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Kylene Kehnhall - One of the best experts on this subject based on the ideXlab platform.
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venezuelan equine Encephalitis virus induces apoptosis through the unfolded protein response activation of egr1
Journal of Virology, 2016Co-Authors: Alan Baer, Lindsay Lundberg, Danielle Swales, Nicole Waybright, Chelsea Pinkham, Jonathan D Dinman, Jonathan L Jacobs, Kylene KehnhallAbstract:Venezuelan equine Encephalitis virus (VEEV) is a previously weaponized arthropod-borne virus responsible for causing acute and fatal Encephalitis in animal and human hosts. The increased circulation and spread in the Americas of VEEV and other encephalitic arboviruses, such as eastern equine Encephalitis virus and West Nile virus, underscore the need for research aimed at characterizing the pathogenesis of viral encephalomyelitis for the development of novel medical countermeasures. The host-pathogen dynamics of VEEV Trinidad donkey-infected human astrocytoma U87MG cells were determined by carrying out RNA sequencing (RNA-Seq) of poly(A) and mRNAs. To identify the critical alterations that take place in the host transcriptome following VEEV infection, samples were collected at 4, 8, and 16 h postinfection and RNA-Seq data were acquired using an Ion Torrent PGM platform. Differential expression of interferon response, stress response factors, and components of the unfolded protein response (UPR) was observed. The protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm of the UPR was activated, as the expression of both activating transcription factor 4 (ATF4) and CHOP (DDIT3), critical regulators of the pathway, was altered after infection. Expression of the transcription factor early growth response 1 (EGR1) was induced in a PERK-dependent manner. EGR1−/− mouse embryonic fibroblasts (MEFs) demonstrated lower susceptibility to VEEV-induced cell death than isogenic wild-type MEFs, indicating that EGR1 modulates proapoptotic pathways following VEEV infection. The influence of EGR1 is of great importance, as neuronal damage can lead to long-term sequelae in individuals who have survived VEEV infection. IMPORTANCE Alphaviruses represent a group of clinically relevant viruses transmitted by mosquitoes to humans. In severe cases, viral spread targets neuronal tissue, resulting in significant and life-threatening inflammation dependent on a combination of virus-host interactions. Currently there are no therapeutics for infections cause by encephalitic alphaviruses due to an incomplete understanding of their molecular pathogenesis. Venezuelan equine Encephalitis virus (VEEV) is an alphavirus that is prevalent in the Americas and that is capable of infecting horses and humans. Here we utilized next-generation RNA sequencing to identify differential alterations in VEEV-infected astrocytes. Our results indicated that the abundance of transcripts associated with the interferon and the unfolded protein response pathways was altered following infection and demonstrated that early growth response 1 (EGR1) contributed to VEEV-induced cell death.
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modulation of gsk 3β activity in venezuelan equine Encephalitis virus infection
PLOS ONE, 2012Co-Authors: Kylene Kehnhall, Lindsay Lundberg, Chelsea Pinkham, Aarthi Narayanan, Gavin Sampey, Irene Guendel, Rachel Van Duyne, Svetlana Senina, Kimberly L W SchultzAbstract:Alphaviruses, including Venezuelan Equine Encephalitis Virus (VEEV), cause disease in both equine and humans that exhibit overt Encephalitis in a significant percentage of cases. Features of the host immune response and tissue-specific responses may contribute to fatal outcomes as well as the development of Encephalitis. It has previously been shown that VEEV infection of mice induces transcription of pro-inflammatory cytokines genes (e.g., IFN-γ, IL-6, IL-12, iNOS and TNF-α) within 6 h. GSK-3β is a host protein that is known to modulate pro-inflammatory gene expression and has been a therapeutic target in neurodegenerative disorders such as Alzheimer's. Hence inhibition of GSK-3β in the context of encephalitic viral infections has been useful in a neuroprotective capacity. Small molecule GSK-3β inhibitors and GSK-3β siRNA experiments indicated that GSK-3β was important for VEEV replication. Thirty-eight second generation BIO derivatives were tested and BIOder was found to be the most potent inhibitor, with an IC50 of ~0.5 µM and a CC50 of >100 µM. BIOder was a more potent inhibitor of GSK-3β than BIO, as demonstrated through in vitro kinase assays from uninfected and infected cells. Size exclusion chromatography experiments demonstrated that GSK-3β is found in three distinct complexes in VEEV infected cells, whereas GSK-3β is only present in one complex in uninfected cells. Cells treated with BIOder demonstrated an increase in the anti-apoptotic gene, survivin, and a decrease in the pro-apoptotic gene, BID, suggesting that modulation of pro- and anti-apoptotic genes contributes to the protective effect of BIOder treatment. Finally, BIOder partially protected mice from VEEV induced mortality. Our studies demonstrate the utility of GSK-3β inhibitors for modulating VEEV infection.
Anthony R Fooks - One of the best experts on this subject based on the ideXlab platform.
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innate and adaptive immune responses to tick borne flavivirus infection in sheep
Veterinary Microbiology, 2016Co-Authors: Karen L Mansfield, Ashley C. Banyard, Matthew Baylis, Alejandro Núñez, Nicholas Johnson, Tom Solomon, Anthony R FooksAbstract:The flaviviruses tick-borne Encephalitis virus (TBEV) and louping ill virus (LIV) are closely-related genetically and antigenically, have broadly similar host ranges that include rodents and other mammals (including sheep), and are both transmitted by the same tick species, Ixodes ricinus. Although human infection with TBEV results in a febrile illness followed in some cases by Encephalitis, humans appear to be much less susceptible to infection with LIV. However, these viruses demonstrate different susceptibilities in sheep; LIV infection causes encephalitic disease, whereas TBEV infection generally does not. To investigate the role of the immune response in this mixed outcome, groups of sheep were inoculated with either virus, or with a primary inoculation with one virus and secondary inoculation with the other. Markers of both adaptive and innate immune responses were measured. In each group studied, infection resulted in seroconversion, demonstrated by the detection of virus specific neutralising antibodies. This appeared to control infection with TBEV but not LIV, which progressed to a febrile infection, with transient viraemia and elevated levels of serum interferon. This was followed by neuroinvasion, leading to up-regulation of innate immune transcripts in discrete areas of the brain, including interferon inducible genes and chemokines. Prior inoculation with TBEV did not prevent infection with LIV, but did appear to reduce disease severity and viraemia. We postulate that LIV has adapted to replicate efficiently in sheep cells, and disseminate rapidly following infection. By contrast, TBEV fails to disseminate in sheep and is controlled by the immune response.
Alan D T Barrett - One of the best experts on this subject based on the ideXlab platform.
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phylogeography of west nile virus from the cradle of evolution in africa to eurasia australia and the americas
Journal of Virology, 2011Co-Authors: Todd C Davis, Robert B Tesh, Alan D T BarrettAbstract:West Nile virus (WNV) is the most widely distributed of the encephalitic flaviviruses and is a major cause of Encephalitis, with isolates obtained from all continents, apart from Antarctica. Subsequent to its divergence from the other members of the Japanese Encephalitis virus complex, presumably in Africa, WNV has diverged into individual lineages that mostly correspond with geographic distribution. Here we elucidate the phylogeography and evolutionary history of isolates from lineage 1 of WNV. Interestingly, there are many examples of the same amino acid having evolved independently on multiple occasions. In Africa, WNV exists in an endemic cycle, whereas it is epidemic in Europe, being reintroduced regularly from Africa either directly (in western Europe) or via the Middle East (in eastern Europe). Significantly, introduction into other geographic areas has occurred on one occasion only in each region, leading to subsequent establishment and expansion of the virus in these areas. Only one endemic genotype each is present in India and Australia, suggesting that WNV was successfully introduced into these locations once only. Each introduction occurred many centuries ago, probably due to trade and exploration during the 19th century. Likewise, in the Americas, WNV was successfully introduced in 1999 and subsequently became endemic across most temperate regions of North America (NA). In contrast to previous suggestions, an isolate from the epidemic in Israel in 1998 was not the direct progenitor of the NA epidemic; rather, both epidemics originated from the same (unknown) location.
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analysis of the complete genome of the tick borne flavivirus omsk hemorrhagic fever virus
Virology, 2003Co-Authors: Li Li, Daryl Dick, Robert E Shope, Heinz Feldmann, Alan D T Barrett, Michael R HolbrookAbstract:Abstract Omsk hemorrhagic fever virus (OHF) is a tick-borne flavivirus endemic to Western Siberia. This virus is the only known tick-borne flavivirus to cause hemorrhagic disease in humans in the absence of Encephalitis. OHF virus circulates within a small, defined niche in which other tick-borne complex flaviviruses are also present. The objectives of this study were to genetically classify OHF virus based on its complete genome and to identify genetic determinants that might be involved in tissue tropism and viral replication leading to the disease state caused by this virus. The OHF virus genome was sequenced and phylogenetic analysis demonstrated that OHF virus falls within the tick-borne Encephalitis serocomplex of flaviviruses, yet is distinct from other members of the complex, including those closely associated geographically. OHF is also distinct from Alkhurma (ALK) and Kyasanur forest disease (KFD) viruses, both of which cause disease that includes hemorrhagic and encephalitic manifestations. Several amino acid residues were found to be distinct among OHF, KFD, and ALK viruses; these residues include E-76, which is closely associated with the viral envelope protein fusion peptide. In addition, variation between the viral 5′-untranslated region of OHF and other tick-borne flaviviruses suggests potential variability in viral replication. These data demonstrate that OHF is a unique virus among the tick-borne flaviviruses and also provide insight to viral biodiversity and tropism.
Robert B Tesh - One of the best experts on this subject based on the ideXlab platform.
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phylogeography of west nile virus from the cradle of evolution in africa to eurasia australia and the americas
Journal of Virology, 2011Co-Authors: Todd C Davis, Robert B Tesh, Alan D T BarrettAbstract:West Nile virus (WNV) is the most widely distributed of the encephalitic flaviviruses and is a major cause of Encephalitis, with isolates obtained from all continents, apart from Antarctica. Subsequent to its divergence from the other members of the Japanese Encephalitis virus complex, presumably in Africa, WNV has diverged into individual lineages that mostly correspond with geographic distribution. Here we elucidate the phylogeography and evolutionary history of isolates from lineage 1 of WNV. Interestingly, there are many examples of the same amino acid having evolved independently on multiple occasions. In Africa, WNV exists in an endemic cycle, whereas it is epidemic in Europe, being reintroduced regularly from Africa either directly (in western Europe) or via the Middle East (in eastern Europe). Significantly, introduction into other geographic areas has occurred on one occasion only in each region, leading to subsequent establishment and expansion of the virus in these areas. Only one endemic genotype each is present in India and Australia, suggesting that WNV was successfully introduced into these locations once only. Each introduction occurred many centuries ago, probably due to trade and exploration during the 19th century. Likewise, in the Americas, WNV was successfully introduced in 1999 and subsequently became endemic across most temperate regions of North America (NA). In contrast to previous suggestions, an isolate from the epidemic in Israel in 1998 was not the direct progenitor of the NA epidemic; rather, both epidemics originated from the same (unknown) location.
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west nile virus infection in the golden hamster mesocricetus auratus a model for west nile Encephalitis
Emerging Infectious Diseases, 2001Co-Authors: Shuyuan Xiao, Hilda Guzman, Hui Zhang, Amelia Travassos P A Da Rosa, Robert B TeshAbstract:This report describes a new hamster model for West Nile (WN) virus Encephalitis. Following intraperitoneal inoculation of a New York isolate of WN virus, hamsters had moderate viremia of 5 to 6 days in duration, followed by the development of humoral antibodies. Encephalitic symptoms began 6 days after infection; about half the animals died between the seventh and 14th days. The appearance of viral antigen in the brain and neuronal degeneration also began on the sixth day. WN virus was cultured from the brains of convalescent hamsters up to 53 days after initial infection, suggesting that persistent virus infection occurs. Hamsters offer an inexpensive model for studying the pathogenesis and treatment of WN virus Encephalitis.
Josep Dalmau - One of the best experts on this subject based on the ideXlab platform.
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the frequency of autoimmune n methyl d aspartate receptor Encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the california Encephalitis project
Clinical Infectious Diseases, 2012Co-Authors: Mary S Gable, Drake H Tilley, Josep Dalmau, Heather Sheriff, Carol A GlaserAbstract:Background. In 2007, the California Encephalitis Project (CEP), which was established to study the epidemiology of Encephalitis, began identifying cases of anti-N-methyl-D-aspartate receptor (anti-NMDAR) Encephalitis. Increasing numbers of anti-NMDAR Encephalitis cases have been identified at the CEP, and this form rivals commonly known viral etiologies as a causal agent. We report here the relative frequency and differences among encephalitides caused by anti-NMDAR and viral etiologies within the CEP experience. Methods. Demographic, frequency, and clinical data from patients with anti-NMDAR Encephalitis are compared with those with viral encephalitic agents: enterovirus, herpes simplex virus type 1 (HSV-1), varicella-zoster virus (VZV), and West Nile virus (WNV). All examined cases presented to the CEP between September 2007 and February 2011 and are limited to individuals aged #30 years because of the predominance of anti-NMDAR Encephalitis in this group. The diagnostic costs incurred in a single case are also included. Results. Anti-NMDAR Encephalitis was identified .4 times as frequently as HSV-1, WNV, or VZV and was the leading entity identified in our cohort. We found that 65% of anti-NMDAR Encephalitis occurred in patients aged #18 years. This disorder demonstrated a predilection, which was not observed with viral etiologies, for females (P, .01). Seizures, language dysfunction, psychosis, and electroencephalographic abnormalities were significantly more frequent in patients with anti-NMDAR Encephalitis (P , .05), and autonomic instability occurred exclusively in this group. Discussion. Anti-NMDAR Encephalitis rivals viral etiologies as a cause of Encephalitis within the CEP cohort. This entity deserves a prominent place on the encephalitic differential diagnosis to avoid unnecessary diagnostic and treatment costs, and to permit a more timely treatment.
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retrospective analysis of nmda receptor antibodies in Encephalitis of unknown origin
Neurology, 2010Co-Authors: Harald Pruss, Josep Dalmau, Lutz Harms, Markus Holtje, Gudrun Ahnerthilger, Kathrin Borowski, Winfried Stoecker, Klauspeter WandingerAbstract:Background: Anti-NMDA-receptor (NMDAR) Encephalitis is a severe disorder that occurs in association with antibodies to the NR1 subunit of the NMDAR and results in a characteristic syndrome. Objective: To determine in a single institution setting whether patients previously diagnosed with Encephalitis of unknown origin had anti-NMDAR Encephalitis. Methods: Charts of 505 patients aged 18 to 35 years admitted to the intensive care unit (ICU) during a 5-year period were retrospectively reviewed for criteria of Encephalitis of unknown etiology. These included encephalitic signs with psychiatric symptoms (agitation, paranoid thoughts, irritability, or hallucinations); seizures; CSF inflammation; and exclusion of viral or bacterial infection. Archived serum and CSF samples of patients fulfilling these criteria were examined for NMDAR antibodies. Follow-up visits allowed the analysis of the natural disease course and estimation of prognosis. Results: Seven patients (all women) fulfilled the indicated criteria; 6 of them had NMDAR antibodies. Ovarian teratomas were detected in 2 patients, in one 3 years after the onset of Encephalitis. Outcome was favorable in all patients. One patient without teratoma improved spontaneously along with disappearance of NMDAR antibodies. Conclusions: Anti-NMDAR Encephalitis represented 1% of all young patients9 admissions to the ICU. Six of 7 cases with the indicated clinical criteria had anti-NMDAR Encephalitis. NMDAR antibodies should be tested in all patients with Encephalitis who fulfill these criteria.
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anti nmda receptor Encephalitis report of ten cases and comparison with viral Encephalitis
European Journal of Clinical Microbiology & Infectious Diseases, 2009Co-Authors: M S Gable, A Radner, Bonita E Lee, L Dyner, Sachin Gavali, Drake H Tilley, Andreas Dengel, A Collins, Josep DalmauAbstract:The California Encephalitis Project (CEP), established in 1998 to explore encephalitic etiologies, has identified patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, the likely etiology of their Encephalitis. This study compares the presentation of such patients to those with viral Encephalitis, so that infectious disease clinicians may identify individuals with this treatable disorder. Patients were physician-referred, and standardized forms were used to gather demographic, clinical, and laboratory data. Features of anti-NMDAR+ patients were compared with the viral encephalitides of enteroviral (EV), rabies, and herpes simplex-1 (HSV-1) origins. Sixteen cases with confirmed viral etiologies were all negative on NMDAR antibody testing. Ten anti-NMDAR+ patients were profiled with a median age of 18.5 years (range 11–31 years). None were Caucasian. They had a characteristic progression with prominent psychiatric symptoms, autonomic instability, significant neurologic abnormalities, and seizures. Two had a teratoma, and, of the remaining eight, four had serologic evidence of acute Mycoplasma infection. The clinical and imaging features of anti-NMDAR+ patients served to differentiate this autoimmune disorder from HSV-1, EV, and rabies. Unlike classic paraneoplastic Encephalitis, anti-NMDAR Encephalitis affects younger patients and is often treatable. The association of NMDAR antibodies in patients with possible Mycoplasma pneumoniae infection warrants further study.
