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At least 19 recordsLinked to original sources
PubMed1979

Cross-reactive cytotoxic T cells to alphavirus infection.

Secondary Tc cells immune to alphaviruses (BEB, SIN and SFV) cross-react between serologically defined subgroups at the level of target lysis and at the level of induction of response. Despite this apparently complete Tc cell cross-reactivity between BEB, SIN and SFV, antisera raised against BEB and SIN showed virus specificity in their ability to block Tc cell-mediated lysis of alphavirus-infected targets. This result suggests that Tc cells recognize the same viral antigen molecule as antibodies, but with less specificity. Other possible interpretations are discussed.

Animals↗
PubMed2026

Quantitative Fluorescence Imaging of Alphavirus Infection for Antiviral Screenings.

Fluorescence microscopy offers a highly sensitive and versatile approach for investigating alphavirus infection at the cellular level. By combining fluorescently labeled viruses with quantitative image analysis, this method enables detailed spatial and temporal characterization of infection dynamics, including the detection of subtle differences in replication kinetics and cell-to-cell spread. A central aim of this protocol is its application in antiviral screening assays. Image-based quantification of fluorescence intensity provides a robust and reproducible means to assess the efficacy of antiviral compounds, allowing early and sensitive detection of inhibitory effects in infected cells. This facilitates the identification of promising antiviral hits and supports the evaluation of dose-dependent responses. The approach is also well-suited for comparative studies of different alphavirus strains or mutants, as variations in replication behavior and dissemination patterns become readily apparent. Its flexibility, compatibility with multiple cell lines, and straightforward integration into automated imaging platforms makes the method scalable and suitable for high-throughput screening campaigns. Overall, this protocol advances the discovery and evaluation of antiviral strategies. Given that several alphaviruses cause significant human and veterinary diseases, lack approved antiviral therapies, and continue to expand geographically with emerging outbreaks, the identification of novel antivirals remains an urgent priority. Therefore, this fluorescence-based workflow represents a valuable and timely contribution to modern alphavirus research.

Antiviral Agents↗
PubMed1979

H-2-linked control of cytotoxic T-cell responsiveness to alphavirus infection. Presence of H-2Dk during differentiation and stimulation converts stem cells of low responder genotype to T cells of responder phenotype.

Secondary Tc cells generated against Sindbis virus (SIN) are restricted to Dk. All other H-2K or D regions tested show low specific responsiveness. F1 hybrids between low and high responders show dominance of responsiveness but lack complementation. When BALB/c (KdIdDd) low responder fetal liver stem cells were allowed to mature in irradiated high responder recipients C3H.OH (KdIdDk) a response to Dk plus SIN could be generated with Tc cells of BALB/c origin. This result, together with the failure of complementation in the F1 hybrids, implies that the lesion of low responsiveness is in the inability of viral antigen to stimulate a Tc-cell response in association with any self H-2K or H-2D molecule (of those tested) other than H-2Dk. Hypotheses compatible with these data are discussed.

Animals↗
PubMed1975

Defective particles in alphavirus infections.

This article summarizes our studies with defective-interfering particles of Sindbis virus obtained by high multiplicity passaging of the virus in BHK cells. Cells infected with these defective passages accumulate a species of RNA (20S) at the expense of 26S RNA--the mRNA coding for the viral structural proteins. Although the structure of the RNA in defective particles remains undefined, our studies of replicative forms and replicative intermediates suggest that it is larger than the intracellular 20S RNA. The defective particles are unable to synthesize detectable amounts of viral structural proteins when they infect a cell in the absence of standard virus and they do not contribute to the stimulation of intracellular viral RNA synthesis. We have proposed a model for the mechanism of interference by these defective particles in which standard and defective RNAs compete for a limited amount of viral-specific replicase.

Cell Line↗
PubMed2026

Rasputin/G3BP mediates subversion of antiviral immunity by o'nyong-nyong virus in Anopheles coluzzii.

Cellular G3BP proteins are essential for alphavirus infection in both vertebrate and mosquito hosts, but the underlying mechanism of their proviral activity is poorly understood in any host. Whether the mosquito G3BP ortholog, Rasputin (Rin), interacts with host immunity to influence alphavirus infection has not been investigated, and anopheline mosquito interactions with arboviruses have been little studied. Here, we find that Rin silencing in Anopheles mosquitoes results in decreased ONNV infection levels, indicating a proviral activity for Anopheles Rin. We find that Rin function is required to maintain basal activity of the antiviral Imd and JAK/STAT pathways in uninfected mosquitoes. However, during ONNV infection, the control of the Imd pathway by Rin activity appears corrupted because Rin silencing leads to overexpression of the Imd positive regulator, Rel2. Thus, silencing of Rin both augments Rel2 transcript abundance and decreases ONNV load. Co-silencing of Rel2 with Rin restores normal ONNV infection levels, indicating that Rin activity is required to inhibit Imd function during ONNV infection, and which explains most of the Rin proviral phenotype. In addition, we show that the ONNV non-structural protein 3 (nsP3), which binds to Rin, strongly alters the pattern of Anopheles cellular protein partners interacting with Rin. In the presence of ONNV nsP3, 48 Rin-binding host proteins are unchanged but seven binding proteins are excluded and eight new cellular proteins bind Rin. The altered cellular protein partners are candidate host factors involved in viral subversion of Rin control over Imd activity. Overall, these results reveal a molecular mechanism in which ONNV, probably through nsP3, co-opts the normal Rin function for basal cellular immune activity by subverting the Imd antiviral pathway to promote infection. These results may be generalizable for Rin function during alphavirus infection of other mosquitoes, as well as for G3BP function in the mammalian host, and could offer a target for development of vector-based genetic control tools against arbovirus transmission.

Animals↗
PubMed1979

Heterologous interference in Aedes albopictus cells infected with alphaviruses.

Maximum amounts of 42S and 26S single-stranded viral RNA and viral structural proteins were synthesized in Aedes albopictus cells at 24 h after Sindbis virus infection. Thereafter, viral RNA and protein syntheses were inhibited. By 3 days postinfection, only small quantities of 42S RNA and no detectable 26S RNA or structural proteins were synthesized in infected cells. Superinfection of A. albopictus cells 3 days after Sindbis virus infection with Sindbis, Semliki Forest, Una, or Chikungunya alphavirus did not lead to the synthesis of intracellular 26S viral RNA. In contrast, infection with snowshoe hare virus, a bunyavirus, induced the synthesis of snowshoe hare virus RNA in both A. Ablpictus cells 3 days after Sindbis virus infection and previously uninfected mosquito cells. These results suggested that at 3 days after infection with Sindbis virus, mosquito cells restricted the replication of both homologous and heterologous alphaviruses but remained susceptible to infection with a bunyavirus. In superinfection experiments the the alphaviruses were differentiated on the basis of plaque morphology and the electrophoretic mobility of their intracellular 26S viral RNA species. Thus, it was shown that within 1 h after infection with eigher Sindbis or Chikungunya virus, A. albopictus cells were resistant to superinfection with Sindbis, Chikungunya, Una, and Semliki Forest viruses. Infected cultures were resistant to superinfection with the homologous virus indefinitely, but maximum resistance to superinfection with heterologous alphaviruses lasted for approximately 8 days. After that time, infected cultures supported the replication of heterologous alphaviruses to the same extent as did persistently infected cultures established months previously. However, the titer of heterologous alphavirus produced after superinfection of persistently infected cultures was 10- to 50-fold less than that produced by an equal number of previously uninfected A. albopictus cells. Only a small proportion (8 to 10%) of the cells in a persistently infected culture was capable of supporting the replication of a heterologous alphavirus.

Aedes↗
PubMed1975

The distribution and prevalence of group A arbovirus neutralizing antibodies among human populations in Southeast Asia and the Pacific islands.

Plaque reduction neutralization tests, using five group A arboviruses (chikungunya, Ross River, Getah, Bebaru and Sindbis), were done on sera from human populations in 44 Southeast Asia and Pacific island localities. Specificity of the plaque neutralization test was determined by examining convalescent sera from patients with known alphavirus infections. Chikungunya-specific neutralizing antibodies were demonstrated in sera of persons living in South Vietnam, Northern Malaysia, Indonesia (Kalimantan and Sulawesi), as well as Luzon, Marinduque, Cebu and Mindanao islands in the Philippines. Evidence of Ross River virus infection was found among populations living in West New Guinea and Papua New Guinea mainland, the Bismark Archipelago, Rossel Island and the Solomon Islands. There appeared to be no geographic overlap in the distribution of chikungunya and Ross River viruses, with the separation in their distribution corresponding with Weber's line in the Pacific. Sindbis neutralizing antibodies were found in 7 of 21 populations sampled, but in general the prevalence of infection was low. Four sera, from Vietnam, Malaysia and Mindanao gave monospecific reactions with Getah virus. No evidence of specific Bebaru virus infection was detected. The epidemiology of these five alphaviruses in Southeast Asia and the Pacific islands is discussed.

Adolescent↗
PubMed1978

Necrotizing myocarditis in mice infected with Western equine encephalitis virus: Clinical, electrocardiographic, and histopathologic correlations.

Western equine encephalitis (WEE) virus was found in myocardial tissue of adult mice during the first five days after inoculation of the virus, with a peak titer (5.0 log plaque-forming units/g) at 24 hr. Light microscopy revealed a multifocal necrotizing myocarditis with a prominent inflammatory response and hyaline and granular degeneration of myofibers. Electron microscopy showed cytoplasmic viral nucleoids and budding and free mature WEE viral particles. Serial electrocardiograms showed the development of disturbances of rate and rhythm, defects in conduction, marked elevation in the ST segment, and low voltage. Myocarditis has not been previously recognized as a complication of alphavirus infection in humans. and we found no evidence for myocardial damage in 11 persons with acute WEE virus infections studied electrocardiographically in 1975. Demonstration of myocarditis in the WEE virus-infected mouse, however, suggests the need to monitor human patients for possible cardiac involvement during future epidemics of WEE virus infection.

Animals↗
PubMed1975

Processing of alphavirus-specific proteins in infected cells.

The RNA of the alphaviruses contains the genetic information for both the non-structural and the structural polypeptides. The former are contained in the initial two-thirds of the sequence (from the 5'-terminus) and are read directly from the virus particle RNA, but whether post-translational cleavage is involved or not is not known. The genes for the structural polypeptides are in the final one-third of the genome, and are probably not read directly but are transcribed selectively to produce a sub-genomic messenger RNA with only one initiation site. Translation produces the structural pooypeptides and post-translation cleavage does occur. However, the rate at which cleavage occurs is variable--cleavage to release the core polypeptide occurs while the nascent polypeptide is still attached to the ribosome, while cleavage to form two of the virus envelope glycoproteins occurs as the virus buds from the cell. The cleavage mechanism which leads to release of the core polypeptide also takes place in vitro and may be catalysed by the structural polypeptide itself.

Arboviruses↗
PubMed2026

Ross River virus transmission, infection, and disease: two and a half decades of research progress-an updated cross-disciplinary review.

SUMMARYRoss River virus (RRV) causes the most mosquito-borne disease notifications in Australia and a considerable burden of non-fatal, yet frequently prolonged rheumatic illness across the Australia-Pacific region, reflected in thousands of notifications each year and notable economic and quality-of-life losses. Research on RRV spans multiple disciplines, encompassing viral genomics, immunopathology, transmission ecology, epidemiology, entomology, and environmental science. This review synthesizes two decades of cross-disciplinary investigations to present an integrated perspective on the biological, clinical, ecological, and environmental dimensions of RRV infection. By consolidating findings from diverse fields, the review enhances understanding of the complex factors influencing RRV transmission and disease outcomes throughout its endemic range.

Humans↗
PubMed2025

Proximity interactome of alphavirus replicase component nsP3 includes proviral host factors eIF4G and AHNAK.

All positive-strand RNA viruses replicate their genomes in association with modified intracellular membranes, inducing either membrane invaginations termed spherules, or double-membrane vesicles. Alphaviruses encode four non-structural proteins nsP1-nsP4, all of which are essential for RNA replication and spherule formation. To understand the host factors associated with the replication complex, we fused the efficient biotin ligase miniTurbo with Semliki Forest virus (SFV) nsP3, which is located on the cytoplasmic surface of the spherules. We characterized the proximal proteome of nsP3 in three cell lines, including cells unable to form stress granules, and identified >300 host proteins constituting the microenvironment of nsP3. These included all the nsPs, as well as several previously characterized nsP3 binding proteins. However, the majority of the identified interactors had no previously identified roles in alphavirus replication, including 39 of the top 50 interacting proteins. The most prominent biological processes involving the proximal proteins were nucleic acid metabolism, translational regulation, cytoskeletal rearrangement and membrane remodeling. siRNA silencing confirmed six novel proviral factors, USP10, AHNAK, eIF4G1, SH3GL1, XAB2 and ANKRD17, which are associated with distinct cellular functions. All of these except SH3GL1 were also important for the replication of chikungunya virus. We discovered that the small molecule 4E1RCat, which inhibits the interaction between the canonical translation initiation factors eIF4G and eIF4E, exhibits antiviral activity against SFV. Since the same molecule was previously found to inhibit coronaviruses, this suggest the possibility that translation initiation factors could be considered as targets for broadly acting antivirals.

Viral Nonstructural Proteins↗
PubMed1977

[Interrelationship of alphavirus-Venezuelan equine encephalomyelitis virus reproduction and oncornavirus type D production with the metabolism of the infected cells].

A comparative study of the reproduction of an alphavirus. Venezuelan equine encephalomyelitis virus (VEE), in chick embryo fibroblasts (CEF) and oncornavirus type D (OV-D) produced spontaneously by human continuous cells (HEp-2) was carried out. The differential index of reproduction of both viruses was the yield of RNA-containing virus structures released from the cells. For VEE this index increased in the course of infection 100-150-fold. For OV-D the index changed little during long-term cultivation of the cells and was only 0.2%--1%. The effect of inhibitors, ethidium bromide and cycloheximide, on the RNA synthesis and production of virus structures was studied. Ethidium bromide was shown to inhibit reproduction of both the viruses considerably, whereas the effect of cyclohemimide on them was dissimilar: its effect on VEE virus depended on the time of its addition, while OV-D virus production did not depend on the time of its addition and was even stimulated in the presence of cycloheximide.

Animals↗
PubMed2026

Cell type-dependent induction of type I interferon and PARP1 activation in astrocytes and neurons during chikungunya virus infection.

Chikungunya virus, a mosquito-borne alphavirus, causes fever, rash, arthritis, and neurological disorders. Its non-structural protein 3 harbors a macrodomain, a key neurovirulence factor that removes adenosine diphosphate ribose from ADP-ribosylated substrates. Notably, chikungunya virus infection results in distinct ADP-ribosylation patterns and non-structural protein 3 macrodomain-mediated replication dynamics in astrocytes and neurons. Understanding the connection between ADP-ribosylation and the activation of innate immunity, particularly interferon release, is key to elucidating how the cellular immunological state influences ADP-ribosylation, an understudied post-translational modification during viral infection. Here, murine astrocytic (C8-D1A) and neuronal (NSC-34) cells were infected with chikungunya virus to profile transcript and protein expression of innate immune mediators and type I IFNs. The role of PARP1 in global ADP-ribosylation patterns was assessed using PARP-specific inhibitors and genetic depletion approaches. Our investigations revealed that neuronal chikungunya virus infection induces ADP-ribosylation through PARP1 activation, driven by caspase-3-mediated apoptosis, without transcriptionally activating PARPs. In contrast, astrocytic infections showed minimal ADP-ribosylation despite transcriptional activation of interferon-stimulated PARPs. Neurons exhibited limited innate immune response gene transcriptional activity, whereas astrocytes demonstrated strong upregulation of genes essential for pattern recognition receptor activation, thus enhancing double-stranded RNA sensing and increasing type I interferon production during infection. We posit that PARP1 activation and type I IFN response differentially regulate ADP-ribosylation in chikungunya virus-infected neural cells in a cell type-dependent manner.IMPORTANCEChikungunya virus is an emergent mosquito-borne alphavirus increasingly associated with neurological infection and subsequent long-term disabilities. Its continued global spread and recurrent outbreaks underscore its significant pandemic potential and the urgent need for effective countermeasures. Chikungunya virus showcases distinct, cell-type dependent replication dynamics within astrocytes and neurons, two major permissive cerebral cell types. However, understanding of the immunological basis of such cell type-specific infection dynamics remains limited, yet is necessary to elucidate virus pathogenesis within the brain and thus identification of downstream drug targets. Our study characterized two distinctly activated innate immunological pathways in chikungunya virus-infected astrocytes versus neurons, thus significantly contributing to molecular understanding cell type-specific chikungunya virus neurovirulence on a molecular level.

Animals↗
PubMedDate not supplied

Arboviruses as aetiological agents of encephalitis in the People's Republic of China.

A serological study was undertaken to determine the role of arboviruses as etiological agents of encephalitis in the People's Republic of China (PRC). Paired sera were collected during mosquito seasons in 1988-1990 from 614 patients with possible viral encephalitis in 15 regions of PRC and tested for haemagglutination inhibiting antibodies to selected arboviruses. Seroconversions were documented to alphavirus and flavivirus antigens in 13.0 and 18.7% of patients respectively in most of the study areas. No California group seroconversion was detected. The age of alphavirus seroconvertors ranged from 2 months to 32 years and of flavivirus seroconvertors from 6 months to 50 years, with higher numbers in males. Serious central nervous system manifestations were seen more commonly in flavivirus seroconvertors. This study affirms the importance of flavivirus as causative agents of encephalitis in PRC and provides evidence that one or more alphaviruses are causing symptomatic infections with neurological involvement in PRC.

Adolescent↗
PubMed1992

Identification of a sequence element in the alphavirus core protein which mediates interaction of cores with ribosomes and the disassembly of cores.

Early in infection core protein is transferred from alphavirus cores to ribosomes (Wengler and Wengler, 1984, Virology 134, 435-442) and it has been suggested that ribosome binding is a property of alphavirus core protein which is involved in core disassembly. Here we describe in vitro analyses of this transfer. Sindbis virus cores, incubated with ribosomes either in a reticulocyte lysate or in buffer, are disassembled with a concomitant transfer of core protein to the large ribosomal subunit. Preincubation of ribosomes with core protein blocks disassembly. Limited proteolysis of Sindbis virus core releases the carboxy-terminal core protein domain as a soluble fragment (Strong and Harrison, 1990, J. Virol. 64, 3992-3994). Trypsin- or proteinase Lys-C-released fragments contain the amino-terminal residue met (106) or gln (94), respectively. The fragment generated by proteinase Lys-C binds to ribosomes and interferes with core disassembly whereas the slightly shorter tryptic fragment has none of these activities. These and further analyses indicate that a conserved sequence element which surrounds amino acid met (106) of SIN CP, the so-called RBSc element, leads to binding of core protein to ribosomes and thereby to core disassembly. Implications of the experiments for regulation of assembly of alphavirus cores and for the core protein-induced resistance to viral multiplication observed in plant virus systems are discussed.

Alphavirus↗
PubMedDate not supplied

[Accelerated method of determining the antiviral activity of interferon inducers in experimental infection].

By the example of trials of two typical interferon inducers: a double-stranded complex of synthetic polyribonucleotides poly (I).poly (C) and polyacrylic acid the use of the proposed rapid method for the determination of the antiviral activity of interferon inducers in an experimental infection of mice with an alphavirus is described. The method permits to perform a statistically treated evaluation of the antiviral effect of a group of preparations within 96 hours. The mean standard error of the method is +/- 0,333 1g PFU per 1 ml of 10% brain suspension.

Acrylates↗
PubMed2026

Development of a Real-Time Reverse Transcription Polymerase Chain Reaction Assay for Una Virus.

Una virus (UNAV) is an understudied alphavirus with the capacity to infect humans. Although it was discovered decades ago in South America, little is still known about this virus because accurate diagnostic tests are still needed. The first UNAV-specific real-time reverse transcription polymerase chain reaction (rRT-PCR) test is described in the present study. This assay targets the nonstructural protein 1 coding region and was designed from an alignment using all available UNAV sequences. The linear range of the UNAV rRT-PCR extended from 6.2 to 0.2 log10 copies/µL, with a lower limit of 95% detection of 2.0 copies/µL. The assay offered sensitive UNAV detection in contrived whole-blood samples. In addition, no amplification was observed in the assay when tested with genomic RNA from multiple closely related arboviruses. The UNAV rRT-PCR exhibits high sensitivity and specificity, which is critical for research into this virus in regions where multiple related alphaviruses co-circulate.

Journal Article↗