific Vascular Endothelial Dysfunction Reflecting Disease Tropism. Cell Rep 2020; 26:1598-1613.e8. [PMID: 30726741 PMCID: PMC6934102 DOI: 10.1016/j.celrep.2019.01.036] [Citation(s) in RCA: 196] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 10/27/2018] [Accepted: 01/09/2019] [Indexed: 01/22/2023] Open
Abstract
Flaviviruses cause systemic or neurotropic-encephalitic pathology in humans. The flavivirus nonstructural protein 1 (NS1) is a secreted glycoprotein involved in viral replication, immune evasion, and vascular leakage during dengue virus infection. However, the contribution of secreted NS1 from related flaviviruses to viral pathogenesis remains unknown. Here, we demonstrate that NS1 from dengue, Zika, West Nile, Japanese encephalitis, and yellow fever viruses selectively binds to and alters permeability of human endothelial cells from lung, dermis, umbilical vein, brain, and liver in vitro and causes tissue-specific vascular leakage in mice, reflecting the pathophysiology of each flavivirus. Mechanistically, each flavivirus NS1 leads to differential disruption of endothelial glycocalyx components, resulting in endothelial hyperpermeability. Our findings reveal the capacity of a secreted viral protein to modulate endothelial barrier function in a tissue-specific manner both in vitro and in vivo, potentially influencing virus dissemination and pathogenesis and providing targets for antiviral therapies and vaccine development. Puerta-Guardo et al. discover that five flavivirus NS1 proteins trigger hyperpermeability and vascular dysfunction in human endothelial cells and mice in a manner reflecting disease tropism. This tissue-specific tropism is partially determined by the capacity of NS1 to bind endothelial cells and is characterized by disruption of endothelial glycocalyx components.
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Affiliation(s)
- Henry Puerta-Guardo
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Dustin R Glasner
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Diego A Espinosa
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Scott B Biering
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Mark Patana
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Kalani Ratnasiri
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Chunling Wang
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - P Robert Beatty
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Eva Harris
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
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17
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A Soluble Version of Nipah Virus Glycoprotein G Delivered by Vaccinia Virus MVA Activates Specific CD8 and CD4 T Cells in Mice. Viruses 2019; 12:v12010026. [PMID: 31878180 PMCID: PMC7019319 DOI: 10.3390/v12010026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 12/17/2019] [Accepted: 12/20/2019] [Indexed: 12/13/2022] Open
Abstract
Nipah virus (NiV) is an emerging zoonotic virus that is transmitted by bats to humans and to pigs, causing severe respiratory disease and often fatal encephalitis. Antibodies directed against the NiV-glycoprotein (G) protein are known to play a major role in clearing NiV infection and in providing vaccine-induced protective immunity. More recently, T cells have been also shown to be involved in recovery from NiV infection. So far, relatively little is known about the role of T cell responses and the antigenic targets of NiV-G that are recognized by CD8 T cells. In this study, NiV-G protein served as the target immunogen to activate NiV-specific cellular immune responses. Modified Vaccinia virus Ankara (MVA), a safety-tested strain of vaccinia virus for preclinical and clinical vaccine research, was used for the generation of MVA–NiV-G candidate vaccines expressing different versions of recombinant NiV-G. Overlapping peptides covering the entire NiV-G protein were used to identify major histocompatibility complex class I/II-restricted T cell responses in type I interferon receptor-deficient (IFNAR−/−) mice after vaccination with the MVA–NiV-G candidate vaccines. We have identified an H2-b-restricted nonamer peptide epitope with CD8 T cell antigenicity and a H2-b 15mer with CD4 T cell antigenicity in the NiV-G protein. The identification of this epitope and the availability of the MVA–NiV-G candidate vaccines will help to evaluate NiV-G-specific immune responses and the potential immune correlates of vaccine-mediated protection in the appropriate murine models of NiV-G infection. Of note, a soluble version of NiV-G was advantageous in activating NiV-G-specific cellular immune responses using these peptides.
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18
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Vidaña B, Johnson N, Fooks AR, Sánchez‐Cordón PJ, Hicks DJ, Nuñez A. West Nile Virus spread and differential chemokine response in the central nervous system of mice: Role in pathogenic mechanisms of encephalitis. Transbound Emerg Dis 2019; 67:799-810. [DOI: 10.1111/tbed.13401] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/07/2019] [Accepted: 10/17/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Beatriz Vidaña
- Pathology Department, Animal and Plant Health Agency APHA‐Weybridge AddlestoneKT15 3NBUK
| | - Nicholas Johnson
- Virology Department, Animal and Plant Health Agency APHA,‐Weybridge AddlestoneKT15 3NBUK
| | - Anthony R. Fooks
- Virology Department, Animal and Plant Health Agency APHA,‐Weybridge AddlestoneKT15 3NBUK
| | | | - Daniel J. Hicks
- Pathology Department, Animal and Plant Health Agency APHA‐Weybridge AddlestoneKT15 3NBUK
| | - Alejandro Nuñez
- Pathology Department, Animal and Plant Health Agency APHA‐Weybridge AddlestoneKT15 3NBUK
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19
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Bai F, Thompson EA, Vig PJS, Leis AA. Current Understanding of West Nile Virus Clinical Manifestations, Immune Responses, Neuroinvasion, and Immunotherapeutic Implications. Pathogens 2019; 8:pathogens8040193. [PMID: 31623175 PMCID: PMC6963678 DOI: 10.3390/pathogens8040193] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/12/2019] [Accepted: 10/13/2019] [Indexed: 12/11/2022] Open
Abstract
West Nile virus (WNV) is the most common mosquito-borne virus in North America. WNV-associated neuroinvasive disease affects all ages, although elderly and immunocompromised individuals are particularly at risk. WNV neuroinvasive disease has killed over 2300 Americans since WNV entered into the United States in the New York City outbreak of 1999. Despite 20 years of intensive laboratory and clinical research, there are still no approved vaccines or antivirals available for human use. However, rapid progress has been made in both understanding the pathogenesis of WNV and treatment in clinical practices. This review summarizes our current understanding of WNV infection in terms of human clinical manifestations, host immune responses, neuroinvasion, and therapeutic interventions.
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Affiliation(s)
- Fengwei Bai
- Department of Cell and Molecular Biology, University of Southern Mississippi, Hattiesburg, MS 39406, USA.
| | - E Ashley Thompson
- Department of Cell and Molecular Biology, University of Southern Mississippi, Hattiesburg, MS 39406, USA.
| | - Parminder J S Vig
- Departments of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
| | - A Arturo Leis
- Methodist Rehabilitation Center, Jackson, MS 39216, USA.
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20
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Idris F, Muharram SH, Zaini Z, Alonso S, Diah S. Invasion of a murine in vitro blood-brain barrier co-culture model by dengue virus serotypes 1 to 4. Arch Virol 2019; 164:1069-1083. [PMID: 30783772 DOI: 10.1007/s00705-019-04175-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 01/16/2019] [Indexed: 01/16/2023]
Abstract
The blood-brain barrier (BBB) is a physical barrier that restricts the passage of cells and molecules as well as pathogens into the central nervous system (CNS). Some viruses enter the CNS by disrupting the BBB, while others can reach the CNS without altering the integrity of the BBB. Even though dengue virus (DENV) is not a distinctive neurotropic virus, the virus is considered to be one of the leading causes of neurological manifestations. In this study, we found that DENV is able to compromise the integrity of a murine in vitro blood-brain barrier (BBB) model, resulting in hyperpermeability, as shown by a significant increase in sucrose and albumin permeability. Infection of brain endothelial cells (ECs) was facilitated by the presence of glycans, in particular, mannose and N-acetyl glucosamine residues, on cell surfaces and viral envelope proteins, and the requirement for glycan moieties for cell infection was serotype-specific. Direct viral disruption of brain ECs was observed, leading to a significant decrease in tight-junction protein expression and peripheral localization, which contributed to the changes in BBB permeability. In conclusion, the hyperpermeability and breaching mechanism of BBB by DENV are primarily due to direct consequences of viral infection of ECs, as shown in this in vitro study.
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Affiliation(s)
- Fakhriedzwan Idris
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, and Immunology Programme Life Sciences Institute, National University of Singapore, Singapore, Singapore. .,Pengiran Anak Puteri Rashidah Sa'adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Jalan Tungku Link, Gadong, BE1410, Brunei Darussalam.
| | - Siti Hanna Muharram
- Pengiran Anak Puteri Rashidah Sa'adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Jalan Tungku Link, Gadong, BE1410, Brunei Darussalam
| | - Zainun Zaini
- Virology Laboratory, Clinical Laboratory Services, Ministry of Health, Gadong, Brunei Darussalam
| | - Sylvie Alonso
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, and Immunology Programme Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Suwarni Diah
- Pengiran Anak Puteri Rashidah Sa'adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Jalan Tungku Link, Gadong, BE1410, Brunei Darussalam
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21
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Patabendige A, Michael BD, Craig AG, Solomon T. Brain microvascular endothelial-astrocyte cell responses following Japanese encephalitis virus infection in an in vitro human blood-brain barrier model. Mol Cell Neurosci 2018; 89:60-70. [PMID: 29635016 PMCID: PMC5984247 DOI: 10.1016/j.mcn.2018.04.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Revised: 03/16/2018] [Accepted: 04/04/2018] [Indexed: 12/22/2022] Open
Abstract
Japanese encephalitis virus (JEV) remains a leading cause of encephalitis, globally, which continues to grow in importance despite the availability of vaccines. Viral entry into the brain can occur via the blood-brain barrier (BBB), and inflammation at the BBB is a common final pathway in many brain infections. However, the role of the BBB during JEV infection and the contribution of the endothelial and astrocytic cell inflammation in facilitating virus entry into the brain are incompletely understood. We established a BBB model using human brain endothelial cells (HBECs) and human astrocytes. HBECs are polarised, and therefore the model was inoculated by JEV from the apical side to simulate the in vivo situation. The effects of JEV on the BBB permeability and release of inflammatory mediators from both apical and basolateral sides, representing the blood and the brain side respectively were investigated. JEV infected HBECs with limited active virus production, before crossing the BBB and infecting astrocytes. Control of JEV production by HBECs was associated with a significant increase in permeability, and with elevation of many host mediators, including cytokines, chemokines, cellular adhesion molecules, and matrix metalloproteases. When compared to the controls, significantly higher amounts of mediators were released from the apical side as opposed to the basolateral side. The increased release of mediators over time also correlated with increased BBB permeability. Treatment with dexamethasone led to a significant reduction in the release of interleukin 6 (IL6), C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) from the apical side with a reduction in BBB disruption and no change in JEV production. The results are consistent with the hypothesis that JEV infection of the BBB triggers the production of a range of host mediators from both endothelial cells and astrocytes, which control JEV production but disrupt BBB integrity thus allowing virus entry into the brain. Dexamethasone treatment controlled the host response and limited BBB disruption in the model without increasing JEV production, supporting a re-investigation of its use therapeutically.
Japanese encephalitis virus (JEV) infects human brain endothelial cells (HBECs). This triggers the production of a range of host mediators from both HBECs and astrocytes. JEV infection adversely affects blood-brain barrier (BBB) integrity. Dexamethasone treatment following JEV infection reduces the inflammation. Dexamethasone restores BBB integrity without increasing the levels of JEV particles.
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Affiliation(s)
- Adjanie Patabendige
- The Institute of Infection and Global Health, University of Liverpool, Liverpool, UK; The School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, Australia; The Hunter Medical Research Institute, Newcastle, Australia.
| | - Benedict D Michael
- The Institute of Infection and Global Health, University of Liverpool, Liverpool, UK; The Walton Centre NHS Foundation Trust, Liverpool, UK; Center for Immunology and Inflammatory Disease, Massachusetts General Hospital, Harvard Medical School, USA
| | | | - Tom Solomon
- The Institute of Infection and Global Health, University of Liverpool, Liverpool, UK; The Walton Centre NHS Foundation Trust, Liverpool, UK; National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool, UK
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Abstract
Although long recognized as a human pathogen, West Nile virus (WNV) emerged as a significant public health problem following its introduction and spread across North America. Subsequent years have seen a greater understanding of all aspects of this viral infection. The North American epidemic resulted in a further understanding of the virology, pathogenesis, clinical features, and epidemiology of WNV infection. Approximately 80% of human WNV infections are asymptomatic. Most symptomatic people experience an acute systemic febrile illness; less than 1% of infected people develop neuroinvasive disease, which typically manifests as meningitis, encephalitis, or anterior myelitis resulting in acute flaccid paralysis. Older age is associated with more severe illness and higher mortality; other risk factors for poor outcome have been challenging to identify. In addition to natural infection through mosquito bites, transfusion- and organ transplant-associated infections have occurred. Since there is no definitive treatment for WNV infection, protection from mosquito bites and other preventative measures are critical. WNV has reached an endemic pattern in North America, but the future epidemiologic pattern is uncertain.
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Paul AM, Acharya D, Duty L, Thompson EA, Le L, Stokic DS, Leis AA, Bai F. Osteopontin facilitates West Nile virus neuroinvasion via neutrophil "Trojan horse" transport. Sci Rep 2017; 7:4722. [PMID: 28680095 PMCID: PMC5498593 DOI: 10.1038/s41598-017-04839-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 05/22/2017] [Indexed: 01/26/2023] Open
Abstract
West Nile virus (WNV) can cause severe human neurological diseases including encephalitis and meningitis. The mechanisms by which WNV enters the central nervous system (CNS) and host-factors that are involved in WNV neuroinvasion are not completely understood. The proinflammatory chemokine osteopontin (OPN) is induced in multiple neuroinflammatory diseases and is responsible for leukocyte recruitment to sites of its expression. In this study, we found that WNV infection induced OPN expression in both human and mouse cells. Interestingly, WNV-infected OPN deficient (Opn -/-) mice exhibited a higher survival rate (70%) than wild type (WT) control mice (30%), suggesting OPN plays a deleterious role in WNV infection. Despite comparable levels of viral load in circulating blood cells and peripheral organs in the two groups, WNV-infected polymorphonuclear neutrophil (PMN) infiltration and viral burden in brain of Opn -/- mice were significantly lower than in WT mice. Importantly, intracerebral administration of recombinant OPN into the brains of Opn -/- mice resulted in increased WNV-infected PMN infiltration and viral burden in the brain, which was coupled to increased mortality. The overall results suggest that OPN facilitates WNV neuroinvasion by recruiting WNV-infected PMNs into the brain.
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Affiliation(s)
- Amber M Paul
- Department of Biological Sciences, The University of Southern Mississippi, Hattiesburg, MS, 39406, USA
| | - Dhiraj Acharya
- Department of Biological Sciences, The University of Southern Mississippi, Hattiesburg, MS, 39406, USA
| | - Laurel Duty
- Department of Biological Sciences, The University of Southern Mississippi, Hattiesburg, MS, 39406, USA
| | - E Ashley Thompson
- Department of Biological Sciences, The University of Southern Mississippi, Hattiesburg, MS, 39406, USA
| | - Linda Le
- Department of Biological Sciences, The University of Southern Mississippi, Hattiesburg, MS, 39406, USA
| | - Dobrivoje S Stokic
- Center for Neuroscience and Neurological Recovery, Methodist Rehabilitation Center, Jackson, MS, 39216, USA
| | - A Arturo Leis
- Center for Neuroscience and Neurological Recovery, Methodist Rehabilitation Center, Jackson, MS, 39216, USA.,Department of Neurology, Mayo Clinic, Scottsdale, AZ, 85259, USA
| | - Fengwei Bai
- Department of Biological Sciences, The University of Southern Mississippi, Hattiesburg, MS, 39406, USA.
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Kim JH, Hossain FMA, Patil AM, Choi JY, Kim SB, Uyangaa E, Park SY, Lee JH, Kim B, Kim K, Eo SK. Ablation of CD11c(hi) dendritic cells exacerbates Japanese encephalitis by regulating blood-brain barrier permeability and altering tight junction/adhesion molecules. Comp Immunol Microbiol Infect Dis 2016; 48:22-32. [PMID: 27638116 DOI: 10.1016/j.cimid.2016.07.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 07/18/2016] [Accepted: 07/23/2016] [Indexed: 12/16/2022]
Abstract
Japanese encephalitis (JE), characterized by extensive neuroinflammation following infection with neurotropic JE virus (JEV), is becoming a leading cause of viral encephalitis due to rapid changes in climate and demography. The blood-brain barrier (BBB) plays an important role in restricting neuroinvasion of peripheral leukocytes and virus, thereby regulating the progression of viral encephalitis. In this study, we explored the role of CD11c(hi) dendritic cells (DCs) in regulating BBB integrity and JE progression using a conditional depletion model of CD11c(hi) DCs. Transient ablation of CD11c(hi) DCs resulted in markedly increased susceptibility to JE progression along with highly increased neuro-invasion of JEV. In addition, exacerbated JE progression in CD11c(hi) DC-ablated hosts was closely associated with increased expression of proinflammatory cytokines (IFN-β, IL-6, and TNF-α) and CC chemokines (CCL2, CCL3, CXCL2) in the brain. Moreover, our results revealed that the exacerbation of JE progression in CD11c(hi) DC-ablated hosts was correlated with enhanced BBB permeability and reduced expression of tight junction and adhesion molecules (claudin-5, ZO-1, occluding, JAMs). Ultimately, our data conclude that the ablation of CD11c(hi) DCs provided a subsidiary impact on BBB integrity and the expression of tight junction/adhesion molecules, thereby leading to exacerbated JE progression. These findings provide insight into the secondary role of CD11c(hi) DCs in JE progression through regulation of BBB integrity and the expression of tight junction/adhesion molecules.
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Affiliation(s)
- Jin Hyoung Kim
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Ferdaus Mohd Altaf Hossain
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Ajit Mahadev Patil
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Jin Young Choi
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Seong Bum Kim
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Erdenebelig Uyangaa
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Sang-Youel Park
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea; Department of Bioactive Material Sciences, Graduate School, Chonbuk National University, Jeonju 54896, Republic of Korea
| | - John-Hwa Lee
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea; Department of Bioactive Material Sciences, Graduate School, Chonbuk National University, Jeonju 54896, Republic of Korea
| | - Bumseok Kim
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea
| | - Koanhoi Kim
- Department of Pharmacology, Pusan National University, School of Medicine, Yangsan 50612, Republic of Korea
| | - Seong Kug Eo
- College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan 54596, Republic of Korea; Department of Bioactive Material Sciences, Graduate School, Chonbuk National University, Jeonju 54896, Republic of Korea.
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Saeed U, Piracha ZZ. Bridging the importance of Toll like receptors in human viral infections. ASIAN PACIFIC JOURNAL OF TROPICAL DISEASE 2016. [DOI: 10.1016/s2222-1808(16)61089-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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26
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Neuroinvasion and Inflammation in Viral Central Nervous System Infections. Mediators Inflamm 2016; 2016:8562805. [PMID: 27313404 PMCID: PMC4897715 DOI: 10.1155/2016/8562805] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 03/16/2016] [Accepted: 04/12/2016] [Indexed: 12/31/2022] Open
Abstract
Neurotropic viruses can cause devastating central nervous system (CNS) infections, especially in young children and the elderly. The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) have been described as relevant sites of entry for specific viruses as well as for leukocytes, which are recruited during the proinflammatory response in the course of CNS infection. In this review, we illustrate examples of established brain barrier models, in which the specific reaction patterns of different viral families can be analyzed. Furthermore, we highlight the pathogen specific array of cytokines and chemokines involved in immunological responses in viral CNS infections. We discuss in detail the link between specific cytokines and chemokines and leukocyte migration profiles. The thorough understanding of the complex and interrelated inflammatory mechanisms as well as identifying universal mediators promoting CNS inflammation is essential for the development of new diagnostic and treatment strategies.
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27
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Mathew S, Faheem M, Ibrahim SM, Iqbal W, Rauff B, Fatima K, Qadri I. Hepatitis C virus and neurological damage. World J Hepatol 2016; 8:545-556. [PMID: 27134702 PMCID: PMC4840160 DOI: 10.4254/wjh.v8.i12.545] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 03/19/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders.
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Affiliation(s)
- Shilu Mathew
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Muhammed Faheem
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Sara M Ibrahim
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Waqas Iqbal
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Bisma Rauff
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Kaneez Fatima
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ishtiaq Qadri
- Shilu Mathew, Muhammed Faheem, Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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28
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De Jesús Andino F, Jones L, Maggirwar SB, Robert J. Frog Virus 3 dissemination in the brain of tadpoles, but not in adult Xenopus, involves blood brain barrier dysfunction. Sci Rep 2016; 6:22508. [PMID: 26931458 PMCID: PMC4773881 DOI: 10.1038/srep22508] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 02/16/2016] [Indexed: 12/28/2022] Open
Abstract
While increasing evidence points to a key role of monocytes in amphibian host defenses, monocytes are also thought to be important in the dissemination and persistent infection caused by ranavirus. However, little is known about the fate of infected macrophages or if ranavirus exploits immune privileged organs, such as the brain, in order to establish a reservoir. The amphibian Xenopus laevis and Frog Virus 3 (FV3) were established as an experimental platform for investigating in vivo whether ranavirus could disseminate to the brain. Our data show that the FV3 infection alters the BBB integrity, possibly mediated by an inflammatory response, which leads to viral dissemination into the central nervous system in X. laevis tadpole but not adult. Furthermore, our data suggest that the macrophages play a major role in viral dissemination by carrying the virus into the neural tissues.
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Affiliation(s)
- Francisco De Jesús Andino
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Letitia Jones
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Sanjay B Maggirwar
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Jacques Robert
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA
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Abstract
Mosquito-borne diseases affect horses worldwide. Mosquito-borne diseases generally cause encephalomyelitis in the horse and can be difficult to diagnose antemortem. In addition to general disease, and diagnostic and treatment aspects, this review article summarizes the latest information on these diseases, covering approximately the past 5 years, with a focus on new equine disease encroachments, diagnostic and vaccination aspects, and possible therapeutics on the horizon.
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30
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Systemic lipopolysaccharide compromises the blood-labyrinth barrier and increases entry of serum fluorescein into the perilymph. J Assoc Res Otolaryngol 2014; 15:707-19. [PMID: 24952083 DOI: 10.1007/s10162-014-0476-6] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 06/03/2014] [Indexed: 12/20/2022] Open
Abstract
The blood vessels that supply the inner ear form a barrier between the blood and the inner ear fluids to control the exchange of solutes, protein, and water. This barrier, called the blood-labyrinth barrier (BLB) is analogous to the blood-brain barrier (BBB), which plays a critical role in limiting the entry of inflammatory and infectious agents into the central nervous system. We have developed an in vivo method to assess the functional integrity of the BLB by injecting sodium fluorescein into the systemic circulation of mice and measuring the amount of fluorescein that enters perilymph in live animals. In these experiments, perilymph was collected from control and experimental mice in sequential samples taken from the posterior semicircular canal approximately 30 min after systemic fluorescein administration. Perilymph fluorescein concentrations in control mice were compared with perilymph fluorescein concentrations after lipopolysaccharide (LPS) treatment (1 mg/kg IP daily for 2 days). The concentration of perilymphatic fluorescein, normalized to serum fluorescein, was significantly higher in LPS-treated mice compared to controls. In order to assess the contributions of perilymph and endolymph in our inner ear fluid samples, sodium ion concentration of the inner ear fluid was measured using ion-selective electrodes. The sampled fluid from the posterior semicircular canal demonstrated an average sodium concentration of 145 mM, consistent with perilymph. These experiments establish a novel technique to assess the functional integrity of the BLB using quantitative methods and to provide a comparison of the BLB to the BBB.
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31
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Kumar M, Nerurkar VR. Integrated analysis of microRNAs and their disease related targets in the brain of mice infected with West Nile virus. Virology 2014; 452-453:143-51. [PMID: 24606691 DOI: 10.1016/j.virol.2014.01.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 12/06/2013] [Accepted: 01/04/2014] [Indexed: 02/08/2023]
Abstract
To determine whether cellular miRNAs play a role in West Nile virus (WNV) neuropathogenesis, we evaluated WNV-infected mice brain for the expression profile of miRNAs, their potential functions and their correlation with genes involved in inflammatory pathways. A total of 528 miRNAs and 168 mRNA genes were examined. One hundred thirty-nine miRNAs were significantly differentially expressed in WNV-infected mice brain. Ingenuity pathway analysis demonstrated that these miRNAs and their target genes are involved in pathways related to inflammatory response, immune-cell trafficking and cell death. Moreover, we demonstrate an inverse correlation between WNV-modulated miRNAs and their target neuroinflammatory genes in the same mice brain. We demonstrate that miR-196a, miR-202-3p, miR-449c, and miR-125a-3p target multiple genes involving cytokines, chemokines, and apoptotic genes, which belong to different signaling pathways that play critical role in WNV neuropathogenesis. Functional studies targeting specific miRNA are warranted to develop therapeutics for the management of WNV disease.
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Affiliation(s)
- Mukesh Kumar
- Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, USA; Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, USA
| | - Vivek R Nerurkar
- Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, USA; Pacific Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, USA.
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Pattern recognition receptor MDA5 modulates CD8+ T cell-dependent clearance of West Nile virus from the central nervous system. J Virol 2013; 87:11401-15. [PMID: 23966390 DOI: 10.1128/jvi.01403-13] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Many viruses induce type I interferon responses by activating cytoplasmic RNA sensors, including the RIG-I-like receptors (RLRs). Although two members of the RLR family, RIG-I and MDA5, have been implicated in host control of virus infection, the relative role of each RLR in restricting pathogenesis in vivo remains unclear. Recent studies have demonstrated that MAVS, the adaptor central to RLR signaling, is required to trigger innate immune defenses and program adaptive immune responses, which together restrict West Nile virus (WNV) infection in vivo. In this study, we examined the specific contribution of MDA5 in controlling WNV in animals. MDA5(-/-) mice exhibited enhanced susceptibility, as characterized by reduced survival and elevated viral burden in the central nervous system (CNS) at late times after infection, even though small effects on systemic type I interferon response or viral replication were observed in peripheral tissues. Intracranial inoculation studies and infection experiments with primary neurons ex vivo revealed that an absence of MDA5 did not impact viral infection in neurons directly. Rather, subtle defects were observed in CNS-specific CD8(+) T cells in MDA5(-/-) mice. Adoptive transfer into recipient MDA5(+/+) mice established that a non-cell-autonomous deficiency of MDA5 was associated with functional defects in CD8(+) T cells, which resulted in a failure to clear WNV efficiently from CNS tissues. Our studies suggest that MDA5 in the immune priming environment shapes optimal CD8(+) T cell activation and subsequent clearance of WNV from the CNS.
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Le Coupanec A, Babin D, Fiette L, Jouvion G, Ave P, Misse D, Bouloy M, Choumet V. Aedes mosquito saliva modulates Rift Valley fever virus pathogenicity. PLoS Negl Trop Dis 2013; 7:e2237. [PMID: 23785528 PMCID: PMC3681724 DOI: 10.1371/journal.pntd.0002237] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Accepted: 04/15/2013] [Indexed: 01/10/2023] Open
Abstract
Background Rift Valley fever (RVF) is a severe mosquito-borne disease affecting humans and domestic ruminants. Mosquito saliva contains compounds that counteract the hemostatic, inflammatory, and immune responses of the host. Modulation of these defensive responses may facilitate virus infection. Indeed, Aedes mosquito saliva played a crucial role in the vector's capacity to effectively transfer arboviruses such as the Cache Valley and West Nile viruses. The role of mosquito saliva in the transmission of Rift Valley fever virus (RVFV) has not been investigated. Objective Using a murine model, we explored the potential for mosquitoes to impact the course of RVF disease by determining whether differences in pathogenesis occurred in the presence or absence of mosquito saliva and salivary gland extract. Methods C57BL/6NRJ male mice were infected with the ZH548 strain of RVFV via intraperitoneal or intradermal route, or via bites from RVFV-exposed mosquitoes. The virus titers in mosquitoes and mouse organs were determined by plaque assays. Findings After intraperitoneal injection, RVFV infection primarily resulted in liver damage. In contrast, RVFV infection via intradermal injection caused both liver and neurological symptoms and this route best mimicked the natural infection by mosquitoes. Co-injections of RVFV with salivary gland extract or saliva via intradermal route increased the mortality rates of mice, as well as the virus titers measured in several organs and in the blood. Furthermore, the blood cell counts of infected mice were altered compared to those of uninfected mice. Interpretation Different routes of infection determine the pattern in which the virus spreads and the organs it targets. Aedes saliva significantly increases the pathogenicity of RVFV. Rift Valley fever is an endemic and epidemic zoonosis in Africa and the Arabic Peninsula. In humans, in the most severe cases the viral infection causes fulminant hepatitis associated with haemorrhagic fever, permanent blindness or severe encephalitis. Despite the importance of vector transmission in the spread of arboviruses, few studies on the physiopathology of viral infection have considered the role of the arthropod in the efficiency of viral infection. Moreover, the route of virus inoculation and the presence of the vector's saliva can potentially affect virus pathogenicity. Our results show that saliva from Aedes mosquitoes increases Rift Valley fever pathogenicity. Importantly, our study also revealed that RVFV transmitted via mosquito bites spread differently than virus inoculated by other routes. These observations may have interesting repercussions given the role mosquitoes were shown to play in the transmission of RVFV in humans during the last outbreak of the disease in Saudi Arabia. Identification of salivary proteins able to increase RVFV virulence may pave the way to new approaches to prevent or cure the disease.
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Affiliation(s)
- Alain Le Coupanec
- Unité de Génétique Moléculaire des Bunyavirus, Institut Pasteur, Paris, France
| | - Divya Babin
- Unité de Génétique Moléculaire des Bunyavirus, Institut Pasteur, Paris, France
| | - Laurence Fiette
- Unité d'Histopathologie humaine et modèles animaux, Institut Pasteur, Paris, France
| | - Grégory Jouvion
- Unité d'Histopathologie humaine et modèles animaux, Institut Pasteur, Paris, France
| | - Patrick Ave
- Unité d'Histopathologie humaine et modèles animaux, Institut Pasteur, Paris, France
| | - Dorothee Misse
- MIVEGEC (IRD 224 CNRS 5290-UM1-UM2) Maladies infectieuses et vecteurs: écologie, génétique, évolution et contrôle, Centre IRD de Montpellier, Montpellier, France
| | - Michèle Bouloy
- Unité de Génétique Moléculaire des Bunyavirus, Institut Pasteur, Paris, France
| | - Valerie Choumet
- Unité de Génétique Moléculaire des Bunyavirus, Institut Pasteur, Paris, France
- * E-mail:
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Infectious diseases: West Nile virus on the rise. JAAPA 2013; 26:13, 17. [PMID: 23355996 DOI: 10.1097/01720610-201301000-00004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Immune responses to West Nile virus infection in the central nervous system. Viruses 2012; 4:3812-30. [PMID: 23247502 PMCID: PMC3528292 DOI: 10.3390/v4123812] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Revised: 12/07/2012] [Accepted: 12/10/2012] [Indexed: 12/16/2022] Open
Abstract
West Nile virus (WNV) continues to cause outbreaks of severe neuroinvasive disease in humans and other vertebrate animals in the United States, Europe, and other regions of the world. This review discusses our understanding of the interactions between virus and host that occur in the central nervous system (CNS), the outcome of which can be protection, viral pathogenesis, or immunopathogenesis. We will focus on defining the current state of knowledge of WNV entry, tropism, and host immune response in the CNS, all of which affect the balance between injury and successful clearance.
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Singh P, Agnihotri SK, Tewari MC, Kumar S, Sachdev M, Tripathi RK. HIV-1 Nef breaches placental barrier in rat model. PLoS One 2012; 7:e51518. [PMID: 23240037 PMCID: PMC3519864 DOI: 10.1371/journal.pone.0051518] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 11/01/2012] [Indexed: 11/18/2022] Open
Abstract
The vertical transmission of HIV-1 from the mother to fetus is known, but the molecular mechanism regulating this transmission is not fully characterized. The fetus is highly protected by the placenta, which does not permit microbial pathogens to cross the placental barrier. In the present study, a rat model was established to observe the effect of HIV-1 protein Nef on placental barrier. Evans blue dye was used to assay permeability of placental barrier and fourteen day pregnant Sprague Dawley rats were injected intravenously with 2% Evans blue dye along with various concentrations of recombinant Nef. After an hour, animals were sacrificed and dye migration was observed through the assimilation of peripheral blood into fetus. Interestingly, traces of recombinant Nef protein were detected in the embryo as well as amniotic fluid and amniotic membrane along with placenta and uterus. Our study indicates that recombinant HIV-1-Nef protein breaches the placental barrier and allows the migration of Evans blue dye to the growing fetus. Further the concentration of Nef protein in blood is directly proportional to the intensity of dye migration and to the amount of Nef protein detected in uterus, placenta, amniotic membrane, amniotic fluid and embryo. Based on this study, it can be concluded that the HIV-1 Nef protein has a direct effect on breaching of the placental barrier in the model we have established in this study. Our observations will be helpful to understand the molecular mechanisms related to this breach of placental barrier by Nef in humans and may be helpful to identify specific Nef inhibitors.
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Affiliation(s)
- Poonam Singh
- Toxicology Division, Central Drug Research Institute (Council of Scientific and Industrial Research), Lucknow, Uttar Pradesh, India
| | - Saurabh Kumar Agnihotri
- Endocrinology Division, Central Drug Research Institute (Council of Scientific and Industrial Research), Lucknow, Uttar Pradesh, India
| | - Mahesh Chandra Tewari
- Endocrinology Division, Central Drug Research Institute (Council of Scientific and Industrial Research), Lucknow, Uttar Pradesh, India
| | - Sadan Kumar
- Toxicology Division, Central Drug Research Institute (Council of Scientific and Industrial Research), Lucknow, Uttar Pradesh, India
| | - Monika Sachdev
- Endocrinology Division, Central Drug Research Institute (Council of Scientific and Industrial Research), Lucknow, Uttar Pradesh, India
- * E-mail: (MS); (RK)
| | - Raj Kamal Tripathi
- Toxicology Division, Central Drug Research Institute (Council of Scientific and Industrial Research), Lucknow, Uttar Pradesh, India
- * E-mail: (MS); (RK)
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Carta MG, Angst J, Moro MF, Mura G, Hardoy MC, Balestrieri C, Chessa L, Serra G, Lai ME, Farci P. Association of chronic hepatitis C with recurrent brief depression. J Affect Disord 2012; 141:361-6. [PMID: 22609196 DOI: 10.1016/j.jad.2012.03.020] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2012] [Revised: 03/12/2012] [Accepted: 03/12/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND Depressive syndromes, including recurrent brief depression (RBD), have frequently been observed in association with chronic diseases characterized by immune activation, such as autoimmune thyroiditis or celiac disease. However, the association of RBD with chronic hepatitis C (CHC), a disease with an increased incidence of major depressive disorders, is unknown. CASES 135 (83 males, 52 females) consecutive treatment-naïve patients with CHC. EXCLUSION CRITERIA previous treatment with IFN-alpha, co-infection with hepatitis C virus (HCV) and hepatitis B virus, infection with human immunodeficiency virus (HIV), drug or alcohol abuse, or malignancy. CONTROLS 540 (332 males, 208 females) subjects without evidence of hepatitis, randomly extracted from the database of a previous epidemiological study. The psychiatric diagnosis was based on the Composite International Diagnostic Interview Simplified (CIDI-S), containing a specific section on RBD. RESULTS A significantly higher rate of RBD was observed among both male and female patients with CHC (n=21, 15.5%) as compared to controls (n=34, 6.3%) (OR=2.6, CI 95% from 1.37 to 4.93). CONCLUSION The present study provides the first evidence of an association between CHC and RBD, independent of treatment with IFN-alpha and not influenced by substance or alcohol abuse. The results are similar to those found in other conditions with immune activation. RBD may be another expression of mood disorders in such conditions.
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Affiliation(s)
- Mauro G Carta
- Department of Public Health, University of Cagliari, Italy.
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Wang P, Bai F, Zenewicz LA, Dai J, Gate D, Cheng G, Yang L, Qian F, Yuan X, Montgomery RR, Flavell RA, Town T, Fikrig E. IL-22 signaling contributes to West Nile encephalitis pathogenesis. PLoS One 2012; 7:e44153. [PMID: 22952908 PMCID: PMC3429482 DOI: 10.1371/journal.pone.0044153] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Accepted: 07/30/2012] [Indexed: 01/21/2023] Open
Abstract
The Th17 cytokine, IL-22, regulates host immune responses to extracellular pathogens. Whether IL-22 plays a role in viral infection, however, is poorly understood. We report here that Il22(-/-) mice were more resistant to lethal West Nile virus (WNV) encephalitis, but had similar viral loads in the periphery compared to wild type (WT) mice. Viral loads, leukocyte infiltrates, proinflammatory cytokines and apoptotic cells in the central nervous system (CNS) of Il22(-/-) mice were also strikingly reduced. Further examination showed that Cxcr2, a chemokine receptor that plays a non-redundant role in mediating neutrophil migration, was significantly reduced in Il22(-/-) compared to WT leukocytes. Expression of Cxcr2 ligands, cxcl1 and cxcl5, was lower in Il22(-/-) brains than wild type mice. Correspondingly, neutrophil migration from the blood into the brain was attenuated following lethal WNV infection of Il22(-/-) mice. Our results suggest that IL-22 signaling exacerbates lethal WNV encephalitis likely by promoting WNV neuroinvasion.
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Affiliation(s)
- Penghua Wang
- Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
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Sultana H, Neelakanta G, Foellmer HG, Montgomery RR, Anderson JF, Koski RA, Medzhitov RM, Fikrig E. Semaphorin 7A contributes to West Nile virus pathogenesis through TGF-β1/Smad6 signaling. THE JOURNAL OF IMMUNOLOGY 2012; 189:3150-8. [PMID: 22896629 DOI: 10.4049/jimmunol.1201140] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Semaphorin 7A (Sema7A) is a membrane-associated/secreted protein that plays an essential role in connecting the vertebrate neuronal and immune systems. However, the role of Sema7A has not been elucidated in viral pathogenesis. In this study, we show that abrogation of Sema7A protects mice from lethal West Nile virus (WNV) infection. Mice lacking Sema7A showed increased survival, reduced viral burden, and less blood-brain barrier permeability upon WNV infection. Increased Sema7A levels were evident in murine tissues, as well as in murine cortical neurons and primary human macrophages upon WNV infection. Treatment with Sema7A Ab blocked WNV infection in both of these cell types. Furthermore, Sema7A positively regulates the production of TGF-β1 and Smad6 to facilitate WNV pathogenesis in mice. Collectively, these data elucidate the role of Sema7A in shared signaling pathways used by the immune and nervous systems during viral pathogenesis that may lead to the development of Sema7A-blocking therapies for WNV and possibly other flaviviral infections.
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Affiliation(s)
- Hameeda Sultana
- Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
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40
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West Nile virus infection causes endocytosis of a specific subset of tight junction membrane proteins. PLoS One 2012; 7:e37886. [PMID: 22655077 PMCID: PMC3359987 DOI: 10.1371/journal.pone.0037886] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 04/30/2012] [Indexed: 12/22/2022] Open
Abstract
West Nile virus (WNV) is a blood-borne pathogen that causes systemic infections and serious neurological disease in human and animals. The most common route of infection is mosquito bites and therefore, the virus must cross a number of polarized cell layers to gain access to organ tissue and the central nervous system. Resistance to trans-cellular movement of macromolecules between epithelial and endothelial cells is mediated by tight junction complexes. While a number of recent studies have documented that WNV infection negatively impacts the barrier function of tight junctions, the intracellular mechanism by which this occurs is poorly understood. In the present study, we report that endocytosis of a subset of tight junction membrane proteins including claudin-1 and JAM-1 occurs in WNV infected epithelial and endothelial cells. This process, which ultimately results in lysosomal degradation of the proteins, is dependent on the GTPase dynamin and microtubule-based transport. Finally, infection of polarized cells with the related flavivirus, Dengue virus-2, did not result in significant loss of tight junction membrane proteins. These results suggest that neurotropic flaviviruses such as WNV modulate the host cell environment differently than hemorrhagic flaviviruses and thus may have implications for understanding the molecular basis for neuroinvasion.
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Fletcher NF, Wilson GK, Murray J, Hu K, Lewis A, Reynolds GM, Stamataki Z, Meredith LW, Rowe IA, Luo G, Lopez–ramirez MIGUELA, Baumert TF, Weksler B, Couraud PO, Kim KS, Romero IA, Jopling C, Morgello S, Balfe P, Mckeating JA. Hepatitis C virus infects the endothelial cells of the blood-brain barrier. Gastroenterology 2012; 142:634-643.e6. [PMID: 22138189 PMCID: PMC3801216 DOI: 10.1053/j.gastro.2011.11.028] [Citation(s) in RCA: 187] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2011] [Revised: 10/18/2011] [Accepted: 11/15/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic syndromes, including central nervous system (CNS) abnormalities. However, it is unclear whether such cognitive abnormalities are a function of systemic disease, impaired hepatic function, or virus infection of the CNS. METHODS We measured levels of HCV RNA and expression of the viral entry receptor in brain tissue samples from 10 infected individuals (and 3 uninfected individuals, as controls) and human brain microvascular endothelial cells by using quantitative polymerase chain reaction and immunochemical and confocal imaging analyses. HCV pseudoparticles and cell culture-derived HCV were used to study the ability of endothelial cells to support viral entry and replication. RESULTS Using quantitative polymerase chain reaction, we detected HCV RNA in brain tissue of infected individuals at significantly lower levels than in liver samples. Brain microvascular endothelia and brain endothelial cells expressed all of the recognized HCV entry receptors. Two independently derived brain endothelial cell lines, hCMEC/D3 and HBMEC, supported HCV entry and replication. These processes were inhibited by antibodies against the entry factors CD81, scavenger receptor BI, and claudin-1; by interferon; and by reagents that inhibit NS3 protease and NS5B polymerase. HCV infection promotes endothelial permeability and cellular apoptosis. CONCLUSIONS Human brain endothelial cells express functional receptors that support HCV entry and replication. Virus infection of the CNS might lead to HCV-associated neuropathologies.
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Affiliation(s)
- Nicola F. Fletcher
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Garrick K. Wilson
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Jacinta Murray
- School of Pharmacy, University of Nottingham, Nottingham, England
| | - Ke Hu
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Andrew Lewis
- School of Pharmacy, University of Nottingham, Nottingham, England
| | - Gary M. Reynolds
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Zania Stamataki
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Luke W. Meredith
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Ian A. Rowe
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Guangxiang Luo
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
| | | | - Thomas F. Baumert
- Université de Strasbourg and Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | | | - Pierre-Olivier Couraud
- Institut Cochin, CNRS UMR 8104, INSERM Unité 567, Université Paris Descartes, Paris, France
| | - Kwang Sik Kim
- Division of Infectious Diseases, The Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Ignacio A. Romero
- Department of Life Sciences, The Open University, Milton Keynes, England
| | | | - Susan Morgello
- Department of Pathology, Mount Sinai School of Medicine, New York, New York
| | - Peter Balfe
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
| | - Jane A. Mckeating
- Hepatitis C Research Group, Institute for Biomedical Research, University of Birmingham, Birmingham, England
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Yang EJ, Seo JW, Choi IH. Ribosomal Protein L19 and L22 Modulate TLR3 Signaling. Immune Netw 2011; 11:155-62. [PMID: 21860608 PMCID: PMC3153667 DOI: 10.4110/in.2011.11.3.155] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 05/30/2011] [Accepted: 06/09/2011] [Indexed: 01/12/2023] Open
Abstract
Background Toll-like receptor 3 (TLR3) recognizes double-stranded RNA (dsRNA) and induces inflammation. In this study we attempted to ascertain if there are endogenous host molecules controlling the production of cytokines and chemokines. Two candidates, ribosomal protein L19 and L22, were analyzed to determine if they influence cytokine production followed by TLR3 activation. In this study we report that L19 acts upon production of IP-10 or IL-8 differently in glioblastoma cells. Methods L19 or L22 was transfected into HEK293-TLR3, A549 or A172 cells. After treatment with several inhibitors of NF-kB, PI3K, p38 or ERK, production of IL-8 or IP-10 was measured by ELISA. siRNA was introduced to suppress expression of L19. After Vesicular stomatitis virus infection, viral multiplication was measured by western blot. Results L19 increased ERK activation to produce IL-8. In A172 cells, in which TLR3 is expressed at endosomes, L19 inhibited interferon regulatory factor 3 (IRF3) activation and IP-10 production to facilitate viral multiplication, whereas L19 inhibited viral multiplication in A549 cells bearing TLR3 on their cell membrane. Conclusion Our results suggest that L19 regulates TLR3 signaling, which is cell type specific and may be involved in pathogenesis of autoimmune diseases and chronic inflammatory diseases.
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Affiliation(s)
- Eun-Jeong Yang
- Department of Microbiology, Instititute for Immunology and Immunological Diseases, and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea
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43
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Růžek D, Salát J, Singh SK, Kopecký J. Breakdown of the blood-brain barrier during tick-borne encephalitis in mice is not dependent on CD8+ T-cells. PLoS One 2011; 6:e20472. [PMID: 21629771 PMCID: PMC3100324 DOI: 10.1371/journal.pone.0020472] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Accepted: 04/26/2011] [Indexed: 12/30/2022] Open
Abstract
Tick-borne encephalitis (TBE) virus causes severe encephalitis with serious sequelae in humans. The disease is characterized by fever and debilitating encephalitis that can progress to chronic illness or fatal infection. In this study, changes in permeability of the blood-brain barrier (BBB) in two susceptible animal models (BALB/c, and C57Bl/6 mice) infected with TBE virus were investigated at various days after infection by measuring fluorescence in brain homogenates after intraperitoneal injection of sodium fluorescein, a compound that is normally excluded from the central nervous system. We demonstrate here that TBE virus infection, in addition to causing fatal encephalitis in mice, induces considerable breakdown of the BBB. The permeability of the BBB increased at later stages of TBE infection when high virus load was present in the brain (i.e., BBB breakdown was not necessary for TBE virus entry into the brain), and at the onset of the first severe clinical symptoms of the disease, which included neurological signs associated with sharp declines in body weight and temperature. The increased BBB permeability was in association with dramatic upregulation of proinflammatory cytokine/chemokine mRNA expression in the brain. Breakdown of the BBB was also observed in mice deficient in CD8+ T-cells, indicating that these cells are not necessary for the increase in BBB permeability that occurs during TBE. These novel findings are highly relevant to the development of future therapies designed to control this important human infectious disease.
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Affiliation(s)
- Daniel Růžek
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic.
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44
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Mansfield KL, Johnson N, Cosby SL, Solomon T, Fooks AR. Transcriptional upregulation of SOCS 1 and suppressors of cytokine signaling 3 mRNA in the absence of suppressors of cytokine signaling 2 mRNA after infection with West Nile virus or tick-borne encephalitis virus. Vector Borne Zoonotic Dis 2011; 10:649-53. [PMID: 20854017 DOI: 10.1089/vbz.2009.0259] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Suppressors of cytokine signaling (SOCS) proteins are a family of proteins that are able to act in a classic negative feedback loop to regulate cytokine signal transduction. The regulation of the immune response by SOCS proteins may contribute to persistent infection or even a fatal outcome. In this study, we have investigated the induction of SOCS 1-3 after peripheral infection with West Nile virus (WNV) or tick-borne encephalitis virus (TBEV) in the murine model. We have shown that the cytokine response after infection of mice with WNV or TBEV induces an upregulation in the brain of mRNA transcripts for SOCS 1 and SOCS 3, but not SOCS 2. We hypothesize that SOCS proteins may play a role in limiting cytokine responses in the brain as a neuroprotective mechanism, which may actually enhance the ability of neuroinvasive viruses such as WNV and TBEV to spread and cause disease.
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Affiliation(s)
- Karen L Mansfield
- Rabies and Wildlife Zoonoses Group, Veterinary Laboratories Agency, New Haw, Addlestone, United Kingdom
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45
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Kumar M, Verma S, Nerurkar VR. Pro-inflammatory cytokines derived from West Nile virus (WNV)-infected SK-N-SH cells mediate neuroinflammatory markers and neuronal death. J Neuroinflammation 2010; 7:73. [PMID: 21034511 PMCID: PMC2984415 DOI: 10.1186/1742-2094-7-73] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2010] [Accepted: 10/31/2010] [Indexed: 12/20/2022] Open
Abstract
Background WNV-associated encephalitis (WNVE) is characterized by increased production of pro-inflammatory mediators, glial cells activation and eventual loss of neurons. WNV infection of neurons is rapidly progressive and destructive whereas infection of non-neuronal brain cells is limited. However, the role of neurons and pathological consequences of pro-inflammatory cytokines released as a result of WNV infection is unclear. Therefore, the objective of this study was to examine the role of key cytokines secreted by WNV-infected neurons in mediating neuroinflammatory markers and neuronal death. Methods A transformed human neuroblastoma cell line, SK-N-SH, was infected with WNV at multiplicity of infection (MOI)-1 and -5, and WNV replication kinetics and expression profile of key pro-inflammatory cytokines were analyzed by plaque assay, qRT-PCR, and ELISA. Cell death was measured in SK-N-SH cell line in the presence and absence of neutralizing antibodies against key pro-inflammatory cytokines using cell viability assay, TUNEL and flow cytometry. Further, naïve primary astrocytes were treated with UV-inactivated supernatant from mock- and WNV-infected SK-N-SH cell line and the activation of astrocytes was measured using flow cytometry and ELISA. Results WNV-infected SK-N-SH cells induced the expression of IL-1β, -6, -8, and TNF-α in a dose- and time-dependent manner, which coincided with increase in virus-induced cell death. Treatment of cells with anti-IL-1β or -TNF-α resulted in significant reduction of the neurotoxic effects of WNV. Furthermore treatment of naïve astrocytes with UV-inactivated supernatant from WNV-infected SK-N-SH cell line increased expression of glial fibrillary acidic protein and key inflammatory cytokines. Conclusion Our results for the first time suggest that neurons are one of the potential sources of pro-inflammatory cytokines in WNV-infected brain and these neuron-derived cytokines contribute to WNV-induced neurotoxicity. Moreover, cytokines released from neurons also mediate the activation of astrocytes. Our data define specific role(s) of WNV-induced pro-inflammatory cytokines and provide a framework for the development of anti-inflammatory drugs as much-needed therapeutic interventions to limit symptoms associated with WNVE.
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Affiliation(s)
- Mukesh Kumar
- Retrovirology Research Laboratory, Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A, Burns School of Medicine, University of Hawaii at Manoa, 651 Ilalo Street, BSB 325AA, Honolulu, Hawaii 96813, USA
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Liu TH, Liang LC, Wang CC, Liu HC, Chen WJ. The blood-brain barrier in the cerebrum is the initial site for the Japanese encephalitis virus entering the central nervous system. J Neurovirol 2010; 14:514-21. [PMID: 19023687 DOI: 10.1080/13550280802339643] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Japanese encephalitis (JE) virus is a member of the encephalitic flaviviruses and frequently causes neurological sequelae in a proportion of patients who survive the acute phase of the infection. In the present study, we molecularly identified viral infection in the brain of mice with rigidity of hindlimbs and/or abnormal gait, in which JE virus particles appeared within membrane-bound vacuoles of neurons throughout the central nervous system. Deformation of tight junctions (TJs) shown as dissociation of endothelial cells in capillaries, implying that the integrity of the blood-brain barrier (BBB) has been compromised by JE virus infection. BBB permeability evidently increased in the cerebrum, but not in the cerebellum, of JE virus-infected mice intravenously injected with the tracer of Evans blue dye. This suggests that the permeability of the BBB differentially changed in response to viral infection, leading to the entry of JE virions and/or putatively infected leukocytes from the periphery to the cerebrum as the initial site of infection in the central nervous system (CNS). Theoretically, the virus spread to the cerebellum soon after the cerebrum became infected.
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Affiliation(s)
- Tsan-Hsiun Liu
- Departments of Anatomy, Kaohsiung Medical University, Kaohsiung, Taiwan
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Abstract
West Nile virus (WNV) is responsible for thousands of cases of morbidity and mortality in birds, horses, and humans. Epidemics were localized to Europe, Africa, the Middle East, and parts of Asia, and primarily caused a mild febrile illness in humans. In the late 1990s, the virus became more virulent and spread to North America. In humans, the clinical presentation ranges from asymptomatic, seen frequently, to encephalitis/paralysis and death, seen rarely. There is no FDA (Food and Drug Administration)-licensed vaccine for human use, and the only recommended treatment is supportive care. Often, there is a long recovery period. This article reviews the current literature summarizing the molecular virology, epidemiology, clinical manifestations, pathogenesis, diagnosis, treatment, immunology, and protective measures against WNV and WNV infections in humans.
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Affiliation(s)
- Shannan L Rossi
- Department of Microbiology and Molecular Genetics, Center for Vaccine Research, University of Pittsburgh, PA 15261, USA
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Verma S, Kumar M, Gurjav U, Lum S, Nerurkar VR. Reversal of West Nile virus-induced blood-brain barrier disruption and tight junction proteins degradation by matrix metalloproteinases inhibitor. Virology 2009; 397:130-8. [PMID: 19922973 DOI: 10.1016/j.virol.2009.10.036] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2009] [Revised: 09/05/2009] [Accepted: 10/21/2009] [Indexed: 11/26/2022]
Abstract
Though compromised blood-brain barrier (BBB) is a pathological hallmark of WNV-associated neurological sequelae, underlying mechanisms are unclear. We characterized the expression of matrix metalloproteinases (MMP) in WNV-infected human brain microvascular endothelial cells (HBMVE) and human brain cortical astrocytes (HBCA), components of BBB and their role in BBB disruption. Expression of multiple MMPs was significantly induced in WNV-infected HBCA cells. Naïve HBMVE cells incubated with the supernatant from WNV-infected HBCA cells demonstrated loss of tight junction proteins, which were rescued in the presence of MMP inhibitor, GM6001. Further, supernatant from WNV-infected HBCA cells compromised the in vitro BBB model integrity. Our data suggest astrocytes as one of the sources of MMP in the brain, which mediates BBB disruption allowing unrestricted entry of immune cells into the brain, thereby contributing to WNV neuropathogenesis. Because of the unavailability of WNV antivirals and vaccines, use of MMP inhibitors as an adjunct therapy to ameliorate WNV disease progression is warranted.
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Affiliation(s)
- Saguna Verma
- Retrovirology Research Laboratory, Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, Honolulu, HI 96813, USA
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CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharmacol 2009; 4:462-75. [PMID: 19669892 PMCID: PMC2773117 DOI: 10.1007/s11481-009-9166-2] [Citation(s) in RCA: 158] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2009] [Accepted: 07/22/2009] [Indexed: 12/11/2022]
Abstract
While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as “immune privilege,” it is now clear that immune responses do occur in the CNS—giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue.
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50
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Sultana H, Foellmer HG, Neelakanta G, Oliphant T, Engle M, Ledizet M, Krishnan MN, Bonafé N, Anthony KG, Marasco WA, Kaplan P, Montgomery RR, Diamond MS, Koski RA, Fikrig E. Fusion loop peptide of the West Nile virus envelope protein is essential for pathogenesis and is recognized by a therapeutic cross-reactive human monoclonal antibody. THE JOURNAL OF IMMUNOLOGY 2009; 183:650-60. [PMID: 19535627 DOI: 10.4049/jimmunol.0900093] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
West Nile virus is an emerging pathogen that can cause fatal neurological disease. A recombinant human mAb, mAb11, has been described as a candidate for the prevention and treatment of West Nile disease. Using a yeast surface display epitope mapping assay and neutralization escape mutant, we show that mAb11 recognizes the fusion loop, at the distal end of domain II of the West Nile virus envelope protein. Ab mAb11 cross-reacts with all four dengue viruses and provides protection against dengue (serotypes 2 and 4) viruses. In contrast to the parental West Nile virus, a neutralization escape variant failed to cause lethal encephalitis (at higher infectious doses) or induce the inflammatory responses associated with blood-brain barrier permeability in mice, suggesting an important role for the fusion loop in viral pathogenesis. Our data demonstrate that an intact West Nile virus fusion loop is critical for virulence, and that human mAb11 targeting this region is efficacious against West Nile virus infection. These experiments define the molecular determinant on the envelope protein recognized by mAb11 and demonstrate the importance of this region in causing West Nile encephalitis.
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Affiliation(s)
- Hameeda Sultana
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
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