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Japanese Encephalitis Virus wild strain infection suppresses dendritic cells maturation and function, and causes the expansion of regulatory T cells
Shengbo Cao, Yaoming Li, Jing Ye, Xiaohong Yang, Long Chen, Xueqin Liu, Huanchun Chen
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-39
Abstract: We examined the alterations of phenotype and function of DCs including bone marrow-derived DCs (bmDCs) in vitro and spleen-derived DCs (spDCs) in vivo due to JEV P3 wild strain infection. Our results showed that JEV P3 infected DCs in vitro and in vivo. The viral infection inhibited the expression of cell maturation surface markers (CD40, CD80 and CD83) and MHCⅠ, and impaired the ability of P3-infected DCs for activating allogeneic na?ve T cells. In addition, P3 infection suppressed the expression of interferon (IFN)-α and tumor necrosis factor (TNF)-α but enhanced the production of chemokine (C-C motif) ligand 2 (CCL2) and interleukin (IL)-10 of DCs. The infected DCs expanded the population of CD4+ Foxp3+ regulatory T cell (Treg).JEV P3 infection of DCs impaired cell maturation and T cell activation, modulated cytokine productions and expanded regulatory T cells, suggesting a possible mechanism of JE development.JEV is a causative agent of JE which causes at least 50,000 clinical cases and about 10,000 deaths each year. It is a member of the mosquito-borne encephalitis complex of the Flaviviridae family and has recently been discovered in previously non-affected areas like Australia [1] and Pakistan [2]. The neurons in the central nervous system (CNS) are target cells of JEV. Studies show that a direct viral cytopathic response and both direct and indirect immunological responses can contribute to CNS degeneration through JEV-infected cell exclusion by macrophages and CTLs, secretion of cytokines and chemokines and activation of microglia [3-6]. However, few studies have investigated the mechanisms by which JEV evades the immune surveillance of the host and passes through the blood-brain barrier (BBB) to the CNS.Dendritic cells (DCs) are the most prominent antigen-presenting cells (APCs) which induce dual humoral and cellular responses. While DCs also play unique role in inducing immune tolerance, avoiding immune surveillance and causing persistent infection. There
NLRP3 Inflammasome: Key Mediator of Neuroinflammation in Murine Japanese Encephalitis  [PDF]
Deepak Kumar Kaushik, Malvika Gupta, Kanhaiya Lal Kumawat, Anirban Basu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032270
Abstract: Background Japanese Encephalitis virus (JEV) is a common cause of acute and epidemic viral encephalitis. JEV infection is associated with microglial activation resulting in the production of pro-inflammatory cytokines including Interleukin-1 β (IL-1β) and Interleukin-18 (IL-18). The Pattern Recognition Receptors (PRRs) and the underlying mechanism by which microglia identify the viral particle leading to the production of these cytokines is unknown. Methodology/Principal Findings For our studies, we have used murine model of JEV infection as well as BV-2 mouse microglia cell line. In this study, we have identified a signalling pathway which leads to the activation of caspase-1 as the key enzyme responsible for the maturation of both IL-1β and IL-18 in NACHT, LRR and PYD domains-containing protein-3 (NLRP3) dependent manner. Depletion of NLRP3 results in the reduction of caspase-1 activity and subsequent production of these cytokines. Conclusion/Significance Our results identify a mechanism mediated by Reactive Oxygen Species (ROS) production and potassium efflux as the two danger signals that link JEV infection to caspase-1 activation resulting in subsequent IL-1β and IL-18 maturation.
Effect of catanospermine, 1-deoxynojirimycin or 1-deoxymannojirimycin on biological and functional activities of Japanese encephalitis virus in porcine stable kidney cells  [cached]
Vaibhavi Jawahar Lad,Vikas R. Shende,Ashok Kumar Gupta
Microbiology Research , 2013, DOI: 10.4081/mr.2013.e3
Abstract: In the present study, effect of catanospermine (CST), 1-deoxynojirimycin (DNJ) or 1-deoxymannojirimycin (DMJ) was studied on porcine stable kidney (PS) cells infected with Japanese encephalitis virus (JEV). As both CST and DNJ are potent inhibitors of ER alpha-glucosidases 1 and II, while DMJ is an inhibitor of Golgi mannosidase which removes alpha (1, 2) Man residues from the N-glycan precursor. Treatment of infected cells with CST (200 uM/mL), DNJ (100 uM/mL) or DMJ (200 uM/mL) did not produce much effect on viral gpE epitope presentation within the cells as well as on the cell surface as detected in the immunofluorescence employing monoclonal (MAbs) and polyclonal (PAbs) antibodies. As well the treated (infected) cells showed only a marginal decrease in infectious virus yield along with a slight decrease in haemagglutination activity of the virus that was recorded in comparison to the untreated infected (control) cells and the cells infected with Dengue virus. Immuno-blotting of the separated proteins from infected lysed cells and probed with anti-gpE MAbs also revealed a band corresponding to JEV gpE (MW 53kDa) both with inhibitor treated and the untreated cells; the reactivity with the former however, was somewhat less intense and prominent in comparison to latter (control untreated) indicating some effect on JEV. The present results indicate that these inhibitors by in large, do not affect maturation and the release of infective JE virions in PS cells.
Isolation of Saint Louis Encephalitis Virus from a Horse with Neurological Disease in Brazil  [PDF]
Roberta Rosa,Erica Azevedo Costa,Rafael Elias Marques,Taismara Simas Oliveira,Ronaldo Furtini,Maria Rosa Quaresma Bomfim,Mauro Martins Teixeira,Tatiane Alves Paix?o,Renato Lima Santos
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0002537
Abstract: St. Louis encephalitis virus (SLEV) is a causative agent of encephalitis in humans in the Western hemisphere. SLEV is a positive-sense RNA virus that belongs to the Flavivirus genus, which includes West Nile encephalitis virus, Japanese encephalitis virus, Dengue virus and other medically important viruses. Recently, we isolated a SLEV strain from the brain of a horse with neurological signs in the countryside of Minas Gerais, Brazil. The SLEV isolation was confirmed by reverse-transcription RT-PCR and sequencing of the E protein gene. Virus identity was also confirmed by indirect immunofluorescence using commercial antibodies against SLEV. To characterize this newly isolated strain in vivo, serial passages in newborn mice were performed and led to hemorrhagic manifestations associated with recruitment of inflammatory cells into the central nervous system of newborns. In summary this is the first isolation of SLEV from a horse with neurological signs in Brazil.
Estimating the Burden of Japanese Encephalitis Virus and Other Encephalitides in Countries of the Mekong Region  [PDF]
Arnaud Tarantola ,Flavie Goutard,Paul Newton,Xavier de Lamballerie,Olivier Lortholary,Julien Cappelle,Philippe Buchy
PLOS Neglected Tropical Diseases , 2014, DOI: 10.1371/journal.pntd.0002533
Abstract: Diverse aetiologies of viral and bacterial encephalitis are widely recognized as significant yet neglected public health issues in the Mekong region. A robust analysis of the corresponding health burden is lacking. We retrieved 75 articles on encephalitis in the region published in English or in French from 1965 through 2011. Review of available data demonstrated that they are sparse and often derived from hospital-based studies with significant recruitment bias. Almost half (35 of 75) of articles were on Japanese encephalitis virus (JEV) alone or associated with dengue. In the Western Pacific region the WHO reported 30,000–50,000 annual JEV cases (15,000 deaths) between 1966 and 1996 and 4,633 cases (200 deaths) in 2008, a decline likely related to the introduction of JEV vaccination in China, Vietnam, or Thailand since the 1980s. Data on dengue, scrub typhus and rabies encephalitis, among other aetiologies, are also reviewed and discussed. Countries of the Mekong region are undergoing profound demographic, economic and ecological change. As the epidemiological aspects of Japanese encephalitis (JE) are transformed by vaccination in some countries, highly integrated expert collaborative research and objective data are needed to identify and prioritize the human health, animal health and economic burden due to JE and other pathogens associated with encephalitides.
Seroepidemiological survey on Japanese encephalitis virus in swine raising on the southern border of Thailand
Antarasena, C.,Prommuang, P.,Prommuang, P.,Promkuntod, N.
Songklanakarin Journal of Science and Technology , 2002,
Abstract: From February to March 1999, a seroepidemiological survey on Japanese encephalitis virus (JEV) was carried out. One thousand and thirteen serum samples of swine were collected from 37 farms in 4 provinces at the southern border of Thailand; Songkhla, Yala, Narathiwat and Satun. Japanese encephalitis virus antibody was measured using microtiter hemagglutination inhibition (HI) test. The results indicated that 95.12 - 99.42% of the breeder pigs had JE-HI antibodies at > 1:40 compared with 89.08% of the gilts. The percentages of seropositive animals were 49.75%, 50.65% and 100% in fattening pigs, weaning and suckling piglets, respectively. The study demonstrated a high exposure rate of JEV infection among swine population raised on the southern border of Thailand.
Development of a vaccine to prevent Japanese encephalitis: a brief review
Viroj Wiwanitkit
International Journal of General Medicine , 2009,
Abstract: Viroj WiwanitkitWiwanitkit House, Bangkhae, Bangkok, ThailandAbstract: Japanese encephalitis (ICD 10: A83.0) is an important specific viral encephalitis caused by the Japanese encephalitis virus, a virus of the Flavivirus group. Millions of people, especially those in endemic areas of developing countries in Asia, are at high risk from this infection. Therefore proper management to deal with this virus is essential. There is no specific treatment for Japanese encephalitis virus. Supportive and symptomatic treatments are usually used, which emphasize the importance of prevention in this specific neurological disorder. Vector control or vaccination can be used to prevent the disease. Because the existing Japanese encephalitis vaccine poses some undesirable problems, a new vaccine is needed. The process of developing a new vaccine is briefly discussed.Keywords: Japanese encephalitis, vaccine, concept, prevention, development
Transcriptomic profile of host response in Japanese encephalitis virus infection
Nimesh Gupta, PV Lakshmana Rao
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-92
Abstract: The comparison between viral replication efficiency and disease progression confirms the active role of host response in immunopathology and disease severity. The histopathological analysis confirms the severe damage in the brain in a time dependent manner. Interestingly, the transcription profile reveals significant and differential expression of various pattern recognition receptors, chemotactic genes and the activation of inflammasome. The increased leukocyte infiltration and aggravated CNS inflammation may be the cause of disease severity.This is the first report that provides a detailed picture of the host transcriptional response in a natural route of exposure and opens up new avenues for potential therapeutic and prophylactic strategies against Japanese encephalitis virus.The host response to infection is central to the effective control and ultimate clearance of invading pathogens or removal of infected cells. Infection of host with a viral pathogen marks the onset of changes in the host cell's microenvironment. Such changes in host gene expression could be a cellular antivirus response, a virus induced response that facilitate its own replication and spread or a non-specific response that neither promotes nor prevents virus infection. This alteration of expression of many cellular genes can be identified using cDNA microarray [1].Defining the transcriptional regulation of host genes on virus infection can be used as a tool to obtain an elaborate insight into mechanisms of host-virus interactions and to unravel the molecular basis of disease pathogenesis. Viruses from several families can infect neurons in the CNS (Central Nervous System) and the study of gene expression changes in the CNS during virus infection can lead to identification of new genes whose function is essential either for the promotion or prevention of virus infection [2,3].Japanese Encephalitis is one of the most dreaded mosquito borne encephalitis virus causing acute encephalitis in human
Japanese Encephalitis Virus Generated Neurovirulence, Antigenicity, and Host Immune Responses  [PDF]
Ravi Kant Upadhyay
ISRN Virology , 2013, DOI: 10.5402/2013/830396
Abstract: In response to a JE virus attack, infected body cells start secretion of different cytokines and activate innate immune response. Virus starts neuronal invasion by entering into nerve cells and inflecting the central nervous system. It avoids exposure of body’s natural immunity and generates neurotrophic effects. Virus causes acute susceptibility to CNS and establishes encephalitis syndrome that results in very high fatality in children. In survivors, JEV inhibits the growth and proliferation of NCPs and imposes permanent neuronal disorders like cognitive, motor, and behavioral impairments. However, body cells start TCR mediated interactions, to recognize viral antigens with class I MHC complex on specific target cells, and operate mass killing of virus infected cells by increased CTL activity. Thus, both cell mediated and antibody interactions plays a central role in protection against JEV. In the present review article virus generated neurovirulence, antigenicity, and host immune responses are described in detail. More emphasis is given on diagnosis, clinical care, and active immunization with well-designed potential antiflavivirus vaccines. Further, for achieving an elite success against JEV, global eradication strategies are to be needed for making vaccination program more responsible and effective in endemic areas. 1. Introduction 1.1. Japanese Encephalitis Virus Japanese encephalitis virus (JEV) is an enveloped positive single stranded RNA virus that belongs to genus Flavivirus in the family Flaviviridae. JE is one of the most important endemic diseases that exists in Eastern Asia and Southeastern Asia including India, Nepal, Japan, China, Korea, Thailand, Indonesia, Malaysia, Vietnam, Taiwan, and the Philippines. Recently disease has shown its presence in Continental Australia and New Zealand. JE is a major public health problem, which causes high morbidity and mortality in pediatric groups. It is caused by a dreadful mosquito-borne virus (arbovirus) which is transmitted to human by mosquito, that is, Culex tritaeniorhynchus and Culex vishnui throughout rural areas of Asia. The natural cycle of Japanese encephalitis (JE) virus in endemic areas involves presence of water birds and Culex mosquitoes, particularly Culex tritaeniorhynchus, with pigs being also involved as an amplifying host and providing a link to humans through their proximity to housing. These play important role in amplification, dispersal, and epidemiology of JEV [1]. Transmission of JEV is seasonal, which increases with the increase in number of culicine mosquitoes after more
Molecular Detection and Genotyping of Japanese Encephalitis Virus in Mosquitoes during a 2010 Outbreak in the Republic of Korea  [PDF]
Hyun-Ji Seo, Heung Chul Kim, Terry A. Klein, Andrew M. Ramey, Ji-Hye Lee, Soon-Goo Kyung, Jee-Yong Park, Yun Sang Cho, In-Soo Cho, Jung-Yong Yeh
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055165
Abstract: Japanese encephalitis virus (JEV), a mosquito-borne zoonotic pathogen, is one of the major causes of viral encephalitis. To reduce the impact of Japanese encephalitis among children in the Republic of Korea (ROK), the government established a mandatory vaccination program in 1967. Through the efforts of this program only 0–7 (mean 2.1) cases of Japanese encephalitis were reported annually in the ROK during the period of 1984–2009. However, in 2010 there was an outbreak of 26 confirmed cases of Japanese encephalitis, including 7 deaths. This represented a >12-fold increase in the number of confirmed cases of Japanese encephalitis in the ROK as compared to the mean number reported over the last 26 years and a 3.7-fold increase over the highest annual number of cases during this same period (7 cases). Surveillance of adult mosquitoes was conducted during the 2010 outbreak of Japanese encephalitis in the ROK. A total of 6,328 culicine mosquitoes belonging to 12 species from 5 genera were collected at 6 survey sites from June through October 2010 and assayed by reverse-transcription polymerase chain reaction (RT-PCR) for the presence of JEV. A total of 34/371 pooled samples tested positive for JEV (29/121 Culex tritaeniorhynchus, 4/64 Cx. pipiens, and 1/26 Cx. bitaeniorhynchus) as confirmed by sequencing of the pre-membrane and envelope protein coding genes. The maximum likelihood estimates of JEV positive individuals per 1,000 culicine vectors for Cx. tritaeniorhynchus, Cx. pipiens, and Cx. bitaeniorhynchus were 11.8, 5.6, and 2.8, respectively. Sequences of the JEV pre-membrane and envelope protein coding genes amplified from the culicine mosquitoes by RT-PCR were compared with those of JEV genotypes I-V. Phylogenetic analyses support the detection of a single genotype (I) among samples collected from the ROK in 2010.
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