Research

16 pages, 2376 KiB

Open AccessArticle

The Susceptibility of Chickens to Zika Virus: A Comprehensive Study on Age-Dependent Infection Dynamics and Host Responses

by Ruth H. Nissly, Levina Lim, Margo R. Keller, Ian M. Bird, Gitanjali Bhushan, Sougat Misra, Shubhada K. Chothe, Miranda C. Sill, Nagaram Vinod Kumar, A. V. N. Sivakumar, B. Rambabu Naik, Bhushan M. Jayarao and Suresh V. Kuchipudi

Viruses 2024, 16(4), 569; https://doi.org/10.3390/v16040569 - 07 Apr 2024

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Abstract

Zika virus (ZIKV) remains a public health concern, with epidemics in endemic regions and sporadic outbreaks in new areas posing significant threats. Several mosquito-borne flaviviruses that can cause human illness, including West Nile, Usutu, and St. Louis encephalitis, have associations with birds. However, [...] Read more.

Zika virus (ZIKV) remains a public health concern, with epidemics in endemic regions and sporadic outbreaks in new areas posing significant threats. Several mosquito-borne flaviviruses that can cause human illness, including West Nile, Usutu, and St. Louis encephalitis, have associations with birds. However, the susceptibility of chickens to ZIKV and their role in viral epidemiology is not currently known. We investigated the susceptibility of chickens to experimental ZIKV infection using chickens ranging from 1-day-old chicks to 6-week-old birds. ZIKV caused no clinical signs in chickens of all age groups tested. Viral RNA was detected in the blood and tissues during the first 5 days post-inoculation in 1-day and 4-day-old chicks inoculated with a high viral dose, but ZIKV was undetectable in 6-week-old birds at all timepoints. Minimal antibody responses were observed in 6-week-old birds, and while present in younger chicks, they waned by 28 days post-infection. Innate immune responses varied significantly between age groups. Robust type I interferon and inflammasome responses were measured in older chickens, while limited innate immune activation was observed in younger chicks. Signal transducer and activator of transcription 2 (STAT2) is a major driver of host restriction to ZIKV, and chicken STAT2 is distinct from human STAT2, potentially contributing to the observed resistance to ZIKV infection. The rapid clearance of the virus in older chickens coincided with an effective innate immune response, highlighting age-dependent susceptibility. Our study indicates that chickens are not susceptible to productive ZIKV infection and are unlikely to play a role in the ZIKV epidemiology. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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13 pages, 250 KiB

Open AccessArticle

Potential Serological Misdiagnosis of Barmah Forest Virus and Ross River Virus Diseases as Chikungunya Virus Infections in Australia: Comparison of ELISA with Neutralization Assay Results

by Joanne Kizu, Melissa Graham and Wenjun Liu

Viruses 2024, 16(3), 384; https://doi.org/10.3390/v16030384 - 29 Feb 2024

Viewed by 786

Abstract

To evaluate the frequency of errors in the diagnosis of medical laboratory-diagnosed Chikungunya virus (CHIKV) infections in Australia, we studied 42 laboratory-diagnosed CHIKV serum samples from one Queensland medical laboratory by ELISA IgG/IgM and measured the specific neutralization antibodies (Nab) against Barmah Forest [...] Read more.

To evaluate the frequency of errors in the diagnosis of medical laboratory-diagnosed Chikungunya virus (CHIKV) infections in Australia, we studied 42 laboratory-diagnosed CHIKV serum samples from one Queensland medical laboratory by ELISA IgG/IgM and measured the specific neutralization antibodies (Nab) against Barmah Forest virus (BFV), CHIKV and Ross River virus (RRV). The sero-positivity rates for the sera were as follows: anti-BFV IgG⁺ 19% (8/42), IgM⁺ 2.4% (1/42) and Nab⁺ 16.7% (7/42); anti-CHIKV IgG⁺ 90.5% (38/42), IgM⁺ 21.4% (9/42) and Nab⁺ 90.5% (38/42); anti-RRV IgG⁺ 88.1% (37/42), IgM⁺ 28.6% (12/42) and Nab⁺ 83.2% (35/42), respectively. Among the samples with multiple antibody positivity, 2.4% (1/42) showed triple ELISA IgM⁺, and 14.3% (6/42) exhibited double IgM RRV⁺CHIKV⁺; 9.5% (4/42) showed triple IgG⁺, 76.2% (32/42) displayed double IgG RRV⁺CHIKV⁺, 4.8% (2/42) showed IgG BFV⁺RRV⁺ and 4.8% (2/42) showed IgG BFV⁺+CHIKV⁺; and 9.5% (4/42) showed triple Nab⁺ and 69% (29/42) exhibited double Nab RRV⁺CHIKV⁺, respectively. Our analysis of the single-virus infection control Nab results suggested no cross-neutralization between RRV and BFV, and only mild cross-neutralization between CHIKV and RRV, BFV and CHIKV, all with a ≥4-fold Nab titre ratio difference between the true virus infection and cross-reactivity counterpart virus. Subsequently, we re-diagnosed these 42 patients as 1 BFV⁺, 8 CHIKV⁺ and 23 RRV⁺ single-virus infections, along with five RRV⁺/BFV⁺ and four RRV⁺/CHIKV⁺ double infections, and one possible RRV⁺/BFV⁺ or RRV⁺CHIKV⁺, respectively. These findings suggests that a substantial proportion of medically attended RRV and BFV infections were misdiagnosed as CHIKV infections, highlighting the imperative need for diagnostic laboratory tests capable of distinguishing between CHIKV infections and actively co-circulating RRV and BFV. For a correct diagnosis, it is crucial to consider reliable diagnostic methods such as the neutralization assay to exclude RRV and BFV. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

10 pages, 791 KiB

Open AccessArticle

Phylogenetics, Epidemiology and Temporal Patterns of Dengue Virus in Araraquara, São Paulo State

by Caio Santos de Souza, Giovana Santos Caleiro, Ingra Morales Claro, Jaqueline Goes de Jesus, Thaís Moura Coletti, Camila Alves Maia da Silva, Ângela Aparecida Costa, Marta Inenami, Andreia C. Ribeiro, Alvina Clara Felix, Anderson Vicente de Paula, Walter M. Figueiredo, Expedito José de Albuquerque Luna, Ester C. Sabino and Camila M. Romano

Viruses 2024, 16(2), 274; https://doi.org/10.3390/v16020274 - 09 Feb 2024

Viewed by 844

Abstract

Dengue virus (DENV) is a prominent arbovirus with global spread, causing approximately 390 million infections each year. In Brazil, yearly epidemics follow a well-documented pattern of serotype replacement every three to four years on average. Araraquara, located in the state of São Paulo, [...] Read more.

Dengue virus (DENV) is a prominent arbovirus with global spread, causing approximately 390 million infections each year. In Brazil, yearly epidemics follow a well-documented pattern of serotype replacement every three to four years on average. Araraquara, located in the state of São Paulo, has faced significant impacts from DENV epidemics since the emergence of DENV-1 in 2010. The municipality then transitioned from low to moderate endemicity in less than 10 years. Yet, there remains an insufficient understanding of virus circulation dynamics, particularly concerning DENV-1, in the region, as well as the genetic characteristics of the virus. To address this, we sequenced 37 complete or partial DENV-1 genomes sampled from 2015 to 2022 in Araraquara. Then, using also Brazilian and worldwide DENV-1 sequences we reconstructed the evolutionary history of DENV-1 in Araraquara and estimated the time to the most recent common ancestor (tMRCA) for serotype 1, for genotype V and its main lineages. Within the last ten years, there have been at least three introductions of genotype V in Araraquara, distributed in two main lineages (L Ia and L Ib, and L II). The tMRCA for the first sampled lineage (2015/2016 epidemics) was approximately 15 years ago (in 2008). Crucially, our analysis challenges existing assumptions regarding the emergence time of the DENV-1 genotypes, suggesting that genotype V might have diverged more recently than previously described. The presence of the two lineages of genotype V in the municipality might have contributed to the extended persistence of DENV-1 in the region. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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12 pages, 1404 KiB

Open AccessArticle

Evidence of Differences in Cellular Regulation of Wolbachia-Mediated Viral Inhibition between Alphaviruses and Flaviviruses

by Stephanie M. Rainey, Daniella A. Lefteri, Christie Darby, Alain Kohl, Andres Merits and Steven P. Sinkins

Viruses 2024, 16(1), 115; https://doi.org/10.3390/v16010115 - 13 Jan 2024

Viewed by 1055

Abstract

The intracellular bacterium Wolbachia is increasingly being utilised in control programs to limit the spread of arboviruses by Aedes mosquitoes. Achieving a better understanding of how Wolbachia strains can reduce viral replication/spread could be important for the long-term success of such programs. Previous [...] Read more.

The intracellular bacterium Wolbachia is increasingly being utilised in control programs to limit the spread of arboviruses by Aedes mosquitoes. Achieving a better understanding of how Wolbachia strains can reduce viral replication/spread could be important for the long-term success of such programs. Previous studies have indicated that for some strains of Wolbachia, perturbations in lipid metabolism and cholesterol storage are vital in Wolbachia-mediated antiviral activity against the flaviviruses dengue and Zika; however, it has not yet been examined whether arboviruses in the alphavirus group are affected in the same way. Here, using the reporters for the alphavirus Semliki Forest virus (SFV) in Aedes albopictus cells, we found that Wolbachia strains wMel, wAu and wAlbB blocked viral replication/translation early in infection and that storage of cholesterol in lipid droplets is not key to this inhibition. Another alphavirus, o’nyong nyong virus (ONNV), was tested in both Aedes albopictus cells and in vivo in stable, transinfected Aedes aegypti mosquito lines. The strains wMel, wAu and wAlbB show strong antiviral activity against ONNV both in vitro and in vivo. Again, 2-hydroxypropyl-β-cyclodextrin (2HPCD) was not able to rescue ONNV replication in cell lines, suggesting that the release of stored cholesterol caused by wMel is not able to rescue blockage of ONNV. Taken together, this study shows that alphaviruses appear to be inhibited early in replication/translation and that there may be differences in how alphaviruses are inhibited by Wolbachia in comparison to flaviviruses. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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18 pages, 3369 KiB

Open AccessArticle

Genomic Analysis of Sindbis Virus Reveals Uncharacterized Diversity within the Australasian Region, and Support for Revised SINV Taxonomy

by Alice Michie, Timo Ernst, Alyssa T. Pyke, Jay Nicholson, John S. Mackenzie, David W. Smith and Allison Imrie

Viruses 2024, 16(1), 7; https://doi.org/10.3390/v16010007 - 20 Dec 2023

Viewed by 958

Abstract

Sindbis virus (SINV) is a widely dispersed mosquito-borne alphavirus. Reports of Sindbis disease are largely restricted to northern Europe and South Africa. SINV is frequently sampled in Australian mosquito-based arbovirus surveillance programs, but human disease has rarely been reported. Molecular epidemiological studies have [...] Read more.

Sindbis virus (SINV) is a widely dispersed mosquito-borne alphavirus. Reports of Sindbis disease are largely restricted to northern Europe and South Africa. SINV is frequently sampled in Australian mosquito-based arbovirus surveillance programs, but human disease has rarely been reported. Molecular epidemiological studies have characterized six SINV genotypes (G1–G6) based on E2 gene phylogenies, mostly comprising viruses derived from the African–European zoogeographical region and with limited representation of Australasian SINV. In this study, we conducted whole genome sequencing of 66 SINV isolates sampled between 1960 and 2014 from countries of the Australasian region: Australia, Malaysia, and Papua New Guinea. G2 viruses were the most frequently and widely sampled, with three distinct sub-lineages defined. No new G6 SINV were identified, confirming geographic restriction of these viruses to south-western Australia. Comparison with global SINV characterized large-scale nucleotide and amino acid sequence divergence between African–European G1 viruses and viruses that circulate in Australasia (G2 and G3) of up to 26.83% and 14.55%, respectively, divergence that is sufficient for G2/G3 species demarcation. We propose G2 and G3 are collectively a single distinct alphavirus species that we name Argyle virus, supported by the inapparent or mild disease phenotype and the higher evolutionary rate compared with G1. Similarly, we propose G6, with 24.7% and 12.61% nucleotide and amino acid sequence divergence, is a distinct alphavirus species that we name Thomson’s Lake virus. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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16 pages, 3052 KiB

Open AccessArticle

326K at E Protein Is Critical for Mammalian Adaption of TMUV

by Xingpo Liu, Dawei Yan, Shan Peng, Yuee Zhang, Bangfeng Xu, Luzhao Li, Xiaona Shi, Tianxin Ma, Xuesong Li, Qiaoyang Teng, Chunxiu Yuan, Qinfang Liu and Zejun Li

Viruses 2023, 15(12), 2376; https://doi.org/10.3390/v15122376 - 01 Dec 2023

Viewed by 869

Abstract

Outbreaks of Tembusu virus (TMUV) infection have caused huge economic losses to the poultry industry in China since 2010. However, the potential threat of TMUV to mammals has not been well studied. In this study, a TMUV HB strain isolated from diseased ducks [...] Read more.

Outbreaks of Tembusu virus (TMUV) infection have caused huge economic losses to the poultry industry in China since 2010. However, the potential threat of TMUV to mammals has not been well studied. In this study, a TMUV HB strain isolated from diseased ducks showed high virulence in BALB/c mice inoculated intranasally compared with the reference duck TMUV strain. Further studies revealed that the olfactory epithelium is one pathway for the TMUV HB strain to invade the central nervous system of mice. Genetic analysis revealed that the TMUV HB virus contains two unique residues in E and NS3 proteins (326K and 519T) compared with duck TMUV reference strains. K326E substitution weakens the neuroinvasiveness and neurovirulence of TMUV HB in mice. Remarkably, the TMUV HB strain induced significantly higher levels of IL-1β, IL-6, IL-8, and interferon (IFN)-α/β than mutant virus with K326E substitution in the brain tissue of the infected mice, which suggested that TMUV HB caused more severe inflammation in the mouse brains. Moreover, application of IFN-β to infected mouse brain exacerbated the disease, indicating that overstimulated IFN response in the brain is harmful to mice upon TMUV infection. Further studies showed that TMUV HB upregulated RIG-I and IRF7 more significantly than mutant virus containing the K326E mutation in mouse brain, which suggested that HB stimulated the IFN response through the RIG-I-IRF7 pathway. Our findings provide insights into the pathogenesis and potential risk of TMUV to mammals. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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22 pages, 3369 KiB

Open AccessArticle

Defining the Cynomolgus Macaque (Macaca fascicularis) Animal Model for Aerosolized Venezuelan Equine Encephalitis: Importance of Challenge Dose and Viral Subtype

by Crystal W. Burke, Christina L. Gardner, Aimee I. Goodson, Ashley E. Piper, Rebecca A. Erwin-Cohen, Charles E. White and Pamela J. Glass

Viruses 2023, 15(12), 2351; https://doi.org/10.3390/v15122351 - 29 Nov 2023

Viewed by 921

Abstract

Venezuelan equine encephalitis virus (VEEV) outbreaks occur sporadically. Additionally, VEEV has a history of development as a biothreat agent. Yet, no FDA-approved vaccine or therapeutic exists for VEEV disease. The sporadic outbreaks present a challenge for testing medical countermeasures (MCMs) in humans; therefore, [...] Read more.

Venezuelan equine encephalitis virus (VEEV) outbreaks occur sporadically. Additionally, VEEV has a history of development as a biothreat agent. Yet, no FDA-approved vaccine or therapeutic exists for VEEV disease. The sporadic outbreaks present a challenge for testing medical countermeasures (MCMs) in humans; therefore, well-defined animal models are needed for FDA Animal Rule licensure. The cynomolgus macaque (CM) model has been studied extensively at high challenge doses of the VEEV Trinidad donkey strain (>1.0 × 10⁸ plaque-forming units [PFU]), doses that are too high to be a representative human dose. Based on viremia of two subtypes of VEEV, IC, and IAB, we found the CM infectious dose fifty (ID₅₀) to be low, 12 PFU, and 6.7 PFU, respectively. Additionally, we characterized the pattern of three clinical parameters (viremia, temperature, and lymphopenia) across a range of doses to identify a challenge dose producing consistent signs of infection. Based on these studies, we propose a shift to using a lower challenge dose of 1.0 × 10³ PFU in the aerosol CM model of VEEV disease. At this dose, NHPs had the highest viremia, demonstrated a fever response, and had a measurable reduction in complete lymphocyte counts—biomarkers that can demonstrate MCM efficacy. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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16 pages, 5480 KiB

Open AccessArticle

Development of Zika Virus Mini-Replicon Based Single-Round Infectious Particles as Gene Delivery Vehicles

by Joh-Sin Wu, Ju-Ying Kan, Hsueh-Chou Lai and Cheng-Wen Lin

Viruses 2023, 15(8), 1762; https://doi.org/10.3390/v15081762 - 18 Aug 2023

Viewed by 1263

Abstract

Zika virus (ZIKV) is a type of RNA virus that belongs to the Flaviviridae family. We have reported the construction of a DNA-launched replicon of the Asian-lineage Natal RGN strain and the production of single-round infectious particles (SRIPs) via the combination of prM/E [...] Read more.

Zika virus (ZIKV) is a type of RNA virus that belongs to the Flaviviridae family. We have reported the construction of a DNA-launched replicon of the Asian-lineage Natal RGN strain and the production of single-round infectious particles (SRIPs) via the combination of prM/E virus-like particles with the replicon. The main objective of the study was to engineer the ZIKV replicon as mammalian expression vectors and evaluate the potential of ZIKV mini-replicon-based SRIPs as delivery vehicles for heterologous gene expression in vitro and in vivo. The mini-replicons contained various genetic elements, including NS4B, an NS5 methyltransferase (MTase) domain, and an NS5 RNA-dependent RNA polymerase (RdRp) domain. Among these mini-replicons, only ZIKV mini-replicons 2 and 3, which contained the full NS5 and NS4B-NS5 genetic elements, respectively, exhibited the expression of reporters (green fluorescent protein (GFP) and cyan fluorescent protein–yellow fluorescent fusion protein (CYP)) and generated self-replicating RNAs. When the mini-replicons were transfected into the cells expressing ZIKV prM/E, this led to the production of ZIKV mini-replicon-based SRIPs. ZIKV mini-replicon 3 SRIPs showed a significantly higher yield titer and a greater abundance of self-replicating replicon RNAs when compared to ZIKV mini-replicon 2 SRIPs. Additionally, there were disparities in the dynamics of CYP expression and cytotoxic effects observed in various infected cell types between ZIKV mini-replicon 2-CYP and 3-CYP SRIPs. In particular, ZIKV mini-replicon 3-CYP SRIPs led to a substantial decrease in the survival rates of infected cells at a MOI of 2. An in vivo gene expression assay indicated that hACE2 expression was detected in the lung and brain tissues of mice following the intravenous administration of ZIKV mini-replicon 3-hACE2 SRIPs. Overall, this study highlights the potential of ZIKV mini-replicon-based SRIPs as promising vehicles for gene delivery applications in vitro and in vivo. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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16 pages, 2582 KiB

Open AccessArticle

Host Derivation of Sindbis Virus Influences Mammalian Type I Interferon Response to Infection

by John M. Crawford, Aaron M. Buechlein, Davis A. Moline, Douglas B. Rusch and Richard W. Hardy

Viruses 2023, 15(8), 1685; https://doi.org/10.3390/v15081685 - 03 Aug 2023

Viewed by 1112

Abstract

Arboviruses are defined by their ability to replicate in both mosquito vectors and mammalian hosts. There is good evidence that arboviruses “prime” their progeny for infection of the next host, such as via differential glycosylation of their outer glycoproteins or packaging of host [...] Read more.

Arboviruses are defined by their ability to replicate in both mosquito vectors and mammalian hosts. There is good evidence that arboviruses “prime” their progeny for infection of the next host, such as via differential glycosylation of their outer glycoproteins or packaging of host ribosomal subunits. We and others have previously shown that mosquito-derived viruses more efficiently infect mammalian cells than mammalian-derived viruses. These observations are consistent with arboviruses acquiring host-specific adaptations, and we hypothesized that a virus derived from either the mammalian host or mosquito vector elicits different responses when infecting the mammalian host. Here, we perform an RNA-sequencing analysis of the transcriptional response of Human Embryonic Kidney 293 (HEK-293) cells to infection with either mosquito (Aedes albopictus, C7/10)- or mammalian (Baby Hamster Kidney, BHK-21)-derived Sindbis virus (SINV). We show that the C7/10-derived virus infection leads to a more robust transcriptional response in HEK-293s compared to infection with the BHK-derived virus. Surprisingly, despite more efficient infection, we found an increase in interferon-β (IFN-β) and interferon-stimulated gene (ISG) transcripts in response to the C7/10-derived virus infection versus the BHK-derived virus infection. However, translation of interferon-stimulated genes was lower in HEK-293s infected with the C7/10-derived virus, starkly contrasting with the transcriptional response. This inhibition of ISG translation is reflective of a more rapid overall shut-off of host cell translation following infection with the C7/10-derived virus. Finally, we show that the C7/10-derived virus infection of HEK-293 cells leads to elevated levels of phosphorylated eukaryotic translation elongation factor-2 (eEF2), identifying a potential mechanism leading to the more rapid shut-off of host translation. We postulate that the rapid shut-off of host translation in mammalian cells infected with the mosquito-derived virus acts to counter the IFN-β-stimulated transcriptional response. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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15 pages, 6523 KiB

Open AccessArticle

Interaction between hTIM-1 and Envelope Protein Is Important for JEV Infection

by Zhenjie Liang, Junhui Pan, Shengda Xie, Xingmiao Yang and Ruibing Cao

Viruses 2023, 15(7), 1589; https://doi.org/10.3390/v15071589 - 21 Jul 2023

Cited by 1 | Viewed by 1023

Abstract

Japanese encephalitis virus (JEV), a mosquito-borne zoonotic virus, is one of the most important causes of human viral encephalitis. JEV relies on various attachment or entry co-factors to enter host cells. Among these co-factors, hTIM-1 has been identified as an attachment factor to [...] Read more.

Japanese encephalitis virus (JEV), a mosquito-borne zoonotic virus, is one of the most important causes of human viral encephalitis. JEV relies on various attachment or entry co-factors to enter host cells. Among these co-factors, hTIM-1 has been identified as an attachment factor to promote JEV infection through interacting with phosphatidylserine (PS) on the viral envelope. However, the reasons why JEV prefers to use hTIM-1 over other PS binding receptors are unknown. Here, we demonstrated that hTIM-1 can directly interact with JEV E protein. The interaction between hTIM-1 and JEV relies on specific binding sites, respectively, ND114115 in the hTIM-1 IgV domain and K38 of the E protein. Furthermore, during the early stage of infection, hTIM-1 and JEV are co-internalized into cells and transported into early and late endosomes. Additionally, we found that the hTIM-1 soluble ectodomain protein effectively inhibits JEV infection in vitro. Moreover, hTIM-1-specific antibodies have been shown to downregulate JEV infectivity in cells. Taken together, these findings suggested that hTIM-1 protein directly interacts with JEV E protein and mediates JEV infection, in addition to the PS-TIM-1 interaction. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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14 pages, 3390 KiB

Open AccessArticle

Cholesterol-Lowering Drugs as Potential Antivirals: A Repurposing Approach against Flavivirus Infections

by Juan Fidel Osuna-Ramos, Carlos Noe Farfan-Morales, Carlos Daniel Cordero-Rivera, Luis Adrián De Jesús-González, José Manuel Reyes-Ruiz, Arianna M. Hurtado-Monzón, Selvin Noé Palacios-Rápalo, Ricardo Jiménez-Camacho, Marco Antonio Meraz-Ríos and Rosa María Del Ángel

Viruses 2023, 15(7), 1465; https://doi.org/10.3390/v15071465 - 28 Jun 2023

Cited by 5 | Viewed by 1976

Abstract

Flaviviruses, including Dengue (DENV), Zika (ZIKV), and Yellow Fever (YFV) viruses, represent a significant global health burden. The development of effective antiviral therapies against these viruses is crucial to mitigate their impact. This study investigated the antiviral potential of the cholesterol-lowering drugs atorvastatin [...] Read more.

Flaviviruses, including Dengue (DENV), Zika (ZIKV), and Yellow Fever (YFV) viruses, represent a significant global health burden. The development of effective antiviral therapies against these viruses is crucial to mitigate their impact. This study investigated the antiviral potential of the cholesterol-lowering drugs atorvastatin and ezetimibe in monotherapy and combination against DENV, ZIKV, and YFV. In vitro results demonstrated a dose-dependent reduction in the percentage of infected cells for both drugs. The combination of atorvastatin and ezetimibe showed a synergistic effect against DENV 2, an additive effect against DENV 4 and ZIKV, and an antagonistic effect against YFV. In AG129 mice infected with DENV 2, monotherapy with atorvastatin or ezetimibe significantly reduced clinical signs and increased survival. However, the combination of both drugs did not significantly affect survival. This study provides valuable insights into the potential of atorvastatin and ezetimibe as antiviral agents against flaviviruses and highlights the need for further investigations into their combined therapeutic effects. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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Review

Jump to: Research, Other

55 pages, 2287 KiB

Open AccessReview

Mechanisms of Yellow Fever Transmission: Gleaning the Overlooked Records of Importance and Identifying Problems, Puzzles, Serious Issues, Surprises and Research Questions

by Goro Kuno

Viruses 2024, 16(1), 84; https://doi.org/10.3390/v16010084 - 04 Jan 2024

Viewed by 2190

Abstract

In viral disease research, few diseases can compete with yellow fever for the volume of literature, historical significance, richness of the topics and the amount of strong interest among both scientists and laypersons. While the major foci of viral disease research shifted to [...] Read more.

In viral disease research, few diseases can compete with yellow fever for the volume of literature, historical significance, richness of the topics and the amount of strong interest among both scientists and laypersons. While the major foci of viral disease research shifted to other more pressing new diseases in recent decades, many critically important basic tasks still remain unfinished for yellow fever. Some of the examples include the mechanisms of transmission, the process leading to outbreak occurrence, environmental factors, dispersal, and viral persistence in nature. In this review, these subjects are analyzed in depth, based on information not only in old but in modern literatures, to fill in blanks and to update the current understanding on these topics. As a result, many valuable facts, ideas, and other types of information that complement the present knowledge were discovered. Very serious questions about the validity of the arbovirus concept and some research practices were also identified. The characteristics of YFV and its pattern of transmission that make this virus unique among viruses transmitted by Ae. aegypti were also explored. Another emphasis was identification of research questions. The discovery of a few historical surprises was an unexpected benefit. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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13 pages, 2690 KiB

Open AccessReview

Immune Response to Chikungunya Virus: Sex as a Biological Variable and Implications for Natural Delivery via the Mosquito

by Meagan Taylor and Jonathan O. Rayner

Viruses 2023, 15(9), 1869; https://doi.org/10.3390/v15091869 - 03 Sep 2023

Cited by 1 | Viewed by 2304

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne virus with significant public health implications around the world. Climate change, as well as rapid urbanization, threatens to expand the population range of Aedes vector mosquitoes globally, increasing CHIKV cases worldwide in return. Epidemiological data suggests a [...] Read more.

Chikungunya virus (CHIKV) is a mosquito-borne virus with significant public health implications around the world. Climate change, as well as rapid urbanization, threatens to expand the population range of Aedes vector mosquitoes globally, increasing CHIKV cases worldwide in return. Epidemiological data suggests a sex-dependent response to CHIKV infection. In this review, we draw attention to the importance of studying sex as a biological variable by introducing epidemiological studies from previous CHIKV outbreaks. While the female sex appears to be a risk factor for chronic CHIKV disease, the male sex has recently been suggested as a risk factor for CHIKV-associated death; however, the underlying mechanisms for this phenotype are unknown. Additionally, we emphasize the importance of including mosquito salivary components when studying the immune response to CHIKV. As with other vector-transmitted pathogens, CHIKV has evolved to use these salivary components to replicate more extensively in mammalian hosts; however, the response to natural transmission of CHIKV has not been fully elucidated. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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Other

Jump to: Research, Review

0 pages, 1918 KiB

Open AccessBrief Report

Dengue Types 1 and 3 Identified in Travelers Returning from Kathmandu, Nepal, during the October 2022 Outbreak Are Related to Strains Recently Identified in India

by Neta S. Zuckerman, Eli Schwartz, Prativa Pandey, Oran Erster, Osnat Halpern, Efrat Bucris, Hagar Morad-Eliyahu, Marina Wax and Yaniv Lustig

Viruses 2023, 15(12), 2334; https://doi.org/10.3390/v15122334 - 28 Nov 2023

Cited by 1 | Viewed by 885

Abstract

Phylogenetic analysis of dengue serotypes 1 and 3, which were diagnosed in travelers and Nepalese infected in Kathmandu during the October 2022 outbreak, revealed that both serotypes were clustered closest to the sequences sampled in India. This suggests both serotypes may have originated [...] Read more.

Phylogenetic analysis of dengue serotypes 1 and 3, which were diagnosed in travelers and Nepalese infected in Kathmandu during the October 2022 outbreak, revealed that both serotypes were clustered closest to the sequences sampled in India. This suggests both serotypes may have originated in India. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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12 pages, 7492 KiB

Open AccessBrief Report

Transient Blockade of Type I Interferon Signalling Promotes Replication of Dengue Virus Strain D2Y98P in Adult Wild-Type Mice

by Lucas Wilken, Sonja Stelz, Chittappen Kandiyil Prajeeth and Guus F. Rimmelzwaan

Viruses 2023, 15(4), 814; https://doi.org/10.3390/v15040814 - 23 Mar 2023

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Abstract

Dengue virus serotypes 1 to 4 (DENV1–4) place nearly half the global population at risk of infection and the licenced tetravalent dengue vaccine fails to protect individuals who have not previously been exposed to DENV. The development of intervention strategies had long been [...] Read more.

Dengue virus serotypes 1 to 4 (DENV1–4) place nearly half the global population at risk of infection and the licenced tetravalent dengue vaccine fails to protect individuals who have not previously been exposed to DENV. The development of intervention strategies had long been hampered by the lack of a suitable small animal model. DENV does not replicate in wild-type mice due to its inability to antagonise the mouse type I interferon (IFN) response. Mice deficient in type I IFN signalling (Ifnar1^−/− mice) are highly susceptible to DENV infection, but their immunocompromised status makes it difficult to interpret immune responses elicited by experimental vaccines. To develop an alternative mouse model for vaccine testing, we treated adult wild-type mice with MAR1-5A3—an IFNAR1-blocking, non-cell-depleting antibody—prior to infection with the DENV2 strain D2Y98P. This approach would allow for vaccination of immunocompetent mice and subsequent inhibition of type I IFN signalling prior to challenge infection. While Ifnar1^−/− mice quickly succumbed to infection, MAR1-5A3-treated mice did not show any signs of illness but eventually seroconverted. Infectious virus was recovered from the sera and visceral organs of Ifnar1^−/− mice, but not from those of mice treated with MAR1-5A3. However, high levels of viral RNA were detected in the samples of MAR1-5A3-treated mice, indicating productive viral replication and dissemination. This transiently immunocompromised mouse model of DENV2 infection will aid the pre-clinical assessment of next-generation vaccines as well as novel antiviral treatments. Full article

(This article belongs to the Special Issue Advances in Alphavirus and Flavivirus Research)

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