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1
Wang, Hua, Carol D. Blair, Ken E. Olson, and Rollie J. Clem. "Effects of inducing or inhibiting apoptosis on Sindbis virus replication in mosquito cells." Journal of General Virology 89, no. 11 (November 1, 2008): 2651–61. http://dx.doi.org/10.1099/vir.0.2008/005314-0.
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Sindbis virus (SINV) is a mosquito-borne virus in the genus Alphavirus, family Togaviridae. Like most alphaviruses, SINVs exhibit lytic infection (apoptosis) in many mammalian cell types, but are generally thought to cause persistent infection with only moderate cytopathic effects in mosquito cells. However, there have been several reports of apoptotic-like cell death in mosquitoes infected with alphaviruses or flaviviruses. Given that apoptosis has been shown to be an antiviral response in other systems, we have constructed recombinant SINVs that express either pro-apoptotic or anti-apoptotic genes in order to test the effects of inducing or inhibiting apoptosis on SINV replication in mosquito cells. Recombinant SINVs expressing the pro-apoptotic genes reaper (rpr) from Drosophila or michelob_x (mx) from Aedes aegypti caused extensive apoptosis in cells from the mosquito cell line C6/36, thus changing the normal persistent infection observed with SINV to a lytic infection. Although the infected cells underwent apoptosis, high levels of virus replication were still observed during the initial infection. However, virus production subsequently decreased compared with persistently infected cells, which continued to produce high levels of virus over the next several days. Infection of C6/36 cells with SINV expressing the baculovirus caspase inhibitor P35 inhibited actinomycin D-induced caspase activity and protected infected cells from actinomycin D-induced apoptosis, but had no observable effect on virus replication. This study is the first to test directly whether inducing or inhibiting apoptosis affects arbovirus replication in mosquito cells.
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Koren, Ravit, Ravit Bassal, Tamy Shohat, Daniel Cohen, Orna Mor, Ella Mendelson, and Yaniv Lustig. "Presence of Antibodies against Sindbis Virus in the Israeli Population: A Nationwide Cross-Sectional Study." Viruses 11, no. 6 (June 11, 2019): 542. http://dx.doi.org/10.3390/v11060542.
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Sindbis virus (SINV) is a mosquito-borne alphavirus circulating globally. SINV outbreaks have been mainly reported in North-European countries. In Israel, SINV was detected in 6.3% of mosquito pools; however, SINV infection in humans has rarely been diagnosed. A serologic survey to detect SINV IgG antibodies was conducted to evaluate the seroprevalence of SINV in the Israeli population. In total, 3145 serum samples collected in 2011–2014, representing all age and population groups in Israel, were assessed using an indirect ELISA assay, and a neutralization assay was performed on all ELISA-positive samples. The prevalence rates of SINV IgG antibodies were calculated. Logistic regressions models were applied to assess the association between demographic characteristics and SINV seropositivity. Overall, 113 (3.6%) and 59 (1.9%) samples were positive for ELISA and neutralization SINV IgG, respectively. Multivariable analysis demonstrated that SINV seropositivity was significantly associated with older age and residence outside metropolitan areas. These results demonstrate that, despite no outbreaks or clinical presentation, SINV infects the human population in Israel. Seropositivity is countrywide, more frequent in people of older age, and less diffuse in Israel’s metropolitan areas. Seroprevalence studies from other countries will add to our understanding of the global burden of SINV and the risk for potential SINV outbreaks.
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Ayhan, Nazli, Aissam Hachid, Laurence Thirion, Kamel Eddine Benallal, Laura Pezzi, Fayez Ahmed Khardine, Chahrazed Benbetka, Sihem Benbetka, Zoubir Harrat, and Remi Charrel. "Detection and Isolation of Sindbis Virus from Field Collected Mosquitoes in Timimoun, Algeria." Viruses 14, no. 5 (April 25, 2022): 894. http://dx.doi.org/10.3390/v14050894.
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Sindbis virus (SINV) is a zoonotic alphavirus (family Togaviridae, genus Alphavirus) that causes human diseases in Africa, Europe, Asia, and Australia. Occasionally, SINV outbreaks were reported in South Africa and northern Europe. Birds are the main amplifying hosts of SINV, while mosquitoes play the role of the primary vector. Culex mosquitoes were collected in Algeria and subsequently tested for SINV. SINV RNA was detected in 10 pools out of 40, from a total of 922 mosquitoes tested. A strain of SINV was isolated from a pool displaying high viral load. Whole-genome sequencing and phylogenetic analysis showed that the SINV Algeria isolate was most closely related to a Kenyan strain. This was the first record of SINV in Algeria and more broadly in northwestern Africa, which can be a potential risk for human health in the circulating area. Further studies are needed to measure the impact on public health through seroprevalence studies in Algeria.
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Ayhan, Nazli, Aissam Hachid, Laurence Thirion, Kamel Eddine Benallal, Laura Pezzi, Fayez Ahmed Khardine, Chahrazed Benbetka, Sihem Benbetka, Zoubir Harrat, and Remi Charrel. "Detection and Isolation of Sindbis Virus from Field Collected Mosquitoes in Timimoun, Algeria." Viruses 14, no. 5 (April 25, 2022): 894. http://dx.doi.org/10.3390/v14050894.
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Sindbis virus (SINV) is a zoonotic alphavirus (family Togaviridae, genus Alphavirus) that causes human diseases in Africa, Europe, Asia, and Australia. Occasionally, SINV outbreaks were reported in South Africa and northern Europe. Birds are the main amplifying hosts of SINV, while mosquitoes play the role of the primary vector. Culex mosquitoes were collected in Algeria and subsequently tested for SINV. SINV RNA was detected in 10 pools out of 40, from a total of 922 mosquitoes tested. A strain of SINV was isolated from a pool displaying high viral load. Whole-genome sequencing and phylogenetic analysis showed that the SINV Algeria isolate was most closely related to a Kenyan strain. This was the first record of SINV in Algeria and more broadly in northwestern Africa, which can be a potential risk for human health in the circulating area. Further studies are needed to measure the impact on public health through seroprevalence studies in Algeria.
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Ayhan, Nazli, Aissam Hachid, Laurence Thirion, Kamel Eddine Benallal, Laura Pezzi, Fayez Ahmed Khardine, Chahrazed Benbetka, Sihem Benbetka, Zoubir Harrat, and Remi Charrel. "Detection and Isolation of Sindbis Virus from Field Collected Mosquitoes in Timimoun, Algeria." Viruses 14, no. 5 (April 25, 2022): 894. http://dx.doi.org/10.3390/v14050894.
Full textAbstract:
Sindbis virus (SINV) is a zoonotic alphavirus (family Togaviridae, genus Alphavirus) that causes human diseases in Africa, Europe, Asia, and Australia. Occasionally, SINV outbreaks were reported in South Africa and northern Europe. Birds are the main amplifying hosts of SINV, while mosquitoes play the role of the primary vector. Culex mosquitoes were collected in Algeria and subsequently tested for SINV. SINV RNA was detected in 10 pools out of 40, from a total of 922 mosquitoes tested. A strain of SINV was isolated from a pool displaying high viral load. Whole-genome sequencing and phylogenetic analysis showed that the SINV Algeria isolate was most closely related to a Kenyan strain. This was the first record of SINV in Algeria and more broadly in northwestern Africa, which can be a potential risk for human health in the circulating area. Further studies are needed to measure the impact on public health through seroprevalence studies in Algeria.
6
Ding, Lin, David M. Brown, and John I. Glass. "Rescue of Infectious Sindbis Virus by Yeast Spheroplast-Mammalian Cell Fusion." Viruses 13, no. 4 (April 1, 2021): 603. http://dx.doi.org/10.3390/v13040603.
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Sindbis virus (SINV), a positive-sense single stranded RNA virus that causes mild symptoms in humans, is transmitted by mosquito bites. SINV reverse genetics have many implications, not only in understanding alphavirus transmission, replication cycle, and virus-host interactions, but also in biotechnology and biomedical applications. The rescue of SINV infectious particles is usually achieved by transfecting susceptible cells (BHK-21) with SINV-infectious mRNA genomes generated from cDNA constructed via in vitro translation (IVT). That procedure is time consuming, costly, and relies heavily on reagent quality. Here, we constructed a novel infectious SINV cDNA construct that expresses its genomic RNA in yeast cells controlled by galactose induction. Using spheroplasts made from this yeast, we established a robust polyethylene glycol-mediated yeast: BHK-21 fusion protocol to rescue infectious SINV particles. Our approach is timesaving and utilizes common lab reagents for SINV rescue. It could be a useful tool for the rescue of large single strand RNA viruses, such as SARS-CoV-2.
7
Gu, Youling, Yuanzheng Yang, and Yuechueng Liu. "Imaging Early Steps of Sindbis Virus Infection by Total Internal Reflection Fluorescence Microscopy." Advances in Virology 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/535206.
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Sindbis virus (SINV) is an alphavirus that has a broad host range and has been widely used as a vector for recombinant gene transduction, DNA-based vaccine production, and oncolytic cancer therapy. The mechanism of SINV entry into host cells has yet to be fully understood. In this paper, we used single virus tracking under total internal reflection fluorescence microscopy (TIRFM) to investigate SINV attachment to cell surface. Biotinylated viral particles were labeled with quantum dots, which retained viral viability and infectivity. By time-lapse imaging, we showed that the SINV exhibited a heterogeneous dynamics on the surface of the host cells. Analysis of SINV motility demonstrated a two-step attachment reaction. Moreover, dual color TIRFM of GFP-Rab5 and SINV suggested that the virus was targeted to the early endosomes after endocytosis. These findings demonstrate the utility of quantum dot labeling in studying the early steps and behavior of SINV infection.
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Valles, Steven M., and Charles A. Strong. "Solenopsis invicta virus-1A (SINV-1A): Distinct species or genotype of SINV-1?" Journal of Invertebrate Pathology 88, no. 3 (March 2005): 232–37. http://dx.doi.org/10.1016/j.jip.2005.02.006.
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Valles, Steven M. "Positive-Strand RNA Viruses Infecting the Red Imported Fire Ant,Solenopsis invicta." Psyche: A Journal of Entomology 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/821591.
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The imported fire ants,Solenopsis invictaandS. richteriwere introduced into the USA between 1918 and 1945. Since that time, they have expanded their USA range to include some 138 million hectares. Their introduction has had significant economic consequences with costs associated with damage and control efforts estimated at 6 billion dollars annually in the USA. The general consensus of entomologists and myrmecologists is that permanent, sustainable control of these ants in the USA will likely depend on self-sustaining biological control agents. A metagenomics approach successfully resulted in discovery of three viruses infectingS. invicta.Solenopsis invicta virus 1(SINV-1), SINV-2, and SINV-3 are all positive, single-stranded RNA viruses and represent the first viral discoveries in any ant species. Molecular characterization, host relationships, and potential development and use of SINV-1, SINV-2, and SINV-3 as biopesticides are discussed.
10
Fourie, Isabel, Jumari Snyman, June Williams, Arshad Ismail, Petrus Jansen van Vuren, and Marietjie Venter. "Epidemiological and Genomic Characterisation of Middelburg and Sindbis Alphaviruses Identified in Horses with Febrile and Neurological Infections, South Africa (2014–2018)." Viruses 14, no. 9 (September 11, 2022): 2013. http://dx.doi.org/10.3390/v14092013.
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Although Old World alphaviruses, Middelburg- (MIDV) and Sindbis virus (SINV), have previously been detected in horses and wildlife with neurologic disease in South Africa, the pathogenesis and clinical presentation of MIDV and SINV infections in animals are not well documented. Clinical samples from horses across South Africa with acute or fatal neurologic and febrile infections submitted between 2014–2018 were investigated. In total, 69/1084 (6.36%) and 11/1084 (1.01%) horses tested positive for MIDV and SINV, respectively, by real-time reverse transcription (RT) PCR. Main signs/outcomes for MIDV (n = 69): 73.91% neurological, 75.36% fever, 28.99% icterus and anorexia, respectively, 8.70% fatalities; SINV (n = 11): 54.54% neurological, 72.73% fever, 36.36% anorexia and 18.18% fatalities. MIDV cases peaked in the late summer/autumn across most South African provinces while SINV cases did not show a clear seasonality and were detected in fewer South African provinces. MIDV could still be detected in blood samples via RT-PCR for up to 71,417 and 21 days after onset of signs in 4 horses respectively, suggesting prolonged replication relative to SINV which could only be detected in the initial sample. Phylogenetic analyses based on partial sequences of the nsP4 (MIDV n = 59 and SINV n = 7) and E1 (MIDV n = 45) genes, as well as full genome sequences (MIDV n = 6), clustered the MIDV and SINV strains from the present study with previously detected strains. MIDV infection appears to be more prevalent in horses than SINV infection based on RT-PCR results, however, prevalence estimates might be different when also considering serological surveillance data.
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Holmes, V. Renee, and J. Spencer Johnston. "Differential Gene Expression of Innate Immune Response Genes Consequent to Solenopsis invicta Virus-3 Infection." Genes 14, no. 1 (January 10, 2023): 188. http://dx.doi.org/10.3390/genes14010188.
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The red imported fire ant Solenopsis invicta Buren (fire ant hereafter) is a global pest that inflicts billions of dollars in damages to the United States economy and poses a major threat on a global scale. Concerns with the broad-spectrum application of insecticides have facilitated the hunt for natural enemy-mediated controls. One of these, the virus Solenopsis invicta virus-3 (SINV-3 hereafter) is exceptionally virulent in laboratory settings. However, despite high mortality rates in the laboratory and documented widespread SINV-3 prevalence in the southern United States, the fire ant remains a major pest. To explore this paradox, we document the immune response elicited by the fire ant when infected with SINV-3. We sequence the fire ant transcriptome prior to and following infection with SINV-3, and identify and discuss in detail genes in immune response pathways differentially expressed following infection with SINV-3. This information provides insights into genes and pathways involved in the SINV-3 infection response in the fire ant and offers avenues to pursue, to suppress key immune response genes and force the fire ant to succumb to SINV-3 infection in the field.
12
Sane, Jussi, Satu Kurkela, Niina Putkuri, Eili Huhtamo, Antti Vaheri, and Olli Vapalahti. "Complete coding sequence and molecular epidemiological analysis of Sindbis virus isolates from mosquitoes and humans, Finland." Journal of General Virology 93, no. 9 (September 1, 2012): 1984–90. http://dx.doi.org/10.1099/vir.0.042853-0.
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Sindbis virus (SINV) is an arthropod-borne alphavirus, which causes rash-arthritis, particularly in Finland. SINV is transmitted by mosquitoes in Finland but thus far no virus has been isolated from mosquitoes. In this study, we report the isolation of the first SINV strain from mosquitoes in Finland and its full-length protein-coding sequence. We furthermore describe the full-length coding sequence of six SINV strains previously isolated from humans in Finland and from a mosquito in Russia. The strain isolated from mosquitoes (Ilomantsi-2005M) was very closely related to all the other Northern European SINV strains. We found 9 aa positions, of which five in the nsP3 protein C terminus, to be distinctive signatures for the Northern European strains that may be associated with vector or host species adaptation. Phylogenetic analyses further indicate that SINV has a local circulation in endemic regions in Northern Europe and no novel strains are frequently being introduced.
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Sun, Kangyixin, Xiangwei Shi, Li Li, Xiupeng Nie, Lin Xu, Fan Jia, and Fuqiang Xu. "Oncolytic Viral Therapy for Glioma by Recombinant Sindbis Virus." Cancers 15, no. 19 (September 27, 2023): 4738. http://dx.doi.org/10.3390/cancers15194738.
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Background: The characteristics of glioblastoma, such as drug resistance during treatment, short patient survival, and high recurrence rates, have made patients with glioblastoma more likely to benefit from oncolytic therapy. Methods: In this study, we investigated the safety of the sindbis virus by injecting virus intravenously and intracranially in mice and evaluated the therapeutic effect of the virus carrying different combinations of IL-12, IL-7, and GM-CSF on glioma in a glioma-bearing mouse model. Results: SINV was autologously eliminated from the serum and organs as well as from neural networks after entering mice. Furthermore, SINV was restricted to the injection site in the tree shrew brain and did not spread throughout the whole brain. In addition, we found that SINV-induced apoptosis in conjunction with the stimulation of the immune system by tumor-killing cytokines substantially suppressed tumor development. It is worth mentioning that SINV carrying IL-7 and IL-12 had the most notable glioma-killing effect. Furthermore, in an intracranial glioma model, SINV containing IL-7 and IL-12 effectively prolonged the survival time of mice and inhibited glioma progression. Conclusions: These results suggest that SINV has a significant safety profile as an oncolytic virus and that combining SINV with cytokines is an efficient treatment option for malignant gliomas.
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Bergman, Alexander, Emma Dahl, Åke Lundkvist, and Jenny C. Hesson. "Sindbis Virus Infection in Non-Blood-Fed Hibernating Culex pipiens Mosquitoes in Sweden." Viruses 12, no. 12 (December 14, 2020): 1441. http://dx.doi.org/10.3390/v12121441.
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A crucial, but unresolved question concerning mosquito-borne virus transmission is how these viruses can remain endemic in regions where the transmission is halted for long periods of time, due to mosquito inactivity in, e.g., winter. In northern Europe, Sindbis virus (SINV) (genus alphavirus, Togaviridae) is transmitted among birds by Culex mosquitoes during the summer, with occasional symptomatic infections occurring in humans. In winter 2018–19, we sampled hibernating Culex spp females in a SINV endemic region in Sweden and assessed them individually for SINV infection status, blood-feeding status, and species. The results showed that 35 out of the 767 collected mosquitoes were infected by SINV, i.e., an infection rate of 4.6%. The vast majority of the collected mosquitoes had not previously blood-fed (98.4%) and were of the species Cx. pipiens (99.5%). This is the first study of SINV overwintering, and it concludes that SINV can be commonly found in the hibernating Cx. pipiens population in an endemic region in Sweden, and that these mosquitoes become infected through other means besides blood-feeding. Further studies on mosquito ecology and viral interactions are needed to elucidate the mechanisms of the persistence of these viruses over winter.
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Burdeinick-Kerr, Rebeca, Dhanasekaran Govindarajan, and Diane E. Griffin. "Noncytolytic Clearance of Sindbis Virus Infection from Neurons by Gamma Interferon Is Dependent on Jak/Stat Signaling." Journal of Virology 83, no. 8 (January 28, 2009): 3429–35. http://dx.doi.org/10.1128/jvi.02381-08.
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ABSTRACT The alphavirus Sindbis virus (SINV) causes encephalomyelitis in mice by infecting neurons of the brain and spinal cord. The outcome is age dependent. Young animals develop fatal disease, while older animals recover from infection. Recovery requires noncytolytic clearance of SINV from neurons, and gamma interferon (IFN-γ) is an important contributor to clearance in vivo. IFN-γ-dependent clearance has been studied using immortalized CSM14.1 rat neuronal cells that can be differentiated in vitro. Previous studies have shown that differentiated, but not undifferentiated, cells develop prolonged SINV replication and respond to IFN-γ treatment with noncytolytic clearance of virus preceded by suppression of genomic viral RNA synthesis and reactivation of cellular protein synthesis. To determine the signaling mechanisms responsible for clearance, the responses of SINV-infected differentiated neurons to IFN-γ were examined. IFN-γ treatment of SINV-infected differentiated CSM14.1 cells, AP-7 olfactory neuronal cells, and primary dorsal root ganglia neurons triggered prolonged Stat-1 Tyr701 phosphorylation, Stat-1 Ser727 phosphorylation, and transient Stat-5 phosphorylation. Inhibition of Jak kinase activity with Jak inhibitor I completely reversed the neuroprotective and antiviral activities of IFN-γ in differentiated cells. We conclude that activation of the Jak/Stat pathway is the primary mechanism for IFN-γ-mediated clearance of SINV infection from mature neurons.
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AHLM, C., M. ELIASSON, O. VAPALAHTI, and M. EVANDER. "Seroprevalence of Sindbis virus and associated risk factors in northern Sweden." Epidemiology and Infection 142, no. 7 (September 13, 2013): 1559–65. http://dx.doi.org/10.1017/s0950268813002239.
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SUMMARYMosquito-borne Sindbis virus (SINV) cause disease characterized by rash, fever and arthritis which often leads to long-lasting arthralgia. To determine the seroprevalence of SINV and associated risk factors in northern Sweden, a randomly selected population aged between 25 and 74 years were invited to join the MONICA study. Serum from 1611 samples were analysed for specific IgG antibodies. Overall, 2·9% had IgG against SINV. More men (3·7%) than women (2·0%) were SINV seropositive (P = 0·047) and it was more common in subjects with a lower educational level (P = 0·013) and living in small, rural communities (P < 0·001). Seropositivity was associated with higher waist circumference (P = 0·1), elevated diastolic blood pressure (P = 0·037), and history of a previous stroke (P = 0·011). In a multiple logistic regression analysis, adjusting for known risk factors for stroke, seropositivity for SINV was an independent predictor of having had a stroke (odds ratio 4·3, 95% confidence interval 1·4–13·0, P = 0·011).
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Uusitalo, Ruut, Mika Siljander, C. Lorna Culverwell, Guy Hendrickx, Andreas Lindén, Timothée Dub, Juha Aalto, et al. "Predicting Spatial Patterns of Sindbis Virus (SINV) Infection Risk in Finland Using Vector, Host and Environmental Data." International Journal of Environmental Research and Public Health 18, no. 13 (July 1, 2021): 7064. http://dx.doi.org/10.3390/ijerph18137064.
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Pogosta disease is a mosquito-borne infection, caused by Sindbis virus (SINV), which causes epidemics of febrile rash and arthritis in Northern Europe and South Africa. Resident grouse and migratory birds play a significant role as amplifying hosts and various mosquito species, including Aedes cinereus, Culex pipiens, Cx. torrentium and Culiseta morsitans are documented vectors. As specific treatments are not available for SINV infections, and joint symptoms may persist, the public health burden is considerable in endemic areas. To predict the environmental suitability for SINV infections in Finland, we applied a suite of geospatial and statistical modeling techniques to disease occurrence data. Using an ensemble approach, we first produced environmental suitability maps for potential SINV vectors in Finland. These suitability maps were then combined with grouse densities and environmental data to identify the influential determinants for SINV infections and to predict the risk of Pogosta disease in Finnish municipalities. Our predictions suggest that both the environmental suitability for vectors and the high risk of Pogosta disease are focused in geographically restricted areas. This provides evidence that the presence of both SINV vector species and grouse densities can predict the occurrence of the disease. The results support material for public-health officials when determining area-specific recommendations and deliver information to health care personnel to raise awareness of the disease among physicians.
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Baxter, Victoria Kate, Kimberly L. W. Schultz, and Diane E. Griffin. "Interferon gamma promotes long term retention of tissue resident memory T cells in the brain following alphavirus clearance in mice." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 171.2. http://dx.doi.org/10.4049/jimmunol.204.supp.171.2.
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Abstract The prototypic alphavirus Sindbis virus (SINV) targets neurons in mice, providing a well characterized model of alphavirus encephalomyelitis. SINV clearance from the brain requires a noncytolytic mechanism to avoid neurological damage and dysfunction and is facilitated by synergistic cooperation between anti-SINV antibody and interferon gamma (IFN-γ). While infectious virus is cleared from the brain by 7 to 10 days post infection (DPI), SINV RNA levels decrease slowly and remain detectable at low levels for at least a year following infection. Because alphaviral RNA is infectious, strict control by the immune system is required to prevent virus reactivation and relapse of disease. To characterize the long-term T cell response following clearance of infectious virus, C57BL/6 mice with intact or impaired IFN-γ signaling were infected with the nonfatal TE strain of SINV, and the frequency and functionality of different T cell populations were evaluated in the brain by flow cytometry. While highly proliferative short-lived T effector cells made up the majority of CD4+ and CD8+ T cells during active infection at 7 DPI, long-lived effector memory T cells became the predominant T cell type by 14 DPI. Following the period of virus clearance, both CD4+ and CD8+ T cell polyfunctionality increased, with more cells expressing multiple effector proteins at higher intensities, and PD-1 and TIM-3 exhaustion marker expression decreased. The percentage of CD8+ T cells characterized as CD103+ tissue resident memory (TRM) cells was decreased in mice with impaired IFN-γ signaling. This indicates IFN-γ signaling promotes the development of TRM cells in the brain during SINV infection and suggests IFN-γ supports long term control of SINV reactivation.
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Hong, Eunmee M., Rushika Perera, and Richard J. Kuhn. "Alphavirus Capsid Protein Helix I Controls a Checkpoint in Nucleocapsid Core Assembly." Journal of Virology 80, no. 18 (September 15, 2006): 8848–55. http://dx.doi.org/10.1128/jvi.00619-06.
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ABSTRACT The assembly of the alphavirus nucleocapsid core has been investigated using an in vitro assembly system. The C-terminal two-thirds of capsid protein (CP), residues 81 to 264 in Sindbis virus (SINV), have been previously shown to have all the RNA-CP and CP-CP contacts required for core assembly in vitro. Helix I, which is located in the N-terminal dispensable region of the CP, has been proposed to stabilize the core by forming a coiled coil in the CP dimer formed by the interaction of residues 81 to 264. We examined the ability of heterologous alphavirus CPs to dimerize and form phenotypically mixed core-like particles (CLPs) using an in vitro assembly system. The CPs of SINV and Ross River virus (RRV) do not form phenotypically mixed CLPs, but SINV and Western equine encephalitis virus CPs do form mixed cores. In addition, CP dimers do not form between SINV and RRV in these assembly reactions. In contrast, an N-terminal truncated SINV CP (residues 81 to 264) forms phenotypically mixed CLPs when it is assembled with full-length heterologous CPs, suggesting that the region that controls the mixing is present in the N-terminal 80 residues. Furthermore, this result suggests that the dimeric interaction, which was absent between SINV and RRV CPs, can be restored by the removal of the N-terminal 80 residues of the SINV CP. We mapped the determinant that is responsible for phenotypic mixing onto helix I by using domain swapping experiments. Thus, discrimination of the CP partner in alphavirus core assembly appears to be dependent on helix I sequence compatibility. These results suggest that helix I provides one of the important interactions during nucleocapsid core formation and may play a regulatory role during the early steps of the assembly process.
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Garneau, Nicole L., Kevin J. Sokoloski, Mateusz Opyrchal, C. Preston Neff, Carol J. Wilusz, and Jeffrey Wilusz. "The 3′ Untranslated Region of Sindbis Virus Represses Deadenylation of Viral Transcripts in Mosquito and Mammalian Cells." Journal of Virology 82, no. 2 (October 31, 2007): 880–92. http://dx.doi.org/10.1128/jvi.01205-07.
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ABSTRACT The positive-sense transcripts of Sindbis virus (SINV) resemble cellular mRNAs in that they possess a 5′ cap and a 3′ poly(A) tail. It is likely, therefore, that SINV RNAs must successfully overcome the cytoplasmic mRNA decay machinery of the cell in order to establish an efficient, productive infection. In this study, we have taken advantage of a temperature-sensitive polymerase to shut off viral transcription, and we demonstrate that SINV RNAs are subject to decay during a viral infection in both C6/36 (Aedes albopictus) and baby hamster kidney cells. Interestingly, in contrast to most cellular mRNAs, the decay of SINV RNAs was not initiated by poly(A) tail shortening in either cell line except when most of the 3′ untranslated region (UTR) was deleted from the virus. This block in deadenylation of viral transcripts was recapitulated in vitro using C6/36 mosquito cell cytoplasmic extracts. Two distinct regions of the 319-base SINV 3′ UTR, the repeat sequence elements and a U-rich domain, were shown to be responsible for mediating the repression of deadenylation of viral mRNAs. Through competition studies performed in parallel with UV cross-linking and functional assays, mosquito cell factors—including a 38-kDa protein—were implicated in the repression of deadenylation mediated by the SINV 3′ UTR. This same 38-kDa protein was also implicated in mediating the repression of deadenylation by the 3′ UTR of another alphavirus, Venezuelan equine encephalitis virus. In summary, these data provide clear evidence that SINV transcripts do indeed interface with the cellular mRNA decay machinery during an infection and that the virus has evolved a way to avoid the major deadenylation-dependent pathway of mRNA decay.
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Crawford, John M., Liewei L. Yan, Hani Zaher, and Richard W. Hardy. "Host-Dependent Modifications of Packaged Alphavirus Genomic RNA Influence Virus Replication in Mammalian Cells." Viruses 14, no. 12 (November 23, 2022): 2606. http://dx.doi.org/10.3390/v14122606.
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Alphaviruses must interact efficiently with two distinct host environments in order to replicate and transmit between vertebrate and mosquito hosts. Some host-origin-dependent differences in virus particle composition that appear to facilitate the transmission cycle are known. However, the impact of host-mediated modification of packaged viral genomic RNA on subsequent infection has not been previously investigated. Here we show that in human (HEK-293) cells, mosquito-derived Sindbis virus (SINV) replicates and spreads faster, producing a more infectious virus than its mammalian-derived counterpart. This enhanced replication is neither a result of differences in the stability nor the production of the infecting genomic RNA. Nevertheless, purified genomic RNA from mosquito-derived SINV established infection in HEK-293 cells more efficiently than that of mammalian-derived SINV, indicating that the genomic RNA itself is different between the two producing hosts and this difference is a determinant of infection. In agreement with this idea, we show that mosquito-derived SINV genomic RNA is a more active template for translation than mammalian-derived SINV genomic RNA, and we attribute this difference to host-dependent changes in modification of packaged genomic RNA as determined by LC/MS-MS. Our data support the hypothesis that among other factors, the host-dependent modification profile of the packaged vRNA is likely to play an important role in the efficiency of SINV infection and replication in mammalian cells.
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Jansen, Stephanie, Renke Lühken, Michelle Helms, Björn Pluskota, Wolf Peter Pfitzner, Sandra Oerther, Norbert Becker, Jonas Schmidt-Chanasit, and Anna Heitmann. "Vector Competence of Mosquitoes from Germany for Sindbis Virus." Viruses 14, no. 12 (November 26, 2022): 2644. http://dx.doi.org/10.3390/v14122644.
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Transmission of arthropod-borne viruses (arboviruses) are an emerging global health threat in the last few decades. One important arbovirus family is the Togaviridae, including the species Sindbis virus within the genus Alphavirus. Sindbis virus (SINV) is transmitted by mosquitoes, but available data about the role of different mosquito species as potent vectors for SINV are scarce. Therefore, we investigated seven mosquito species, collected from the field in Germany (Ae. koreicus, Ae. geniculatus, Ae. sticticus, Cx. torrentium, Cx. pipiens biotype pipiens) as well as lab strains (Ae. albopictus, Cx. pipiens biotype molestus, Cx. quinquefasciatus), for their vector competence for SINV. Analysis was performed via salivation assay and saliva was titrated to calculate the amount of infectious virus particles per saliva sample. All Culex and Aedes species were able to transmit SINV. Transmission could be detected at all four investigated temperature profiles (of 18 ± 5 °C, 21 ± 5 °C, 24 ± 5 °C or 27 ± 5 °C), and no temperature dependency could be observed. The concentration of infectious virus particles per saliva sample was in the same range for all species, which may suggest that all investigated mosquito species are able to transmit SINV in Germany.
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Law, Lok Man J., Owen R. Albin, John-William N. Carroll, Christopher T. Jones, Charles M. Rice, and Margaret R. MacDonald. "Identification of a Dominant Negative Inhibitor of Human Zinc Finger Antiviral Protein Reveals a Functional Endogenous Pool and Critical Homotypic Interactions." Journal of Virology 84, no. 9 (February 24, 2010): 4504–12. http://dx.doi.org/10.1128/jvi.02018-09.
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ABSTRACT The zinc finger antiviral protein (ZAP) is a host factor with potent antiviral activity when overexpressed in cells. ZAP blocks replication of the prototype alphavirus Sindbis virus (SINV) at a step at or before translation of the incoming viral genome. The mechanism of ZAP anti-SINV activity and the determinants of its antiviral function, however, have not been defined. Here, we have identified a dominant negative inhibitor of human ZAP. Rat ZAP with a cysteine-to-arginine mutation at position 88 (rZAPC88R), previously reported as a nonfunctional form of ZAP, increases SINV growth in cells. These results led us to discover a previously undetectable pool of endogenous functional ZAP within human cells. Investigation of the mechanism of dominant negative inhibition, combined with a comprehensive mutational analysis of the antiviral factor, revealed that homotypic associations are required for ZAP function in limiting SINV propagation.
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Burdeinick-Kerr, Rebeca, and Diane E. Griffin. "Gamma Interferon-Dependent, Noncytolytic Clearance of Sindbis Virus Infection from Neurons In Vitro." Journal of Virology 79, no. 9 (May 1, 2005): 5374–85. http://dx.doi.org/10.1128/jvi.79.9.5374-5385.2005.
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ABSTRACT Due to the nonrenewable nature of neurons, recovery from viral infection of the central nervous system requires noncytopathic mechanisms for control of virus replication. Recovery from alphavirus encephalitis can occur without apparent neurological damage through the effects of antibody and gamma interferon (IFN-γ). To establish an in vitro cell culture system that will allow the study of mechanisms of IFN-γ-mediated control of Sindbis virus (SINV) replication in neurons, we have characterized the susceptibility to SINV infection and IFN-γ responsiveness of two neuronal cell lines that can be differentiated in vitro: CSM14.1, a rat nigral cell line, and NSC34, a mouse motor neuron cell line. Undifferentiated CSM14.1 and NSC34 cells were permissive for SINV and susceptible to virus-induced cell death. With differentiation, CSM14.1 cells reduced virus replication and became progressively resistant to virus-induced cell death, resulting in prolonged virus replication. NSC34 cells did not differentiate completely and became only partially resistant to SINV infection. Both CSM14.1 and NSC34 cells responded to pretreatment with IFN-γ by decreasing SINV replication. Differentiated CSM14.1 cells treated 24 h after infection with IFN-γ responded with increased cell viability and clearance of infectious virus. IFN-γ treatment sequentially altered the ratio of genomic to subgenomic viral RNA synthesis, promoted recovery of cellular protein synthesis, reduced viral protein synthesis, and inhibited viral RNA transcription within 24 h after treatment. We conclude that CSM14.1 cells provide an excellent model for the study of IFN-γ-mediated noncytolytic clearance of SINV from mature neurons.
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Jansen, Stephanie, Anna Heitmann, Ruut Uusitalo, Essi M. Korhonen, Renke Lühken, Konstantin Kliemke, Unchana Lange, et al. "Vector Competence of Northern European Culex pipiens Biotype pipiens and Culex torrentium to West Nile Virus and Sindbis Virus." Viruses 15, no. 3 (February 21, 2023): 592. http://dx.doi.org/10.3390/v15030592.
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The West Nile Virus (WNV) and Sindbis virus (SINV) are avian-hosted mosquito-borne zoonotic viruses that co-circulate in some geographical areas and share vector species such as Culex pipiens and Culex torrentium. These are widespread in Europe, including northern parts and Finland, where SINV is endemic, but WNV is currently not. As WNV is spreading northwards in Europe, we wanted to assess the experimental vector competence of Finnish Culex pipiens and Culex torrentium mosquitoes to WNV and SINV in different temperature profiles. Both mosquito species were found susceptible to both viruses and got infected via infectious blood meal at a mean temperature of 18 °C. WNV-positive saliva was detected at a mean temperature of 24 °C, whereas SINV-positive saliva was detected already at a mean temperature of 18 °C. Cx. torrentium was found to be a more efficient vector for WNV and SINV over Cx. pipiens. Overall, the results were in line with the previous studies performed with more southern vector populations. The current climate does not seem optimal for WNV circulation in Finland, but temporary summertime transmission could occur in the future if all other essential factors are in place. More field data would be needed for monitoring and understanding the northward spreading of WNV in Europe.
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JALAVA, K., J. SANE, J. OLLGREN, R. RUUHELA, O. RÄTTI, S. KURKELA, P. HELLE, et al. "Climatic, ecological and socioeconomic factors as predictors of Sindbis virus infections in Finland." Epidemiology and Infection 141, no. 9 (November 15, 2012): 1857–66. http://dx.doi.org/10.1017/s095026881200249x.
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SUMMARYMosquito-borne Sindbis virus (SINV) causes rash-arthritis syndrome in Finland. Major outbreaks with approximately 7-year cycles have caused substantial burden of illness. Forest dwelling grouse are suspected to be amplifying hosts, with the infection transmitted to humans by mosquito bites. SINV infection surveillance data for 1984–2010 were used to create a negative binomial hurdle model, with seasonality, long-term cycles, climatic, ecological and socioeconomic variables. Climatic factors during early summer and amount of snow in April described the occurrence and incidence of SINV infections. Regulated water shore and hatch-year black grouse density described the occurrence, while population working in agriculture, agricultural land (negative) and income (negative) described the incidence of the disease. The prediction for 2009 was 85 cases (95% prediction interval 2-1187), while the actual occurrence was 106. We identified novel and known risk factors. The prevention of SINV infections in regulated water areas by infected mosquito populations should be targeted.
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Dahl, Emma, Linnea Öborn, Viktoria Sjöberg, Åke Lundkvist, and Jenny C. Hesson. "Vertical Transmission of Sindbis Virus in Culex Mosquitoes." Viruses 14, no. 9 (August 30, 2022): 1915. http://dx.doi.org/10.3390/v14091915.
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Vertical transmission (VT) is a phenomenon of vector-borne diseases where a pathogen is transferred from an infected arthropod mother to her offspring. For mosquito-borne flavi- and alphaviruses, VT is commonly viewed as rare; however, both field and experimental studies report on vertical transmission efficiency to a notably varying degree. It is likely that this reflects the different experimental methods used to test vertical transmission efficiency as well as differences between virus–vector combinations. There are very few investigations of the VT of an alphavirus in a Culex vector. Sindbis virus (SINV) is an arthritogenic alphavirus that utilizes Culex species as main vectors both in the summer transmission season and for its persistence over the winter period in northern latitudes. In this study, we investigated the vertical transmission of the SINV in Culex vectors, both in the field and in experimental settings. The detection of SINV RNA in field-collected egg rafts and emerging adults shows that vertical transmission takes place in the field. Experimentally infected females gave rise to adult offspring containing SINV RNA at emergence; however, three to four weeks after emergence none of the offspring contained SINV RNA. This study shows that vertical transmission may be connected to SINV’s ability to persist throughout northern winters and also highlights many aspects of viral replication that need further study.
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Kozaki, Tatsuya, Jun Komano, Daiki Kanbayashi, Michihiro Takahama, Takuma Misawa, Takashi Satoh, Osamu Takeuchi, et al. "Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response." Proceedings of the National Academy of Sciences 114, no. 10 (February 17, 2017): 2681–86. http://dx.doi.org/10.1073/pnas.1621508114.
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The innate immune system senses RNA viruses by pattern recognition receptors (PRRs) and protects the host from virus infection. PRRs mediate the production of immune modulatory factors and direct the elimination of RNA viruses. Here, we show a unique PRR that mediates antiviral response. Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP ribose) polymerase (TIPARP), a Cysteine3 Histidine (CCCH)-type zinc finger-containing protein, binds to Sindbis virus (SINV) RNA via its zinc finger domain and recruits an exosome to induce viral RNA degradation. TIPARP typically localizes in the nucleus, but it accumulates in the cytoplasm after SINV infection, allowing targeting of cytoplasmic SINV RNA. Redistribution of TIPARP is induced by reactive oxygen species (ROS)-dependent oxidization of the nuclear pore that affects cytoplasmic-nuclear transport. BCL2-associated X protein (BAX) and BCL2 antagonist/killer 1 (BAK1), B-cell leukemia/lymphoma 2 (BCL2) family members, mediate mitochondrial damage to generate ROS after SINV infection. Thus, TIPARP is a viral RNA-sensing PRR that mediates antiviral responses triggered by BAX- and BAK1-dependent mitochondrial damage.
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Cristea, Ileana M., Heather Rozjabek, Kelly R. Molloy, Sophiya Karki, Laura L. White, Charles M. Rice, Michael P. Rout, Brian T. Chait, and Margaret R. MacDonald. "Host Factors Associated with the Sindbis Virus RNA-Dependent RNA Polymerase: Role for G3BP1 and G3BP2 in Virus Replication." Journal of Virology 84, no. 13 (April 14, 2010): 6720–32. http://dx.doi.org/10.1128/jvi.01983-09.
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ABSTRACT Sindbis virus (SINV) is the prototype member of the Alphavirus genus, whose members cause severe human diseases for which there is no specific treatment. To ascertain host factors important in the replication of the SINV RNA genome, we generated a SINV expressing nsP4, the viral RNA-dependent RNA polymerase, with an in-frame 3×Flag epitope tag. Proteomic analysis of nsP4-containing complexes isolated from cells infected with the tagged virus revealed 29 associated host proteins. Of these, 10 proteins were associated only at a later time of infection (12 h), 14 were associated both early and late, and five were isolated only at the earlier time (6 h postinfection). These results demonstrate the dynamic nature of the virus-host interaction that occurs over the course of infection and suggest that different host proteins may be required for the multiple functions carried out by nsP4. Two related proteins found in association with nsP4 at both times of infection, GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) and G3BP2 were also previously identified as associated with SINV nsP2 and nsP3. We demonstrate a likely overlapping role for these host factors in limiting SINV replication events. The present study also identifies 10 host factors associated with nsP4 6 h after infection that were not found to be associated with nsP2 or nsP3. These factors are candidates for playing important roles in the RNA replication process. Identifying host factors essential for replication should lead to new strategies to interrupt alphavirus replication.
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Atasheva, Svetlana, Rodion Gorchakov, Robert English, Ilya Frolov, and Elena Frolova. "Development of Sindbis Viruses Encoding nsP2/GFP Chimeric Proteins and Their Application for Studying nsP2 Functioning." Journal of Virology 81, no. 10 (February 28, 2007): 5046–57. http://dx.doi.org/10.1128/jvi.02746-06.
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ABSTRACT Sindbis virus (SINV) is one of almost 30 currently known alphaviruses. In infected cells, it produces only a few proteins that function in virus replication and interfere with the development of the antiviral response. One of the viral nonstructural proteins, nsP2, not only exhibits protease and RNA helicase activities that are directly involved in viral RNA replication but also plays critical roles in the development of transcriptional and translational shutoffs in the SINV-infected cells. These multiple activities of nsP2 complicate investigations of this protein's functions and further understanding of its structure. Using a transposon-based approach, we generated a cDNA library of SINV genomes with a green fluorescent protein (GFP) gene randomly inserted into nsP2 and identified a number of sites that can be used for GFP cloning without a strong effect on virus replication. Recombinant SIN viruses encoding nsP2/GFP chimeric protein were capable of growth in tissue culture and interfering with cellular functions. SINV, expressing GFP in the nsP2, was used to isolate nsP2-specific protein complexes formed in the cytoplasm of the infected cells. These complexes contained viral nsPs, all of the cellular proteins that we previously coisolated with SINV nsP3, and some additional protein factors that were not found before in detectable concentrations. The random insertion library-based approach, followed by the selection of the viable variants expressing heterologous proteins, can be applied for mapping the domain structure of the viral nonstructural and structural proteins, cloning of peptide tags for isolation of the protein-specific complexes, and studying their formation by using live-cell imaging. This approach may also be applicable to presentation of additional antigens and retargeting of viruses to new receptors.
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Baxter, Victoria K., and Diane E. Griffin. "Interferon-Gamma Modulation of the Local T Cell Response to Alphavirus Encephalomyelitis." Viruses 12, no. 1 (January 16, 2020): 113. http://dx.doi.org/10.3390/v12010113.
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Infection of mice with Sindbis virus (SINV) provides a model for examining the role of the immune response to alphavirus infection of the central nervous system (CNS). Interferon-gamma (IFN-γ) is an important component of this response, and we show that SINV-infected differentiated neurons respond to IFN-γ in vitro by induction of antiviral genes and suppression of virus replication. To determine the in vivo effects of IFN-γ on SINV clearance and T cell responses, C57BL/6 mice lacking IFN-γ or IFN-γ receptor-1 were compared to wild-type (WT) mice after intracranial SINV infection. In WT mice, IFN-γ was first produced in the CNS by natural killer cells and then by CD4+ and CD8+ T cells. Mice with impaired IFN-γ signaling initiated clearance of viral RNA earlier than WT mice associated with CNS entry of more granzyme B-producing CD8+ T cells. However, these mice established fewer CD8+ tissue-resident memory T (TRM) cells and were more likely to experience reactivation of viral RNA synthesis late after infection. Therefore, IFN-γ suppresses the local development of granzyme B-expressing CD8+ T cells and slows viral RNA clearance but promotes CD8+ TRM cell establishment.
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Pierro, Dennis J., Erik L. Powers, and Ken E. Olson. "Genetic determinants of Sindbis virus strain TR339 affecting midgut infection in the mosquito Aedes aegypti." Journal of General Virology 88, no. 5 (May 1, 2007): 1545–54. http://dx.doi.org/10.1099/vir.0.82577-0.
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Mosquito midgut epithelial cells (MEC) play a major role in determining whether an arbovirus can successfully infect and be transmitted by mosquitoes. The Sindbis virus (SINV) strain TR339 efficiently infects Aedes aegypti MEC but the SINV strain TE/5′2J poorly infects MEC. SINV determinants for MEC infection have been localized to the E2 glycoprotein. The E2 amino acid sequences of TR339 and TE/5′2J differ at two sites, E2-55 and E2-70. We have altered the TE/5′2J virus genome by site-directed mutagenesis to contain two TR339 residues, E2-55 H→Q (histidine to glutamine) and E2-70 K→E (lysine to glutamic acid). We have characterized the growth patterns of derived viruses in cell culture and determined the midgut infection rate (MIR) in A. aegypti mosquitoes. Our results clearly show that the E2-55 H→Q and the E2-70 K→E mutations in the TE/5′2J virus increase MIR both independently and in combination. TE/5′2J virus containing both TR339 E2 residues had MIRs similar to the parental TR339 virus. In addition, SINV propagated in a mammalian cell line had a significantly lower A. aegypti midgut 50 % infectious dose than virus propagated in a mosquito cell line.
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Elmasri, Zeinab, Vashi Negi, Richard J. Kuhn, and Joyce Jose. "Requirement of a functional ion channel for Sindbis virus glycoprotein transport, CPV-II formation, and efficient virus budding." PLOS Pathogens 18, no. 10 (October 3, 2022): e1010892. http://dx.doi.org/10.1371/journal.ppat.1010892.
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Many viruses encode ion channel proteins that oligomerize to form hydrophilic pores in membranes of virus-infected cells and the viral membrane in some enveloped viruses. Alphavirus 6K, human immunodeficiency virus type 1 Vpu (HIV-Vpu), influenza A virus M2 (IAV-M2), and hepatitis C virus P7 (HCV-P7) are transmembrane ion channel proteins that play essential roles in virus assembly, budding, and entry. While the oligomeric structures and mechanisms of ion channel activity are well-established for M2 and P7, these remain unknown for 6K. Here we investigated the functional role of the ion channel activity of 6K in alphavirus assembly by utilizing a series of Sindbis virus (SINV) ion channel chimeras expressing the ion channel helix from Vpu or M2 or substituting the entire 6K protein with full-length P7, in cis. We demonstrate that the Vpu helix efficiently complements 6K, whereas M2 and P7 are less efficient. Our results indicate that while SINV is primarily insensitive to the M2 ion channel inhibitor amantadine, the Vpu inhibitor 5-N, N-Hexamethylene amiloride (HMA), significantly reduces SINV release, suggesting that the ion channel activity of 6K is similar to Vpu, promotes virus budding. Using live-cell imaging of SINV with a miniSOG-tagged 6K and mCherry-tagged E2, we further demonstrate that 6K and E2 colocalize with the Golgi apparatus in the secretory pathway. To contextualize the localization of 6K in the Golgi, we analyzed cells infected with SINV and SINV-ion channel chimeras using transmission electron microscopy. Our results provide evidence for the first time for the functional role of 6K in type II cytopathic vacuoles (CPV-II) formation. We demonstrate that in the absence of 6K, CPV-II, which originates from the Golgi apparatus, is not detected in infected cells, with a concomitant reduction in the glycoprotein transport to the plasma membrane. Substituting a functional ion channel, M2 or Vpu localizing to Golgi, restores CPV-II production, whereas P7, retained in the ER, is inadequate to induce CPV-II formation. Altogether our results indicate that ion channel activity of 6K is required for the formation of CPV-II from the Golgi apparatus, promoting glycoprotein spike transport to the plasma membrane and efficient virus budding.
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Wu, Wenbi, Cody A. Simmons, Jessica Moffitt, Rollie J. Clem, and A. Lorena Passarelli. "Effects of Manipulating Fibroblast Growth Factor Expression on Sindbis Virus Replication In Vitro and in Aedes aegypti Mosquitoes." Viruses 12, no. 9 (August 26, 2020): 943. http://dx.doi.org/10.3390/v12090943.
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Fibroblast growth factors (FGFs) are conserved among vertebrate and invertebrate animals and function in cell proliferation, cell differentiation, tissue repair, and embryonic development. A viral fibroblast growth factor (vFGF) homolog encoded by baculoviruses, a group of insect viruses, is involved in escape of baculoviruses from the insect midgut by stimulating basal lamina remodeling. This led us to investigate whether cellular FGF is involved in the escape of an arbovirus from mosquito midgut. In this study, the effects of manipulating FGF expression on Sindbis virus (SINV) replication and escape from the midgut of the mosquito vector Aedes aegypti were examined. RNAi-mediated silencing of either Ae. aegypti FGF (AeFGF) or FGF receptor (AeFGFR) expression reduced SINV replication following oral infection of Ae. aegypti mosquitoes. However, overexpression of baculovirus vFGF using recombinant SINV constructs had no effect on replication of these viruses in cultured mosquito or vertebrate cells, or in orally infected Ae. aegypti mosquitoes. We conclude that reducing FGF signaling decreases the ability of SINV to replicate in mosquitoes, but that overexpression of vFGF has no effect, possibly because endogenous FGF levels are already sufficient for optimal virus replication. These results support the hypothesis that FGF signaling, possibly by inducing remodeling of midgut basal lamina, is involved in arbovirus midgut escape following virus acquisition from a blood meal.
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Johansen, Cheryl A., John S. Mackenzie, David W. Smith, and Michael D. A. Lindsay. "Prevalence of neutralising antibodies to Barmah Forest, Sindbis and Trubanaman viruses in animals and humans in the south-west of Western Australia." Australian Journal of Zoology 53, no. 1 (2005): 51. http://dx.doi.org/10.1071/zo03042.
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A study was undertaken in the south-west of Western Australia to investigate potential vertebrate hosts of Barmah Forest virus (BFV), Sindbis virus (SINV) and Trubanaman virus (TRUV) following isolation of these viruses from mosquitoes collected during routine surveillance for arboviruses. Over 3000 animal and human sera collected between 1979 and 1995 were tested for the presence of neutralising antibodies to each of the viruses. The overall prevalence of antibodies to BFV, SINV and TRUV was 0.4%, 0.3% and 1.6%, respectively. Antibodies to BFV were detected only in quokkas (3.2%), horses (1.2%) and humans (0.9%). No definitive evidence of infection with BFV was detected in samples collected prior to 1992, supporting previous suggestions that BFV was introduced into the region after this time. Antibodies to SINV were detected in western native cats (16.7%), emus (4.5%), rabbits (0.8%) and horses (0.7%), and evidence of TRUV infection was most common in western grey kangaroos (21.1%), feral pigs (3.6%), rabbits (2.4%), foxes (2.3%), quokkas (1.6%) and horses (1.6%).
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Kelly, Erica M., Daniel C. Moon, and Doria F. Bowers. "Apoptosis in mosquito salivary glands: Sindbis virus-associated and tissue homeostasis." Journal of General Virology 93, no. 11 (November 1, 2012): 2419–24. http://dx.doi.org/10.1099/vir.0.042846-0.
Full textAbstract:
Apoptosis is observed during a spectrum of conditions including exogenous virus infection and endogenous cellular turnover. Adult female Aedes albopictus mosquitoes challenged with increasing titres of Sindbis virus (SINV) via intrathoracic inoculation demonstrated that the injection dosage did not result in significantly different levels of virus growth or mosquito survival at day 10 post-infection. Tissues probed for apoptosis using an in situ TUNEL assay revealed SINV-associated apoptotic cells scattered throughout the proximal and distal regions of the salivary gland (SG) lateral lobes but which were not detected in the median lobe or the midgut and hindgut. Apoptosis was also identified in SG duct cells in both infected and uninfected mosquitoes, suggesting routine tissue homeostasis. SINV-associated apoptosis sequestered to the SG lateral lobes indicates a differential epithelial cell response to an arbovirus and provides insight into mosquito defence mechanisms against pathogens and SG infection barriers, hurdles to transmission of arboviruses of public health concern.
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Pierro, Dennis J., Erik L. Powers, and Ken E. Olson. "Genetic Determinants of Sindbis Virus Mosquito Infection Are Associated with a Highly Conserved Alphavirus and Flavivirus Envelope Sequence." Journal of Virology 82, no. 6 (December 26, 2007): 2966–74. http://dx.doi.org/10.1128/jvi.02060-07.
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ABSTRACT Wild-type Sindbis virus (SINV) strain MRE16 efficiently infects Aedes aegypti midgut epithelial cells (MEC), but laboratory-derived neurovirulent SINV strain TE/5′2J infects MEC poorly. SINV determinants for MEC infection have been localized to the E2 glycoprotein. The E2 amino acid sequences of MRE16 and TE/5′2J differ at 60 residue sites. To identify the genetic determinants of MEC infection of MRE16, the TE/5′2J virus genome was altered to contain either domain chimeras or more focused nucleotide substitutions of MRE16. The growth patterns of derived viruses in cell culture were determined, as were the midgut infection rates (MIR) in A. aegypti mosquitoes. The results showed that substitutions of MRE16 E2 aa 95 to 96 and 116 to 119 into the TE/5′2J virus increased MIR both independently and in combination with each other. In addition, a unique PPF/.GDS amino acid motif was located between these two sites that was found to be a highly conserved sequence among alphaviruses and flaviviruses but not other arboviruses.
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BRUMMER-KORVENKONTIO, M., O. VAPALAHTI, P. KUUSISTO, P. SAIKKU, T. MANNI, P. KOSKELA, T. NYGREN, H. BRUMMER-KORVENKONTIO, and A. VAHERI. "Epidemiology of Sindbis virus infections in Finland 1981–96: possible factors explaining a peculiar disease pattern." Epidemiology and Infection 129, no. 2 (October 2002): 335–45. http://dx.doi.org/10.1017/s0950268802007409.
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Pogosta disease (PD), an epidemic rash-arthritis occurring in late summer is caused by Sindbis virus (SINV) and is transmitted to humans by mosquitoes. Altogether 2183 PD cases were serologically confirmed 1981–96 in Finland, with an annual incidence of 2.7/100000 (18 in the most endemic area of Northern Karelia). The annual average was 136 (varying from 1 to 1282) with epidemics occurring in August–September with a 7-year interval. Studies on 6320 patients with suspected rubella (1973–89) revealed 107 PD cases. The depth of snow cover and the temperature in May–July seemed to predict the number of cases. The morbidity was highest in 45- to 65-year-old females and lowest in children. Subclinical SINV infections were 17 times more common than the clinical ones. The SINV-antibody prevalence in fertile-age females was 0.6% in 1992; the estimated seroprevalence in Finland is about 2%. Among game animals the tetraonids (black grouse and capercaillie) had the highest seroprevalence (65%) in the epidemic year of 1981.
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Xu, Yan, Zhengwei Zhong, Yanxin Ren, Liting Ma, Zhi Ye, Chuang Gao, Jingwen Wang, and Yang Li. "Antiviral RNA interference in disease vector (Asian longhorned) ticks." PLOS Pathogens 17, no. 12 (December 3, 2021): e1010119. http://dx.doi.org/10.1371/journal.ppat.1010119.
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Disease vectors such as mosquitoes and ticks play a major role in the emergence and re-emergence of human and animal viral pathogens. Compared to mosquitoes, however, much less is known about the antiviral responses of ticks. Here we showed that Asian longhorned ticks (Haemaphysalis longicornis) produced predominantly 22-nucleotide virus-derived siRNAs (vsiRNAs) in response to severe fever with thrombocytopenia syndrome virus (SFTSV, an emerging tick-borne virus), Nodamura virus (NoV), or Sindbis virus (SINV) acquired by blood feeding. Notably, experimental acquisition of NoV and SINV by intrathoracic injection also initiated viral replication and triggered the production of vsiRNAs in H. longicornis. We demonstrated that a mutant NoV deficient in expressing its viral suppressor of RNAi (VSR) replicated to significantly lower levels than wildtype NoV in H. longicornis, but accumulated to higher levels after knockdown of the tick Dicer2-like protein identified by phylogeny comparison. Moreover, the expression of a panel of known animal VSRs in cis from the genome of SINV drastically enhanced the accumulation of the recombinant viruses. This study establishes a novel model for virus-vector-mouse experiments with longhorned ticks and provides the first in vivo evidence for an antiviral function of the RNAi response in ticks. Interestingly, comparing the accumulation levels of SINV recombinants expressing green fluorescent protein or SFTSV proteins identified the viral non-structural protein as a putative VSR. Elucidating the function of ticks’ antiviral RNAi pathway in vivo is critical to understand the virus-host interaction and the control of tick-borne viral pathogens.
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Sokoloski, K. J., K. C. Haist, T. E. Morrison, S. Mukhopadhyay, and R. W. Hardy. "Noncapped Alphavirus Genomic RNAs and Their Role during Infection." Journal of Virology 89, no. 11 (April 1, 2015): 6080–92. http://dx.doi.org/10.1128/jvi.00553-15.
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ABSTRACTAlphaviruses are enveloped positive-sense RNA viruses that exhibit a wide host range consisting of vertebrate and invertebrate species. Previously we have reported that the infectivity of Sindbis virus (SINV), the model alphavirus, was largely a function of the cell line producing the viral particles. Mammalian-cell-derived SINV particles, on average, exhibit a higher particle-to-PFU ratio than mosquito cell-derived SINV particles. Nevertheless, the outcome of nonproductive infection, the molecular traits that determine particle infectivity and the biological importance of noninfectious particles were, prior to this study, unknown. Here, we report that the incoming genomic RNAs of noninfectious SINV particles undergo rapid degradation following infection. Moreover, these studies have led to the identification of the absence of the 5′ cap structure as a primary molecular determinant of particle infectivity. We show that the genomic RNAs of alphaviruses are not universally 5′ capped, with a significant number of noncapped genomic RNA produced early in infection. The production of noncapped viral genomic RNAs is important to the establishment and maintenance of alphaviral infection.IMPORTANCEThis report is of importance to the field of virology for three reasons. First, these studies demonstrate that noncapped Sindbis virus particles are produced as a result of viral RNA synthesis. Second, this report is, to our knowledge, the first instance of the direct measurement of the half-life of an incoming genomic RNA from a positive-sense RNA virus. Third, these studies indicate that alphaviral infection is likely a concerted effort of infectious and noninfectious viral particles.
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Yeh, Jane X., Kimberly L. W. Schultz, Valerie Calvert, Emanuel F. Petricoin, and Diane E. Griffin. "The NF-κB/leukemia inhibitory factor/STAT3 signaling pathway in antibody-mediated suppression of Sindbis virus replication in neurons." Proceedings of the National Academy of Sciences 117, no. 46 (November 3, 2020): 29035–45. http://dx.doi.org/10.1073/pnas.2016691117.
Full textAbstract:
Alphaviruses are positive-sense, enveloped RNA viruses that are important causes of viral encephalomyelitis. Sindbis virus (SINV) is the prototype alphavirus and preferentially infects neurons in rodents to induce an encephalomyelitis similar to the human disease. Using a mouse model of SINV infection of the nervous system, many of the immune processes involved in recovery from viral encephalomyelitis have been identified. Antibody specific to the SINV E2 glycoprotein plays an important role in recovery and is sufficient for noncytolytic suppression of virus replication in vivo and in vitro. To investigate the mechanism of anti-E2 antibody-mediated viral suppression, a reverse-phase protein array was used to broadly survey cellular signaling pathway activation following antibody treatment of SINV-infected differentiated AP-7 neuronal cells. Anti-E2 antibody induced rapid transient NF-κB and later sustained Y705 STAT3 phosphorylation, outlining an intracellular signaling cascade activated by antiviral antibody. Because NF-κB target genes include the STAT3-activating IL-6 family cytokines, expression of these messenger RNAS (mRNAs) was assessed. Expression of leukemia inhibitory factor (LIF) cytokine mRNA, but not other IL-6 family member mRNAs, was up-regulated by anti-E2 antibody. LIF induced STAT3 Y705 phosphorylation in infected differentiated AP-7 cells but did not inhibit virus replication. However, anti-E2 antibody localized the LIF receptor to areas of E2 expression on the infected cell surface, and LIF enhanced the antiviral effects of antibody. These findings identify activation of the NF-κB/LIF/STAT3 signaling cascade as involved in inducing antibody-mediated viral suppression and highlight the importance of nonneutralizing antibody functions in viral clearance from neurons.
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Yin, Jun, Christina L. Gardner, Crystal W. Burke, Kate D. Ryman, and William B. Klimstra. "Similarities and Differences in Antagonism of Neuron Alpha/Beta Interferon Responses by Venezuelan Equine Encephalitis and Sindbis Alphaviruses." Journal of Virology 83, no. 19 (July 29, 2009): 10036–47. http://dx.doi.org/10.1128/jvi.01209-09.
Full textAbstract:
ABSTRACT Venezuelan equine encephalitis virus (VEEV) is highly virulent in adult laboratory mice, while Sindbis virus (SINV) is avirulent regardless of dose or inoculation route, dependent upon functioning alpha/beta interferon (IFN-α/β) responses. We have examined each virus' resistance to and/or antagonism of IFN-α/β responses in neurons, a cell type targeted by both viruses in mice, by infecting IFN-α/β-treated or untreated primary cultures with viruses or virus-derived replicons that lacked the structural proteins. Priming with IFN-α/β prior to infection revealed that VEEV replication and progeny virion production were resistant to an established antiviral state while those of SINV were more sensitive. Postinfection IFN-α/β treatment revealed that phosphorylation of STAT1 and STAT2 was partially blocked by infection with either virus, dependent upon expression of nonstructural proteins (nsP), but not structural proteins (sP). However, inhibition of STAT phosphorylation by VEEV replicons was not correlated with inhibition of IFN-stimulated gene (ISG) mRNA induction, yet ISG induction was inhibited when sP were present. Host translation was inhibited by VEEV nsP even when cells were pretreated with IFN-α/β. SINV blocked ISG induction and translation, associated with nsP-mediated shutoff of macromolecular synthesis, but both activities were sensitive to IFN-α/β pretreatment. We conclude that both VEEV and SINV limit ISG induction in infected neurons through shutoff of host transcription and translation but that inhibition by VEEV is more resistant to IFN-α/β priming. Likewise, both viruses inhibit IFN receptor-initiated signaling, although the effect upon host responses is not clear. Finally, VEEV appears to be more resistant to effectors of the preestablished antiviral state.
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Saredy, Jason J., Florence Y. Chim, Zoë L. Lyski, Yani P. Ahearn, and Doria F. Bowers. "Confocal Analysis of the Distribution and Persistence of Sindbis Virus (TaV-GFP) Infection in Midguts of Aedes aegypti Mosquitoes." Microscopy and Microanalysis 26, no. 2 (March 19, 2020): 267–74. http://dx.doi.org/10.1017/s1431927620001270.
Full textAbstract:
AbstractBiological transmission of arthropod-borne viruses (arboviruses) to vertebrate hosts by hematophagous insects poses a global threat because such arboviruses can result in a range of serious public health infectious diseases. Sindbis virus (SINV), the prototype Alphavirus, was used to track infections in the posterior midgut (PMG) of Aedes aegypti adult mosquitoes. Females were fed viremic blood containing a virus reporter, SINV [Thosea asigna virus-green fluorescent protein (TaV-GFP)], that leaves a fluorescent signal in infected cells. We assessed whole-mount PMGs to identify primary foci, secondary target tissues, distribution, and virus persistence. Following a viremic blood meal, PMGs were dissected and analyzed at various days of post blood-feeding. We report that virus foci indicated by GFP in midgut epithelial cells resulted in a 9.8% PMG infection and a 10.8% dissemination from these infected guts. The number of virus foci ranged from 1 to 3 per individual PMG and was more prevalent in the PMG-middle > PMG-frontal > PMG-caudal regions. SINV TaV-GFP was first observed in the PMG (primary target tissue) at 3 days post blood-feeding, was sequestered in circumscribed foci, replicated in PMG peristaltic muscles (secondary target tissue) following dissemination, and GFP was observed to persist in PMGs for 30 days postinfection.
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Frolov, Ilya, Natalia Garmashova, Svetlana Atasheva, and Elena I. Frolova. "Random Insertion Mutagenesis of Sindbis Virus Nonstructural Protein 2 and Selection of Variants Incapable of Downregulating Cellular Transcription." Journal of Virology 83, no. 18 (July 1, 2009): 9031–44. http://dx.doi.org/10.1128/jvi.00850-09.
Full textAbstract:
ABSTRACT Sindbis virus nonstructural protein 2 (SINV nsP2) is an important determinant of virus pathogenesis and downregulation of virus-induced cell response. This protein efficiently inhibits transcription of cellular messenger and ribosomal RNAs and, thus, is capable of inhibiting the activation of genes whose products are involved in development of the antiviral response. Alphavirus nsP2 has a number of predicted functional domains, some of which were confirmed by crystal structure. Our current study demonstrated that none of the putative or known structural domains alone or their combinations was capable of functioning in transcription inhibition. By using random, transposon-mediated mutagenesis, we generated a library of SINV nsP2 variants having short peptide insertions and selected those that lost the ability to inhibit cellular transcription and cause a cytopathic effect. Insertions abrogating the nuclear functions of the protein were found in the three different functional nsP2 domains. Some of the mutated protein variants retained the enzymatic functions required for replication of the viral genome. Such viruses were capable of efficient, productive replication in cells defective in interferon (IFN) signaling but were attenuated and incapable of spreading in cells with an intact type I IFN response. These results revealed new information about the structure of SINV nsP2 and interaction of its domains.
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CRIVEI, Luciana Alexandra, Sara MOUTAILLER, Gaëlle GONZALEZ, Steeve LOWENSKI, Ioana Cristina CRIVEI, Daniela POREA, Dragoș Constantin ANITA, et al. "Detection of West Nile Virus Lineage 2 in Eastern Romania and First Identification of Sindbis Virus RNA in Mosquitoes Analyzed using High-Throughput Microfluidic Real-Time PCR." Viruses 15, no. 1 (January 9, 2023): 186. http://dx.doi.org/10.3390/v15010186.
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The impact of mosquito-borne diseases on human and veterinary health is being exacerbated by rapid environmental changes caused mainly by changing climatic patterns and globalization. To gain insight into mosquito-borne virus circulation from two counties in eastern and southeastern Romania, we have used a combination of sampling methods in natural, urban and peri-urban sites. The presence of 37 mosquito-borne viruses in 16,827 pooled mosquitoes was analyzed using a high-throughput microfluidic real-time PCR assay. West Nile virus (WNV) was detected in 10/365 pools of Culex pipiens (n = 8), Culex modestus (n = 1) and Aedes vexans (n = 1) from both studied counties. We also report the first molecular detection of Sindbis virus (SINV) RNA in the country in one pool of Culex modestus. WNV infection was confirmed by real-time RT-PCR (10/10) and virus isolation on Vero or C6/36 cells (four samples). For the SINV-positive pool, no cytopathic effectwas observed after infection of Vero or C6/36 cells, but no amplification was obtained in conventional SINV RT-PCR. Phylogenetic analysis of WNV partial NS5 sequences revealed that WNV lineage 2 of theCentral-Southeast European clade, has a wider circulation in Romania than previously known.
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Polanía Melo, David, Andrés Hernández Bravo, Juan C. Cruz, and Luis H. Reyes. "Invertase Immobilization on Magnetite Nanoparticles for Efficient Fructooligosaccharide Generation: A Comprehensive Kinetic Analysis and Reactor Design Strategy." ChemEngineering 7, no. 3 (June 12, 2023): 55. http://dx.doi.org/10.3390/chemengineering7030055.
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This study investigated the effectiveness of immobilizing Saccharomyces cerevisiae invertase (SInv) on magnetite nanoparticles to produce fructooligosaccharides (FOSs). Based on the existing literature and accompanied by parameter estimation, a modified kinetic model was employed to represent the kinetics of sucrose hydrolysis and transfructosylation using SInv immobilized on magnetite nanoparticle surfaces. This model was utilized to simulate the performance of batch reactors for both free and immobilized enzymes. The maximum FOS concentration for the free enzyme was determined to be 123.1 mM, while the immobilized case achieved a slightly higher concentration of 125.4 mM. Furthermore, a continuous stirred-tank reactor (CSTR) model was developed for the immobilized enzyme, resulting in a maximum FOS concentration of 73.96 mM at the reactor’s outlet and a dilution rate of 14.2 h−1. To examine the impact of glucose inhibition on FOS production, a glucose oxidase reaction mechanism was integrated into the fitted immobilized theoretical model. In a batch reactor, the reduction or elimination of glucose in the reactive media led to a 2.1% increase in FOS production. Immobilizing the biocatalyst enhanced the overall performance of SInv. This enzyme immobilization approach also holds the potential for coupling glucose oxidase onto functionalized nanoparticles to minimize glucose inhibition, thereby improving FOS synthesis and facilitating optimal enzyme recovery and reuse.
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Lücke, Arlen-Celina, Anja vom Hemdt, Janett Wieseler, Carlo Fischer, Marie Feldmann, Simon Rothenfusser, Jan Felix Drexler, and Beate Mareike Kümmerer. "High-Throughput Platform for Detection of Neutralizing Antibodies Using Flavivirus Reporter Replicon Particles." Viruses 14, no. 2 (February 8, 2022): 346. http://dx.doi.org/10.3390/v14020346.
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Flavivirus outbreaks require fast and reliable diagnostics that can be easily adapted to newly emerging and re-emerging flaviviruses. Due to the serological cross-reactivity among flavivirus antibodies, neutralization tests (NT) are considered the gold standard for sero-diagnostics. Here, we first established wild-type single-round infectious virus replicon particles (VRPs) by packaging a yellow fever virus (YFV) replicon expressing Gaussia luciferase (Gluc) with YFV structural proteins in trans using a double subgenomic Sindbis virus (SINV) replicon. The latter expressed the YFV envelope proteins prME via the first SINV subgenomic promoter and the capsid protein via a second subgenomic SINV promoter. VRPs were produced upon co-electroporation of replicon and packaging RNA. Introduction of single restriction enzyme sites in the packaging construct flanking the prME sequence easily allowed to exchange the prME moiety resulting in chimeric VRPs that have the surface proteins of other flaviviruses including dengue virus 1–-4, Zika virus, West Nile virus, and tick-borne encephalitis virus. Besides comparing the YF-VRP based NT assay to a YF reporter virus NT assay, we analyzed the neutralization efficiencies of different human anti-flavivirus sera or a monoclonal antibody against all established VRPs. The assays were performed in a 96-well high-throughput format setting with Gluc as readout in comparison to classical plaque reduction NTs indicating that the VRP-based NT assays are suitable for high-throughput analyses of neutralizing flavivirus antibodies.
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STORM, N., J. WEYER, W. MARKOTTER, A. KEMP, P. A. LEMAN, V. DERMAUX-MSIMANG, L. H. NEL, and J. T. PAWESKA. "Human cases of Sindbis fever in South Africa, 2006–2010." Epidemiology and Infection 142, no. 2 (April 24, 2013): 234–38. http://dx.doi.org/10.1017/s0950268813000964.
Full textAbstract:
SUMMARYSindbis virus (SINV), the prototype positive-sense RNA alphavirus, causes febrile arthritis and is present throughout Afro-Eurasia. Little is known of the epidemiology of Sindbis fever due to insufficient surveillance in most endemic countries. The epidemiological features of Sindbis fever in humans in South Africa are described here based on a retrospective study of suspected arbovirus cases submitted for laboratory investigation from 2006 to 2010. Cases were detected annually mostly during the late summer/early autumn months and an increase in cases was noted for 2010, coinciding with an outbreak of Rift Valley fever. Cases were reported most often from the central plateau of South Africa and involved mostly males. No severe or fatal cases were reported and cases were associated with febrile arthralgia as commonly reported for SINV infection. Further surveillance is required to reveal the true extent of the morbidity of Sindbis fever in South Africa.
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Jefferson, Matthew, Benjamin Bone, Jasmine L. Buck, and Penny P. Powell. "The Autophagy Protein ATG16L1 Is Required for Sindbis Virus-Induced eIF2α Phosphorylation and Stress Granule Formation." Viruses 12, no. 1 (December 29, 2019): 39. http://dx.doi.org/10.3390/v12010039.
Full textAbstract:
Sindbis virus (SINV) infection induces eIF2α phosphorylation, which leads to stress granule (SG) assembly. SINV infection also stimulates autophagy, which has an important role in controlling the innate immune response. The importance of autophagy to virus-induced translation arrest is not well understood. In this study, we show that the autophagy protein ATG16L1 not only regulates eIF2α phosphorylation and the translation of viral and antiviral proteins, but also controls SG assembly. Early in infection (2hpi), capsids were recruited by host factors Cytotoxic Granule-Associated RNA Binding Protein (TIA1), Y-box binding protein 1 (YBX1), and vasolin-containing protein 1 (VCP), to a single perinuclear body, which co-localized with the viral pattern recognition sensors, double stranded RNA-activated protein-kinase R (PKR) and RIG-I. By 6hpi, there was increased eIF2α phosphorylation and viral protein synthesis. However, in cells lacking the autophagy protein ATG16L1, SG assembly was inhibited and capsid remained in numerous small foci in the cytoplasm containing YBX1, TIA1 with RIG-I, and these persisted for over 8hpi. In the absence of ATG16L1, there was little phosphorylation of eIF2α and low levels of viral protein synthesis. Compared to wild type cells, there was potentiated interferon protein and interferon-stimulated gene (ISG) mRNA expression. These results show that ATG16L1 is required for maximum eIF2α phosphorylation, proper SG assembly into a single perinuclear focus, and for attenuating the innate immune response. Therefore, this study shows that, in the case of SINV, ATG16L1 is pro-viral, required for SG assembly and virus replication.
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Ahearn, Yani P., Jason J. Saredy, and Doria F. Bowers. "The Alphavirus Sindbis Infects Enteroendocrine Cells in the Midgut of Aedes aegypti." Viruses 12, no. 8 (August 4, 2020): 848. http://dx.doi.org/10.3390/v12080848.
Full textAbstract:
Transit of the arthropod-borne-virus (arbovirus) Sindbis (SINV) throughout adult female mosquitoes initiates with its attachment to the gut lumen, entry and amplification in midgut cells, followed by dissemination into the hemolymph. Free-mated adult females, aged day 5–7, were proffered a viremic blood suspension via sausage casings containing SINV-TaV-Green Fluorescent Protein (GFP) at a final titer of 106 PFU/mL. Midguts (MGs) from fully engorged mosquitoes were resected on days 5 and 7 post-bloodmeal, and immunolabeled using FMRFamide antibody against enteroendocrine cells (ECs) with a TX-Red secondary antibody. Following immunolabeling, the organs were investigated via laser confocal microscopy to identify the distribution of GFP and TX-Red. Infection using this reporter virus was observed as multiple GFP expression foci along the posterior midgut (PMG) epithelium and ECs were observed as TX-Red labeled cells scattered along the entire length of the MG. Our results demonstrated that SINVGFP did infect ECs, as indicated by the overlapping GFP and TX-Red channels shown as yellow in merged images. We propose that ECs may be involved in the SINV infection pathway in the mosquito MG. Due to the unique role that ECs have in the exocytosis of secretory granules from the MG and the apical-basolateral position of ECs in the PMG monolayer, we speculate that these cells may assist as a mechanism for arboviruses to cross the gut barriers. These findings suggest that MG ECs are involved in arbovirus infection of the invertebrate host.