scholarly journals The emerging role of perivascular cells (pericytes) in viral pathogenesis

2021 ◽  
Vol 102 (8) ◽  
Author(s):  
Teemapron Butsabong ◽  
Mariana Felippe ◽  
Paola Campagnolo ◽  
Kevin Maringer
Keyword(s):  
Causative Agent ◽  
Viral Pathogenesis ◽  
Viral Gene ◽  
Human Pathogens ◽  
Emerging Viruses ◽  
Perivascular Cells ◽  
Vascular Integrity ◽  
Paracrine Signalling ◽  
Immunodeficiency Syndrome ◽  
Antigen Presenting

Viruses may exploit the cardiovascular system to facilitate transmission or within-host dissemination, and the symptoms of many viral diseases stem at least in part from a loss of vascular integrity. The microvascular architecture is comprised of an endothelial cell barrier ensheathed by perivascular cells (pericytes). Pericytes are antigen-presenting cells (APCs) and play crucial roles in angiogenesis and the maintenance of microvascular integrity through complex reciprocal contact-mediated and paracrine crosstalk with endothelial cells. We here review the emerging ways that viruses interact with pericytes and pay consideration to how these interactions influence microvascular function and viral pathogenesis. Major outcomes of virus-pericyte interactions include vascular leakage or haemorrhage, organ tropism facilitated by barrier disruption, including viral penetration of the blood-brain barrier and placenta, as well as inflammatory, neurological, cognitive and developmental sequelae. The underlying pathogenic mechanisms may include direct infection of pericytes, pericyte modulation by secreted viral gene products and/or the dysregulation of paracrine signalling from or to pericytes. Viruses we cover include the herpesvirus human cytomegalovirus (HCMV, Human betaherpesvirus 5), the retrovirus human immunodeficiency virus (HIV; causative agent of acquired immunodeficiency syndrome, AIDS, and HIV-associated neurocognitive disorder, HAND), the flaviviruses dengue virus (DENV), Japanese encephalitis virus (JEV) and Zika virus (ZIKV), and the coronavirus severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2; causative agent of coronavirus disease 2019, COVID-19). We touch on promising pericyte-focussed therapies for treating the diseases caused by these important human pathogens, many of which are emerging viruses or are causing new or long-standing global pandemics.

Epidermal and splenic antigen-presenting cell function in a retrovirally induced murine immunodeficiency syndrome (MAIDS)

1992 ◽  
Vol 284 (4) ◽  
pp. 189-192 ◽  
Author(s):  
A. Cerny ◽  
S. Izui ◽  
J. -H. Saurat ◽  
F. A. Waldvogel ◽  
H. C. Morse ◽  
...  
Keyword(s):  
Cell Function ◽  
Antigen Presenting Cell ◽  
Immunodeficiency Syndrome ◽  
Antigen Presenting

scholarly journals Novel Arenavirus Entry Inhibitors Discovered by Using a Minigenome Rescue System for High-Throughput Drug Screening

2015 ◽  
Vol 89 (16) ◽  
pp. 8428-8443 ◽  
Author(s):  
Jessica Y. Rathbun ◽  
Magali E. Droniou ◽  
Robert Damoiseaux ◽  
Kevin G. Haworth ◽  
Jill E. Henley ◽  
...  
Keyword(s):  
High Throughput ◽  
Causative Agent ◽  
High Throughput Screening ◽  
Hemorrhagic Fever ◽  
Human Pathogens ◽  
Junin Virus ◽  
Hemorrhagic Fevers ◽  
Argentine Hemorrhagic Fever ◽  
Rescue System ◽  
Junín Virus

ABSTRACTCertain members of theArenaviridaefamily are category A agents capable of causing severe hemorrhagic fevers in humans. Specific antiviral treatments do not exist, and the only commonly used drug, ribavirin, has limited efficacy and can cause severe side effects. The discovery and development of new antivirals are inhibited by the biohazardous nature of the viruses, making them a relatively poorly understood group of human pathogens. We therefore adapted a reverse-genetics minigenome (MG) rescue system based on Junin virus, the causative agent of Argentine hemorrhagic fever, for high-throughput screening (HTS). The MG rescue system recapitulates all stages of the virus life cycle and enables screening of small-molecule libraries under biosafety containment level 2 (BSL2) conditions. The HTS resulted in the identification of four candidate compounds with potent activity against a broad panel of arenaviruses, three of which were completely novel. The target for all 4 compounds was the stage of viral entry, which positions the compounds as potentially important leads for future development.IMPORTANCEThe arenavirus family includes several members that are highly pathogenic, causing acute viral hemorrhagic fevers with high mortality rates. No specific effective treatments exist, and although a vaccine is available for Junin virus, the causative agent of Argentine hemorrhagic fever, it is licensed for use only in areas where Argentine hemorrhagic fever is endemic. For these reasons, it is important to identify specific compounds that could be developed as antivirals against these deadly viruses.

scholarly journals The Antigen-Presenting Activity of Fresh, Adult Parenchymal Microglia and Perivascular Cells from Retina

2004 ◽  
Vol 172 (11) ◽  
pp. 6587-6597 ◽  
Author(s):  
Dale S. Gregerson ◽  
Thien N. Sam ◽  
Scott W. McPherson
Keyword(s):  
Perivascular Cells ◽  
Antigen Presenting

scholarly journals Structural and functional characterization of the Severe fever with thrombocytopenia syndrome virus L protein

2020 ◽  
Author(s):  
Dominik Vogel ◽  
Sigurdur Rafn Thorkelsson ◽  
Emmanuelle R. J. Quemin ◽  
Kristina Meier ◽  
Tomas Kouba ◽  
...  
Keyword(s):  
Biochemical Characterization ◽  
Functional Characterization ◽  
Limiting Factor ◽  
Genome Replication ◽  
Human Pathogens ◽  
Emerging Viruses ◽  
Replication Process ◽  
L Protein ◽  
Severe Fever

ABSTRACTThe Bunyavirales order contains several emerging viruses with high epidemic potential, including Severe fever with thrombocytopenia syndrome virus (SFTSV). The lack of medical countermeasures, such as vaccines and antivirals, is a limiting factor for the containment of any virus outbreak. To develop such antivirals a profound understanding of the viral replication process is essential. The L protein of bunyaviruses is a multi-functional and multi-domain protein performing both virus transcription and genome replication and, therefore, would be an ideal drug target. We established expression and purification procedures for the full-length L protein of SFTSV. By combining single-particle electron-cryo microscopy and X-ray crystallography, we obtained 3D models covering ∼70% of the SFTSV L protein in the apo-conformation including the polymerase core region, the endonuclease and the cap-binding domain. We compared this first L structure of the Phenuiviridae family to the structures of La Crosse peribunyavirus L protein and influenza orthomyxovirus polymerase. Together with a comprehensive biochemical characterization of the distinct functions of SFTSV L protein, this work provides a solid framework for future structural and functional studies of L protein-RNA interactions and the development of antiviral strategies against this group of emerging human pathogens.

scholarly journals Integration of viral transcriptome sequencing with structure and sequence motifs predicts novel regulatory elements in SARS-CoV-2

2020 ◽  
Author(s):  
Brian J. Cox
Keyword(s):  
Regulatory Elements ◽  
Viral Gene ◽  
Template Switching ◽  
Sequence Motif ◽  
Sequence Motifs ◽  
Human Pathogens ◽  
Sequencing Data ◽  
Stem Loop ◽  
Conserved Sequence ◽  
Splice Junctions

SummaryIn the last twenty years, three separate coronaviruses have left their typical animal hosts and became human pathogens. An area of research interest is coronavirus transcription regulation that uses an RNA-RNA mediated template-switching mechanism. It is not known how different transcriptional stoichiometries of each viral gene are generated. Analysis of SARS-CoV-2 RNA sequencing data from whole RNA transcriptomes identified TRS dependent and independent transcripts. Integration of transcripts and 5’-UTR sequence motifs identified that the pentaloop and the stem-loop 3 were also located upstream of spliced genes. TRS independent transcripts were detected as likely non-polyadenylated. Additionally, a novel conserved sequence motif was discovered at either end of the TRS independent splice junctions. While similar both SARS viruses generated similar TRS independent transcripts they were more abundant in SARS-CoV-2. TRS independent gene regulation requires investigation to determine its relationship to viral pathogenicity.

scholarly journals Interactions of Human Myeloid Cells with Natural Killer Cell Subsets In Vitro and In Vivo

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Obinna Chijioke ◽  
Christian Münz
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Experimental Models ◽  
Human Pathogens ◽  
Innate And Adaptive Immunity ◽  
Antigen Presenting

In both human and mouse it has been recently realized that natural killer (NK) cells do not emerge from the bone marrow with full functional competence but rather acquire functions in interaction with antigen-presenting cells (APCs), primarily dendritic cells (DCs). Here we review the mechanisms and the consequences of this NK-cell preactivation, as well as discuss new experimental models that now allow investigating these interactions for human NK cells and their response to human pathogens in vivo. These investigations will allow harnessing NK cells during vaccination for improved innate and adaptive immunity.

scholarly journals Identification of a Mouse Cytomegalovirus Gene Selectively Targeting CD86 Expression on Antigen-Presenting Cells

2004 ◽  
Vol 78 (23) ◽  
pp. 13062-13071 ◽  
Author(s):  
Andrea Loewendorf ◽  
Corinna Krüger ◽  
Eva Maria Borst ◽  
Markus Wagner ◽  
Ursula Just ◽  
...  
Keyword(s):  
Costimulatory Molecule ◽  
Antigen Presenting Cells ◽  
Surface Expression ◽  
Genomic Region ◽  
Murine Cytomegalovirus ◽  
Viral Gene ◽  
Mcmv Infection ◽  
Surface Molecules ◽  
Antigen Presenting

ABSTRACT We and others have shown that infection of dendritic cells with murine cytomegalovirus (MCMV) leads to severe functional impairment of these antigen-presenting cells (D. M. Andrews, C. E. Andoniou, F. Granucci, P. Ricciardi-Castagnoli, and M. A. Degli-Esposti, Nat. Immunol. 2:1077-1084, 2001; S. Mathys, T. Schroeder, J. Ellwart, U. H. Koszinowski, M. Messerle, and U. Just, J. Infect. Dis. 187:988-999, 2003). Phenotypically, reduced surface expression of costimulatory molecules and major histocompatibility complex molecules was detected. In order to identify the molecular basis for the observed effects, we generated MCMV mutants with large deletions of nonessential genes. The study was facilitated by the finding that a monocyte-macrophage cell line displayed similar phenotypic alterations after MCMV infection. By analyzing the expression of cell surface molecules on infected cells, we identified a mutant virus which is no longer able to downmodulate the expression of the costimulatory molecule CD86. Additional mutants with smaller deletions allowed us to pin down the responsible gene to a certain genomic region. RNA analysis led to the identification of the spliced gene m147.5, encoding a protein with 145 amino acids. Experiments with an m147.5 mutant revealed that the protein affects CD86 expression only, suggesting that additional MCMV genes are responsible for downmodulation of the other surface molecules. Identification of viral gene products interfering with functionally important proteins of antigen-presenting cells will provide the basis to dissect the complex interaction of CMV with these important cells and to evaluate the biological importance of these viral genes in vivo.

scholarly journals Simultaneously reconstructing viral cross-species transmission history and identifying the underlying constraints

2013 ◽  
Vol 368 (1614) ◽  
pp. 20120196 ◽  
Author(s):  
Nuno Rodrigues Faria ◽  
Marc A. Suchard ◽  
Andrew Rambaut ◽  
Daniel G. Streicker ◽  
Philippe Lemey
Keyword(s):  
Rabies Virus ◽  
Host Species ◽  
Bayesian Model Averaging ◽  
Model Averaging ◽  
Viral Gene ◽  
Human Pathogens ◽  
New Host ◽  
Discrete State ◽  
Transition Processes ◽  
Host Shifts

The factors that determine the origin and fate of cross-species transmission events remain unclear for the majority of human pathogens, despite being central for the development of predictive models and assessing the efficacy of prevention strategies. Here, we describe a flexible Bayesian statistical framework to reconstruct virus transmission between different host species based on viral gene sequences, while simultaneously testing and estimating the contribution of several potential predictors of cross-species transmission. Specifically, we use a generalized linear model extension of phylogenetic diffusion to perform Bayesian model averaging over candidate predictors. By further extending this model with branch partitioning, we allow for distinct host transition processes on external and internal branches, thus discriminating between recent cross-species transmissions, many of which are likely to result in dead-end infections, and host shifts that reflect successful onwards transmission in the new host species. Our approach corroborates genetic distance between hosts as a key determinant of both host shifts and cross-species transmissions of rabies virus in North American bats. Furthermore, our results indicate that geographical range overlap is a modest predictor for cross-species transmission, but not for host shifts. Although our evolutionary framework focused on the multi-host reservoir dynamics of bat rabies virus, it is applicable to other pathogens and to other discrete state transition processes.

scholarly journals Viral Innate Immune Evasion and the Pathogenesis of Emerging RNA Virus Infections

2019 ◽  
Author(s):  
Tessa Nelemans ◽  
Marjolein Kikkert
Keyword(s):  
Immune Response ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
Public Health Problem ◽  
Innate Immune ◽  
Interferon Response ◽  
Replication Capacity ◽  
Human Pathogens ◽  
Emerging Viruses ◽  
Innate Immune Evasion

Positive-sense single-stranded RNA (+ssRNA) viruses comprise many (re-)emerging human pathogens that pose a public health problem. Our innate immune system and in particular the interferon response form the important first line of defense against these viruses. Given their genetic flexibility, these viruses have therefore developed multiple strategies to evade the innate immune response in order to optimize their replication capacity. Already many molecular mechanisms of innate immune evasion by +ssRNA viruses have been identified. However, research addressing the effect of host innate immune evasion on the pathology caused by the viral infection is less prevalent in literature, though very relevant and interesting. Since interferons have been implicated in inflammatory diseases and immunopathology in addition to their protective role in infection, the influence of antagonizing the immune response may have an ambiguous effect on the clinical outcome of the viral disease. Therefore, this review discusses what is currently known about the role of interferons and host immune evasion in the pathogenesis of emerging viruses belonging to the coronaviruses, alphaviruses and flaviviruses.

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