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The American Journal of Tropical... Jun 2024Mayaro virus (MAYV) is an alphavirus endemic in many parts of Central and South America transmitted to humans by Aedes aegypti. Currently, there is no vaccine or...
Mayaro virus (MAYV) is an alphavirus endemic in many parts of Central and South America transmitted to humans by Aedes aegypti. Currently, there is no vaccine or treatment of Mayaro infection, and therefore it is essential to control transmission by reducing populations of Ae. aegypti. Unfortunately, Ae. aegypti are extremely difficult to control with traditional integrated vector management (IVM) because of factors such as growing resistance to a dwindling list of registered insecticides and cryptic immature and adult habitats. The sterile insect technique (SIT) by irradiation is gaining traction as a novel supplemental tool to IVM. The SIT is being used operationally to release large numbers of sterilized colony-reared male mosquitoes in an intervention area to overwhelm females in the natural population, eventually causing population decline because of high frequencies of unfertilized eggs. However, little is known about the effect of irradiation on vector competence for mosquito-borne viruses such as MAYV in females that may be accidentally reared, irradiated, and released alongside males. In this investigation, we exposed female Ae. aegypti pupae to radiation and evaluated vector competence after inoculation with MAYV. Infection and dissemination rates of irradiated (10 and 40 Gy) Ae. aegypti were higher than those of non-irradiated cohorts at 7 and 14 days after infection. Although these results indicate a need to maintain effective sex sorting prior to irradiation and release of Ae. aegypti, our results are consistent with several previous observations that vectorial capacity and vector competence are likely lower in irradiated than in nonirradiated females.
PubMed: 38917780
DOI: 10.4269/ajtmh.23-0515 -
Emerging Infectious Diseases Jul 2024We conducted a cross-sectional serosurvey for chikungunya virus (CHIKV) exposure in fruit bats in Senegal during 2020-2023. We found that 13.3% (89/671) of bats had...
We conducted a cross-sectional serosurvey for chikungunya virus (CHIKV) exposure in fruit bats in Senegal during 2020-2023. We found that 13.3% (89/671) of bats had CHIKV IgG; highest prevalence was in Eidolon helvum (18.3%, 15/82) and Epomophorus gambianus (13.7%, 63/461) bats. Our results suggest these bats are naturally exposed to CHIKV.
Topics: Animals; Chiroptera; Senegal; Chikungunya virus; Chikungunya Fever; Seroepidemiologic Studies; Antibodies, Viral; Cross-Sectional Studies
PubMed: 38916865
DOI: 10.3201/eid3007.240055 -
BioRxiv : the Preprint Server For... Jun 2024Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034...
Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 ( ) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad spectrum antiviral activity. Analogs of that varied each of three regions of the molecule were synthesized to establish structure-activity relationships for inhibition of (CHIKV) nsP2 protease and viral replication. The covalent warhead was highly sensitive to modifications of the sulfone or vinyl substituents. However, numerous alterations to the core 5-membered heterocycle and its aryl substituent were well tolerated and several analogs were identified that enhanced CHIKV nsP2 binding. For example, the 4-cyanopyrazole analog exhibited a / ratio >10,000 M s . 3-Arylisoxazole was identified an isosteric replacement for the 5-membered heterocycle, which circumvented the intramolecular cyclization that complicated the synthesis of pyrazole-based inhibitors like . The accumulated structure-activity data was used to build a ligand-based model of the enzyme active site, which can be used to guide the design of covalent nsP2 protease inhibitors as potential therapeutics against alphaviruses.
PubMed: 38915519
DOI: 10.1101/2024.06.12.598722 -
Current Microbiology Jun 2024Chikungunya virus (CHIKV) is a causative agent of a disease continuum, ranging from an acute transient chikungunya fever to chronic incapacitating viral arthralgia. The...
Chikungunya virus (CHIKV) is a causative agent of a disease continuum, ranging from an acute transient chikungunya fever to chronic incapacitating viral arthralgia. The interaction between anti-CHIKV antibodies and the complement system has recently received attention. However, the contribution of complement activation in CHIKV-induced pathologies has not been fully elucidated. The present study was undertaken to delineate the possible contribution of complement activation in CHIKV-induced disease progression. In this study, using plasma specimens of chikungunya patients in the acute, chronic, and recovered phases of infection, we explicated the involvement of complement activation in CHIKV disease progression by ELISAs and Bio-Plex assays. Correlation analysis was carried out to demonstrate interrelation among C1q-binding IgG-containing circulating immune complexes (CIC-C1q), complement activation fragments (C3a, C5a, sC5b-9), and complement-modulated pro-inflammatory cytokines (IL-1β, IL-18, IL-6, and TNF-α). We detected elevated complement activation fragments, CIC-C1q, and complement-modulated cytokines in the varied patient groups compared with the healthy controls, indicating persistent activation of the complement system. Furthermore, we observed statistically significant correlations among CIC-C1q with complement activation fragments and C3a with complement modulatory cytokines IL-1β, IL-6, and IL-18 during the CHIKV disease progression. Taken together, the current data provide insight into the plausible association between CICs, complement activation, subsequent complement modulatory cytokine expression, and CHIKV etiopathology.
Topics: Humans; Complement C1q; Chikungunya Fever; Complement Activation; Antigen-Antibody Complex; Chikungunya virus; Male; Cytokines; Middle Aged; Adult; Female; Antibodies, Viral; Aged; Young Adult
PubMed: 38913141
DOI: 10.1007/s00284-024-03732-7 -
Virulence Dec 2024Viral diseases are among the main threats to public health. Understanding the factors affecting viral invasion is important for antiviral research. Until now, it was...
Viral diseases are among the main threats to public health. Understanding the factors affecting viral invasion is important for antiviral research. Until now, it was known that most viruses have very low plaque-forming unit (PFU)-to-particle ratios. However, further investigation is required to determine the underlying factors. Here, using quantitative single-particle analysis methods, the invasion of Semliki Forest virus (SFV), Japanese encephalitis virus (JEV), and influenza A virus (IAV) containing attachment to the cell surface, entry into the cell, transport towards the cell interior, and fusion with endosomes to release nucleocapsids were quantitatively analysed in parallel. It was found that for SFV with an PFU-to-particle ratio of approximately 1:2, an entry efficiency of approximately 31% limited infection. For JEV, whose PFU-to-particle ratio was approximately 1:310, an attachment efficiency of approximately 27% and an entry efficiency of 10% were the main factors limiting its infection. Meanwhile, for IAV with PFU-to-particle ratios of 1:8100, 5% attachment efficiency, 9% entry efficiency, and 53% fusion efficiency significantly limited its infection. These results suggest that viruses with different infectivities have different limited steps in the invasion process. Moreover, there are significant differences in attachment efficiencies among viruses, emphasizing the pivotal role of attachment in viral invasion. The influence of the virus purification method on virus invasion was also investigated. This study, for the first time, reports the efficiencies of different stages of virus invasion, leading to a better understanding of virus invasion and providing a protocol to quantitatively analyse the virus invasion efficiency.
Topics: Virus Internalization; Influenza A virus; Animals; Semliki forest virus; Humans; Encephalitis Virus, Japanese; Cell Line; Virus Attachment; Endosomes
PubMed: 38910312
DOI: 10.1080/21505594.2024.2367671 -
Polish Journal of Microbiology Jun 2024Chikungunya virus (CHIKV) causes a debilitating fever and joint pain, with no specific antiviral treatment available. Halogenated secondary metabolites from plants are a...
Chikungunya virus (CHIKV) causes a debilitating fever and joint pain, with no specific antiviral treatment available. Halogenated secondary metabolites from plants are a promising new class of drug candidates against chikungunya, with unique properties that make them effective against the virus. Plants produce these compounds to defend themselves against pests and pathogens, and they are effective against a wide range of viruses, including chikungunya. This study investigated the interactions of halogenated secondary metabolites with nsP2pro, a therapeutic target for CHIKV. A library of sixty-six halogenated plant metabolites screened previously for ADME properties was used. Metabolites without violation of Lipinski's rule were docked with nsP2pro using AutoDock Vina. To find the stability of the pipoxide chlorohydrin-nsP2pro complex, the GROMACS suite was used for MD simulation. The binding free energy of the ligand-protein complex was computed using MMPBSA. Molecular docking studies revealed that halogenated metabolites interact with nsP2pro, suggesting they are possible inhibitors. Pipoxide chlorohydrin showed the greatest affinity to the target. This was further confirmed by the MD simulations, surface accessible area, and MMPBSA studies. Pipoxide chlorohydrin, a halogenated metabolite, was the most potent against nsP2pro in the survey.
Topics: Chikungunya virus; Molecular Docking Simulation; Antiviral Agents; Chikungunya Fever; Secondary Metabolism; Molecular Dynamics Simulation; Halogenation; Plants; Computer Simulation; Viral Nonstructural Proteins
PubMed: 38905281
DOI: 10.33073/pjm-2024-020 -
Frontiers in Immunology 2024The mitochondrial anti-viral signaling (MAVS) protein is an intermediary adaptor protein of retinoic acid-inducible gene-1 (RIG-I) like receptor (RLR) signaling, which...
MAVS disruption impairs downstream signaling and results in higher virus replication levels of salmonid alphavirus subtype 3 but not infectious pancreatic necrosis virus .
The mitochondrial anti-viral signaling (MAVS) protein is an intermediary adaptor protein of retinoic acid-inducible gene-1 (RIG-I) like receptor (RLR) signaling, which activates the transcription factor interferon (IFN) regulatory factor 3 (IRF3) and NF-kB to produce type I IFNs. MAVS expression has been reported in different fish species, but few studies have shown its functional role in anti-viral responses to fish viruses. In this study, we used the transcription activator-like effector nuclease (TALEN) as a gene editing tool to disrupt the function of MAVS in Chinook salmon () embryonic cells (CHSE) to understand its role in induction of interferon I responses to infections with the (+) RNA virus salmonid alphavirus subtype 3 (SAV-3), and the dsRNA virus infectious pancreatic necrosis virus (IPNV) infection. A MAVS-disrupted CHSE clone with a 7-aa polypeptide (GVFVSRV) deletion mutation at the N-terminal of the CARD domain infected with SAV-3 resulted in significantly lower expression of IRF3, IFNa, and ISGs and increased viral titer (1.5 log) compared to wild-type. In contrast, the IPNV titer in MAVS-disrupted cells was not different from the wild-type. Furthermore, overexpression of salmon MAVS in MAVS-disrupted CHSE cells rescued the impaired type I IFN-mediated anti-viral effect against SAV-3.
Topics: Animals; Infectious pancreatic necrosis virus; Alphavirus; Virus Replication; Signal Transduction; Adaptor Proteins, Signal Transducing; Fish Diseases; Alphavirus Infections; Salmon; Fish Proteins; Interferon Regulatory Factor-3; Birnaviridae Infections
PubMed: 38903507
DOI: 10.3389/fimmu.2024.1401086 -
Virology Journal Jun 2024Despite dengue virus (DENV) outbreak in Gabon a decade ago, less is known on the potential circulation of DENV serotypes in the country. Previous studies conducted in...
BACKGROUND
Despite dengue virus (DENV) outbreak in Gabon a decade ago, less is known on the potential circulation of DENV serotypes in the country. Previous studies conducted in some areas of the country, are limited to hospital-based surveys which reported the presence of some cases of serotype 2 and 3 seven years ago and more recently the serotype 1. As further investigation, we extend the survey to the community of Moyen Ogooué region with the aim to assess the presence of the dengue virus serotypes, additionally to characterize chikungunya (CHIKV) infection and describe the symptomatology associated with infections.
METHOD
A cross-sectional survey was conducted from April 2020 to March 2021. The study included participants of both sexes and any age one year and above, with fever or history of fever in the past seven days until blood collection. Eligible volunteers were clinically examined, and blood sample was collected for the detection of DENV and CHIKV using RT-qPCR. Positive samples were selected for the target sequencing.
RESULTS
A total of 579 volunteers were included. Their mean age (SD) was 20 (20) years with 55% of them being female. Four cases of DENV infection were diagnosed giving a prevalence of 0.7% (95%CI: 0.2-1.8) in our cohort while no case of CHIKV was detected. The common symptoms and signs presented by the DENV cases included fatigue, arthralgia myalgia, cough, and loss of appetite. DENV-1was the only virus detected by RT-qPCR.
CONCLUSION
Our results confirm the presence of active dengue infection in the region, particularly DENV-1, and could suggest the decline of DENV-2 and DENV-3. Continuous surveillance remains paramount to comprehensively describe the extent of dengue serotypes distribution in the Moyen-Ogooué region of Gabon.
Topics: Humans; Gabon; Dengue Virus; Female; Male; Dengue; Serogroup; Cross-Sectional Studies; Adult; Young Adult; Adolescent; Child, Preschool; Child; Middle Aged; Infant; Chikungunya Fever; Aged; Prevalence; Chikungunya virus
PubMed: 38902719
DOI: 10.1186/s12985-024-02406-x -
Frontiers in Cellular and Infection... 2024Chikungunya virus (CHIKV), which causes chikungunya fever, is an arbovirus of public health concern with no approved antiviral therapies. A significant proportion of...
BACKGROUND
Chikungunya virus (CHIKV), which causes chikungunya fever, is an arbovirus of public health concern with no approved antiviral therapies. A significant proportion of patients develop chronic arthritis after an infection. Zinc and magnesium salts help the immune system respond effectively against viral infections. This study explored the antiviral potential of zinc sulphate, zinc acetate, and magnesium sulphate against CHIKV infection.
METHODS
The highest non-toxic concentration of the salts (100 µM) was used to assess the prophylactic, virucidal, and therapeutic anti-CHIKV activities. Dose-dependent antiviral effects were investigated to find out the 50% inhibitory concentration of the salts. Entry bypass assay was conducted to find out whether the salts affect virus entry or post entry stages. Virus output in all these experiments was estimated using a focus-forming unit assay, real-time RT-PCR, and immunofluorescence assay.
RESULTS
Different time- and temperature-dependent assays revealed the therapeutic antiviral activity of zinc and magnesium salts against CHIKV. A minimum exposure of 4 hours and treatment initiation within 1 to 2 hours of infection are required for inhibition of CHIKV. Entry assays revealed that zinc salt affected virus-entry. Entry bypass assays suggested that both salts affected post-entry stages of CHIKV. In infected C57BL6 mice orally fed with zinc and magnesium salts, a reduction in viral RNA copy number was observed.
CONCLUSION
The study results suggest zinc salts exert anti-CHIKV activity at entry and post entry stages of the virus life cycle, while magnesium salt affect CHIKV at post entry stages. Overall, the study highlights the significant antiviral potential of zinc sulphate, zinc acetate, and magnesium sulphate against CHIKV, which can be exploited in designing potential therapeutic strategies for early treatment of chikungunya patients, thereby reducing the virus-associated persistent arthritis.
Topics: Chikungunya virus; Animals; Antiviral Agents; Chikungunya Fever; Zinc Acetate; Zinc Sulfate; Chlorocebus aethiops; Vero Cells; Virus Internalization; Mice; Zinc; Humans; Magnesium Sulfate; Magnesium; Virus Replication; Inhibitory Concentration 50; Salts; Cell Line
PubMed: 38895735
DOI: 10.3389/fcimb.2024.1335189 -
BioRxiv : the Preprint Server For... Jun 2024Alphaviruses are mosquito borne RNA viruses that are a reemerging public health threat. Alphaviruses have a broad host range, and can cause diverse disease outcomes like...
UNLABELLED
Alphaviruses are mosquito borne RNA viruses that are a reemerging public health threat. Alphaviruses have a broad host range, and can cause diverse disease outcomes like arthritis, and encephalitis. The host ubiquitin proteasome system (UPS) plays critical roles in regulating cellular processes to control the infections with various viruses, including alphaviruses. Previous studies suggest alphaviruses hijack UPS for virus infection, but the molecular mechanisms remain poorly characterized. In addition, whether certain E3 ubiquitin ligases or deubiquitinases act as alphavirus restriction factors remains poorly understood. Here, we employed a cDNA expression screen to identify E3 ubiquitin ligase TRIM32 as a novel intrinsic restriction factor against alphavirus infection, including VEEV-TC83, SINV, and ONNV. Ectopic expression of TRIM32 reduces alphavirus infection, whereas depletion of TRIM32 with CRISPR-Cas9 increases infection. We demonstrate that TRIM32 inhibits alphaviruses through a mechanism that is independent of the TRIM32-STING-IFN axis. Combining reverse genetics and biochemical assays, we found that TRIM32 interferes with genome translation after membrane fusion, prior to replication of the incoming viral genome. Furthermore, our data indicate that the monoubiquitination of TRIM32 is important for its antiviral activity. Notably, we also show two TRIM32 pathogenic mutants R394H and D487N, related to Limb-girdle muscular dystrophy (LGMD), have a loss of antiviral activity against VEEV-TC83. Collectively, these results reveal that TRIM32 acts as a novel intrinsic restriction factor suppressing alphavirus infection and provides insights into the interaction between alphaviruses and the host UPS.
AUTHOR SUMMARY
Due to climate change, wildlife habitat loss, and human activities, alphavirus infections are a growing threat to public health. The host UPS has critical role in virus-host interaction, but how the UPS impact alphavirus infection is not completely understood. In this study, we found that the E3 ubiquitin ligase TRIM32 inhibits diverse alphaviruses in multiple cell types. Mechanistically, TRIM32 impairs primary translation of incoming viral genome in a manner that depends on. monoubiquitination of TRIM32. Additionally, disease-associated alleles of TRIM32 have a loss-of-function with respect to viral inhibition. Together, these findings uncover a novel biological function of TRIM32 in regulating alphavirus infection and provide important insights into the interplay between alphaviruses and the host USP.
PubMed: 38895352
DOI: 10.1101/2024.06.04.597282