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MBio Oct 2023Dengue virus (DENV) is a major human pathogen that can cause hemorrhagic fever and shock syndrome. One important factor of DENV pathogenicity is non-structural protein 1...
Dengue virus (DENV) is a major human pathogen that can cause hemorrhagic fever and shock syndrome. One important factor of DENV pathogenicity is non-structural protein 1 (NS1), a glycoprotein that is secreted from infected cells. Here we study the mode of action of the widely used drug ivermectin, used to treat parasitic infections and recently shown to lower NS1 blood levels in DENV-infected patients. We found that ivermectin blocks the nuclear transport of transcription factors required for the expression of chaperones that support the folding and secretion of glycoproteins, including NS1. Impairing nuclear transport of these transcription factors by ivermectin or depleting them from infected cells dampens NS1 folding and thus its secretion. These results reveal a novel mode of action of ivermectin that might apply to other flaviviruses as well.
Topics: Humans; Dengue Virus; Dengue; Endoplasmic Reticulum Chaperone BiP; Ivermectin; Karyopherins; Molecular Chaperones; Transcription Factors; Viral Nonstructural Proteins
PubMed: 37702492
DOI: 10.1128/mbio.01441-23 -
Frontiers in Cellular and Infection... 2020Dengue is an acute febrile disease triggered by dengue virus. Dengue is the widespread and rapidly transmitted mosquito-borne viral disease of humans. Diverse symptoms... (Review)
Review
Dengue is an acute febrile disease triggered by dengue virus. Dengue is the widespread and rapidly transmitted mosquito-borne viral disease of humans. Diverse symptoms and diseases due to Dengue virus (DENV) infection ranges from dengue fever, dengue hemorrhagic fever (life-threatening) and dengue shock syndrome characterized by shock, endothelial dysfunction and vascular leakage. Several studies have linked the severity of dengue with the induction of inflammasome. DENV activates the NLRP3-specific inflammasome in DENV infected human patients, mice; specifically, mouse bone marrow derived macrophages (BMDMs), dendritic cells, endothelial cells, human peripheral blood mononuclear cells (PBMCs), keratinocytes, monocyte-differentiated macrophages (THP-1), and platelets. Dengue virus mediated inflammasome initiates the maturation of IL-1β and IL-18, which are critical for dengue pathology and inflammatory response. Several studies have reported the molecular mechanism through which (host and viral factors) dengue induces inflammasome, unravels the possible mechanisms of DENV pathogenesis and sets up the stage for the advancement of DENV therapeutics. In this perspective article, we discuss the potential implications and our understanding of inflammasome mechanisms of dengue virus and highlight research areas that have potential to inhibit the pathogenesis of viral diseases, specifically for dengue.
Topics: Animals; Dengue; Dengue Virus; Endothelial Cells; Humans; Inflammasomes; Leukocytes, Mononuclear; Mice; Severity of Illness Index
PubMed: 33014899
DOI: 10.3389/fcimb.2020.00489 -
Viruses Nov 2023Subgenomic flaviviral RNAs (sfRNAs) are produced during flavivirus infections in both arthropod and vertebrate cells. They are undegraded products originating from the... (Review)
Review
Subgenomic flaviviral RNAs (sfRNAs) are produced during flavivirus infections in both arthropod and vertebrate cells. They are undegraded products originating from the viral 3' untranslated region (3' UTR), a result of the action of the host 5'-3' exoribonuclease, Xrn1, when it encounters specific RNA structures known as Xrn1-resistant RNAs (xrRNAs) within the viral 3' UTR. Dengue viruses generate three to four distinct species of sfRNAs through the presence of two xrRNAs and two dumbbell structures (DBs). The tertiary structures of xrRNAs have been characterized to form a ringlike structure around the 5' end of the viral RNA, effectively inhibiting the activity of Xrn1. The most important role of DENV sfRNAs is to inhibit host antiviral responses by interacting with viral and host proteins, thereby influencing viral pathogenicity, replicative fitness, epidemiological fitness, and transmission. In this review, we aimed to summarize the biogenesis, structures, and functions of DENV sfRNAs, exploring their implications for viral interference.
Topics: Humans; Flavivirus; Dengue Virus; Subgenomic RNA; 3' Untranslated Regions; Nucleic Acid Conformation; RNA, Viral; Dengue
PubMed: 38140548
DOI: 10.3390/v15122306 -
Journal of Biomedical Science Apr 2024Dengue viruses (DENV) are positive-stranded RNA viruses belonging to the Flaviviridae family. DENV is the causative agent of dengue, the most rapidly spreading viral... (Review)
Review
Dengue viruses (DENV) are positive-stranded RNA viruses belonging to the Flaviviridae family. DENV is the causative agent of dengue, the most rapidly spreading viral disease transmitted by mosquitoes. Each year, millions of people contract the virus through bites from infected female mosquitoes of the Aedes species. In the majority of individuals, the infection is asymptomatic, and the immune system successfully manages to control virus replication within a few days. Symptomatic individuals may present with a mild fever (Dengue fever or DF) that may or may not progress to a more critical disease termed Dengue hemorrhagic fever (DHF) or the fatal Dengue shock syndrome (DSS). In the absence of a universally accepted prophylactic vaccine or therapeutic drug, treatment is mostly restricted to supportive measures. Similar to many other viruses that induce acute illness, DENV has developed several ways to modulate host metabolism to create an environment conducive to genome replication and the dissemination of viral progeny. To search for new therapeutic options, understanding the underlying host-virus regulatory system involved in various biological processes of the viral life cycle is essential. This review aims to summarize the complex interaction between DENV and the host cellular machinery, comprising regulatory mechanisms at various molecular levels such as epigenetic modulation of the host genome, transcription of host genes, translation of viral and host mRNAs, post-transcriptional regulation of the host transcriptome, post-translational regulation of viral proteins, and pathways involved in protein degradation.
Topics: Dengue Virus; Humans; Dengue; Animals; Host-Pathogen Interactions; Virus Replication
PubMed: 38649998
DOI: 10.1186/s12929-024-01030-9 -
Viruses Apr 2017The World Health Organization estimates that the yearly number of dengue cases averages 390 million. This mosquito-borne virus disease is endemic in over 100 countries... (Review)
Review
The World Health Organization estimates that the yearly number of dengue cases averages 390 million. This mosquito-borne virus disease is endemic in over 100 countries and will probably continue spreading, given the observed trend in global warming. So far, there is no antiviral drug available against dengue, but a vaccine has been recently marketed. Dengue virus also serves as a prototype for the study of other pathogenic flaviviruses that are emerging, like West Nile virus and Zika virus. Upon viral entry into the host cell and fusion of the viral lipid membrane with the endosomal membrane, the viral RNA is released and expressed as a polyprotein, that is then matured into three structural and seven non-structural (NS) proteins. The envelope, membrane and capsid proteins form the viral particle while NS1-NS2A-NS2B-NS3-NS4A-NS4B and NS5 assemble inside a cellular replication complex, which is embedded in endoplasmic reticulum (ER)-derived vesicles. In addition to their roles in RNA replication within the infected cell, NS proteins help the virus escape the host innate immunity and reshape the host-cell inner structure. This review focuses on recent progress in characterizing the structure and functions of NS5, a protein responsible for the replication and capping of viral RNA that represents a promising drug target.
Topics: Dengue Virus; Protein Binding; Protein Conformation; RNA, Viral; Viral Nonstructural Proteins; Virus Replication
PubMed: 28441781
DOI: 10.3390/v9040091 -
Annals of Clinical Microbiology and... Jul 2018The introduction of the dengue virus (DENV) in Nepal is recent, first reports date back to 2004 from a Japanese traveller and limited information is available about DENV... (Review)
Review
BACKGROUND
The introduction of the dengue virus (DENV) in Nepal is recent, first reports date back to 2004 from a Japanese traveller and limited information is available about DENV infection in the Nepali population. Within a decade after the first DENV detection, it is now endemic in multiple districts of Nepal with approximately 11.2 million people residing in the Terai belt being at risk of DENV infection. Sporadic cases of DENV infection have been reported every year for the past decade during the monsoon season, mainly in the Terai region.
METHODS
Medline/Embase/Cochrane databases were reviewed for reports on the burden of dengue infection, diagnostic methods, and national surveillance.
RESULTS
Four outbreaks were reported since 2004 including the diagnosis of all serotypes in 2006 and predominance of a single serotype in 2010 (DENV-1), 2013 (DENV-2), and 2016 (DENV-1). The clinical diagnoses showed a predominance of dengue fever while 4/917 (0.4%), 8/642 (1.2%) and 8/1615 (0.4%) dengue haemorrhagic fever/dengue shock syndrome cases were identified during the outbreaks in 2010, 2013 and 2016, respectively. The number of cases reported in males was significantly higher (67.4%) than in females. Disease occurrence was primarily found in the Terai region until 2010 and was increasingly detected in the Hilly region in 2016.
CONCLUSION
In Nepal currently weak diagnostic facilities, very limited research on mosquitoes vectors, and poor surveillance of dengue leading to inappropriate detection and control of DENV. We surmise that improved basic research and epidemiological training courses for local scientists and laboratory personal at national and international level will help better understand the evolution and distribution of DENV transmission and its eventual control.
Topics: Adolescent; Adult; Dengue; Dengue Virus; Disease Outbreaks; Female; Humans; Male; Nepal; Population Surveillance; Serogroup; Young Adult
PubMed: 30008269
DOI: 10.1186/s12941-018-0284-7 -
Viruses Jul 2021The four serotypes of the mature dengue virus can display different morphologies, including the compact spherical, the bumpy spherical and the non-spherical clubshape... (Review)
Review
The four serotypes of the mature dengue virus can display different morphologies, including the compact spherical, the bumpy spherical and the non-spherical clubshape morphologies. In addition, the maturation process of dengue virus is inefficient and therefore some partially immature dengue virus particles have been observed and they are infectious. All these viral particles have different antigenicity profiles and thus may affect the type of the elicited antibodies during an immune response. Understanding the molecular determinants and environmental conditions (e.g., temperature) in inducing morphological changes in the virus and how potent antibodies interact with these particles is important for designing effective therapeutics or vaccines. Several techniques, including cryoEM, site-directed mutagenesis, hydrogen-deuterium exchange mass spectrometry, time-resolve fluorescence resonance energy transfer, and molecular dynamic simulation, have been performed to investigate the structural changes. This review describes all known morphological variants of DENV discovered thus far, their surface protein dynamics and the key residues or interactions that play important roles in the structural changes.
Topics: Antibodies, Neutralizing; Antibodies, Viral; Antibody-Dependent Enhancement; Antigenic Variation; Antigens, Viral; Dengue; Dengue Vaccines; Dengue Virus; Humans; Serogroup; Viral Envelope Proteins
PubMed: 34452312
DOI: 10.3390/v13081446 -
International Journal of Infectious... Jul 2019India is home to nearly a third of the global population at risk of dengue, a viral disease caused by four antigenically and genetically distinct dengue viruses.... (Review)
Review
India is home to nearly a third of the global population at risk of dengue, a viral disease caused by four antigenically and genetically distinct dengue viruses. Clinical illness following dengue virus infection can either be mild and self-limiting dengue fever or severe dengue hemorrhagic fever/dengue shock syndrome, with potentially fatal consequences. A live attenuated vaccine known as Dengvaxia, developed by Sanofi, was licensed in 2015. Following this, long-term follow-up of the Sanofi phase III efficacy trial participants has revealed potential safety concerns. This vaccine, which appears to predispose dengue-naïve recipients to an increased risk of hospitalization in the future, is recommended by the World Health Organization only for adults with a history of prior dengue virus infection. A safe and efficacious dengue vaccine continues to be sought globally. India has joined these efforts in recent years, and is poised to initiate the clinical development of two candidates in the near future, one licensed from abroad and the other developed indigenously. This article provides a glimpse of India's efforts to develop dengue vaccines in the context of the global dengue vaccine development and evaluation landscape and highlights key issues and questions confronting the dengue vaccine community.
Topics: Animals; Dengue; Dengue Vaccines; Dengue Virus; Humans; Vaccines, Attenuated
PubMed: 30684747
DOI: 10.1016/j.ijid.2019.01.029 -
Viruses Mar 2017The Flaviviridae family comprises a number of human pathogens, which, although sharing structural and functional features, cause diseases with very different outcomes.... (Review)
Review
The Flaviviridae family comprises a number of human pathogens, which, although sharing structural and functional features, cause diseases with very different outcomes. This can be explained by the plurality of functions exerted by the few proteins coded by viral genomes, with some of these functions shared among members of a same family, but others being unique for each virus species. These non-canonical functions probably have evolved independently and may serve as the base to the development of specific therapies for each of those diseases. Here it is discussed what is currently known about the non-canonical roles of dengue virus (DENV) non-structural proteins (NSPs), which may account for some of the effects specifically observed in DENV infection, but not in other members of the Flaviviridae family. This review explores how DENV NSPs contributes to the physiopathology of dengue, evasion from host immunity, metabolic changes, and redistribution of cellular components during infection.
Topics: Dengue Virus; Host-Pathogen Interactions; Humans; Viral Nonstructural Proteins
PubMed: 28335410
DOI: 10.3390/v9030042 -
Frontiers in Cellular and Infection... 2022Dengue virus (DENV) is the most common arbovirus, causing a significant burden on both the economy and global healthcare systems. The virus is transmitted by species of... (Review)
Review
Dengue virus (DENV) is the most common arbovirus, causing a significant burden on both the economy and global healthcare systems. The virus is transmitted by species of mosquitoes as a swarm of closely related virus genomes, collectively referred to as a quasispecies. The level of genomic diversity within this quasispecies varies as DENV moves through various ecological niches within its transmission cycle. Here, the factors that influence the level of DENV quasispecies diversity during the course of infection in the mosquito vectors are reviewed.
Topics: Aedes; Animals; Arboviruses; Dengue Virus; Genome, Viral; Mosquito Vectors
PubMed: 35811685
DOI: 10.3389/fcimb.2022.888804