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14 pages, 3814 KiB

Open AccessArticle

Phenotypic and Genetic Studies of the Viral Lineage Associated with the Recent Yellow Fever Outbreak in Brazil

by Nathália Dias Furtado, Mariela Martínez Gómez, Iasmim Silva de Mello, Déberli Ruiz Fernandes and Myrna Cristina Bonaldo

Viruses 2022, 14(8), 1818; https://doi.org/10.3390/v14081818 - 19 Aug 2022

Cited by 1 | Viewed by 1737

Abstract

Yellow fever virus (YFV) caused an outbreak in the Brazilian Southeast from 2016 to 2019, of the most significant magnitude since the 1900s. An investigation of the circulating virus revealed that most of the genomes detected in this period carried nine unique amino [...] Read more.

Yellow fever virus (YFV) caused an outbreak in the Brazilian Southeast from 2016 to 2019, of the most significant magnitude since the 1900s. An investigation of the circulating virus revealed that most of the genomes detected in this period carried nine unique amino acid polymorphisms, with eight located in the non-structural proteins NS3 and NS5, which are pivotal for viral replication. To elucidate the effect of these amino acid changes on viral infection, we constructed viruses carrying amino acid alterations in NS3 and NS5, performed infection in different cells, and assessed their neurovirulence in BALB/c mice and infected AG129 mice. We observed that the residues that compose the YFV 2016–2019 molecular signature in the NS5 protein might have been related to an attenuated phenotype, and that the alterations in the NS3 protein only slightly affected viral infection in AG129 mice, increasing to a low extent the mortality rate of these animals. These results contributed to unveiling the role of specific naturally occurring amino acid changes in the circulating strain of YFV in Brazil. Full article

(This article belongs to the Special Issue Flaviviruses and Flavivirus Vaccines)

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18 pages, 2987 KiB

Open AccessArticle

Avian IRF1 and IRF7 Play Overlapping and Distinct Roles in Regulating IFN-Dependent and -Independent Antiviral Responses to Duck Tembusu Virus Infection

by Chengwei Xiang, Zekun Yang, Ting Xiong, Ting Wang, Jie Yang, Mei Huang, Dingxiang Liu and Ruiai Chen

Viruses 2022, 14(7), 1506; https://doi.org/10.3390/v14071506 - 9 Jul 2022

Cited by 12 | Viewed by 2267

Abstract

Avian interferon regulatory factors 1 and 7 (IRF1 and IRF7) play important roles in the host’s innate immunity against viral infection. Our previous study revealed that duck tembusu virus (DTMUV) infection of chicken fibroblasts (DF1) and duck embryo fibroblasts (DEFs) induced the expression [...] Read more.

Avian interferon regulatory factors 1 and 7 (IRF1 and IRF7) play important roles in the host’s innate immunity against viral infection. Our previous study revealed that duck tembusu virus (DTMUV) infection of chicken fibroblasts (DF1) and duck embryo fibroblasts (DEFs) induced the expression of a variety of IFN-stimulated genes (ISGs), including VIPERIN, IFIT5, CMPK2, IRF1, and IRF7. IRF1 was further shown to play a significant role in regulating the up-expression of VIPERIN, IFIT5, and CMPK2 and inhibiting DTMUV replication. In this study, we confirm, through overexpression and knockout approaches, that both IRF1 and IRF7 inhibit DTMUV replication, mainly via regulation of type I IFN expression, as well as the induction of IRF1, VIPERIN, IFIT5, CMPK2, and MX1. In addition, IRF1 directly promoted the expression of VIPERIN and CMPK2 in an IFN-independent manner when IRF7 and type I IFN signaling were undermined. We also found that non-structural protein 2B (NS2B) of DTMUV was able to inhibit the induction of IFN-β mRNA triggered by Newcastle disease virus (NDV) infection or poly(I:C) treatment, revealing a strategy employed by DTMUV to evade host’s immunosurveillance. This study demonstrates that avian IRF7 and IRF1 play distinct roles in the regulation of type I IFN response during DTMUV infection. Full article

(This article belongs to the Special Issue Flaviviruses and Flavivirus Vaccines)

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11 pages, 1733 KiB

Open AccessArticle

Phylogenetic Characterisation of the Full Genome of a Bagaza Virus Isolate from Bird Fatalities in South Africa

by Adriano Mendes, Olivia Lentsoane, Mushal Allam, Zamantungwaka Khumalo, Arshad Ismail, Jacobus A. W. Coetzer and Marietjie Venter

Viruses 2022, 14(7), 1476; https://doi.org/10.3390/v14071476 - 5 Jul 2022

Cited by 2 | Viewed by 1941

Abstract

Bagaza virus (BAGV), a member of the Ntaya serogroup in the Flavivirus genus of the Flaviviridae, was isolated from the brain tissue of a Himalayan monal pheasant that died following neurological signs in Pretoria, South Africa in 2016. Next-generation sequencing was carried [...] Read more.

Bagaza virus (BAGV), a member of the Ntaya serogroup in the Flavivirus genus of the Flaviviridae, was isolated from the brain tissue of a Himalayan monal pheasant that died following neurological signs in Pretoria, South Africa in 2016. Next-generation sequencing was carried out on this isolate resulting in a genome sequence of 10980nt. The full genome sequence of this isolate, designated ZRU96-16, shared 98% nucleotide identity with a BAGV isolate found in Culex univitattus mosquitoes from Namibia and 97% nucleotide identity with a Spanish BAGV sequence isolated from an infected partridge. In total, seven amino acid variations were unique to ZRU96-16 after alignment with other BAGV and Israel turkey meningoencephalomyelitis (ITV) genomes. The 3′UTR sequence of ZRU96-16 was resolved with sufficient detail to be able to annotate the variable and conserved sequence elements within this region. Multiple sequence alignment of the 3′UTR suggested that it could be useful in lineage designation as more similar viruses carried similar mutations across this region, while also retaining certain unique sites. Maximum likelihood phylogenetic analysis revealed two clusters containing both BAGV and ITVs from Europe, the Middle East and Africa. Broadly, temporal clustering separated isolates into two groups, with one cluster representing viruses from the 1960–2000’s and the other from 2010 onwards. This suggests that there is consistent exchange of BAGV and ITV between Europe and Africa. This investigation provides more information on the phylogenetics of an under-represented member of the Flaviviridae and provides an avenue for more extensive research on its pathogenesis and geographic expansion. Full article

(This article belongs to the Special Issue Flaviviruses and Flavivirus Vaccines)

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20 pages, 4540 KiB

Open AccessArticle

Pathogenesis of West Nile Virus Lineage 2 in Domestic Geese after Experimental Infection

by Hannah Reemtsma, Cora M. Holicki, Christine Fast, Felicitas Bergmann, Martin Eiden, Martin H. Groschup and Ute Ziegler

Viruses 2022, 14(6), 1319; https://doi.org/10.3390/v14061319 - 16 Jun 2022

Cited by 6 | Viewed by 2755

Abstract

West Nile virus (WNV) is an emerging infectious pathogen circulating between mosquitoes and birds but also infecting mammals. WNV has become autochthonous in Germany, causing striking mortality rates in avifauna and occasional diseases in humans and horses. We therefore wanted to assess the [...] Read more.

West Nile virus (WNV) is an emerging infectious pathogen circulating between mosquitoes and birds but also infecting mammals. WNV has become autochthonous in Germany, causing striking mortality rates in avifauna and occasional diseases in humans and horses. We therefore wanted to assess the possible role of free-ranging poultry in the WNV transmission cycle and infected 15 goslings with WNV lineage 2 (German isolate). The geese were monitored daily and sampled regularly to determine viremia, viral shedding, and antibody development by molecular and serological methods. Geese were euthanized at various time points post-infection (pi). All infected geese developed variable degrees of viremia from day 1 to day 10 (maximum) and actively shed virus from days 2 to 7 post-infection. Depending on the time of death, the WN viral genome was detected in all examined tissue samples in at least one individual by RT-qPCR and viable virus was even re-isolated, except for in the liver. Pathomorphological lesions as well as immunohistochemically detectable viral antigens were found mainly in the brain. Furthermore, all of the geese seroconverted 6 days pi at the latest. In conclusion, geese are presumably not functioning as important amplifying hosts but are suitable sentinel animals for WNV surveillance. Full article

(This article belongs to the Special Issue Flaviviruses and Flavivirus Vaccines)

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11 pages, 2269 KiB

Open AccessArticle

Protective Immune Responses Induced by an mRNA-LNP Vaccine Encoding prM-E Proteins against Japanese Encephalitis Virus Infection

by Tao Chen, Shuo Zhu, Ning Wei, Zikai Zhao, Junjun Niu, Youhui Si, Shengbo Cao and Jing Ye

Viruses 2022, 14(6), 1121; https://doi.org/10.3390/v14061121 - 24 May 2022

Cited by 5 | Viewed by 2958

Abstract

Japanese encephalitis virus (JEV) is an important zoonotic pathogen, which causes central nervous system symptoms in humans and reproductive disorders in swine. It has led to severe impacts on human health and the swine industry; however, there is no medicine available for treating [...] Read more.

Japanese encephalitis virus (JEV) is an important zoonotic pathogen, which causes central nervous system symptoms in humans and reproductive disorders in swine. It has led to severe impacts on human health and the swine industry; however, there is no medicine available for treating yet. Therefore, vaccination is the best preventive measure for this disease. In the study, a modified mRNA vaccine expressing the prM and E proteins of the JEV P3 strain was manufactured, and a mouse model was used to assess its efficacy. The mRNA encoding prM and E proteins showed a high level of protein expression in vitro and were encapsulated into a lipid nanoparticle (LNP). Effective neutralizing antibodies and CD8+ T-lymphocytes-mediated immune responses were observed in vaccinated mice. Furthermore, the modified mRNA can protect mice from a lethal challenge with JEV and reduce neuroinflammation caused by JEV. This study provides a new option for the JE vaccine and lays a foundation for the subsequent development of a more efficient and safer JEV mRNA vaccine. Full article

(This article belongs to the Special Issue Flaviviruses and Flavivirus Vaccines)

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13 pages, 4969 KiB

Open AccessArticle

Evidence of Infection with Zoonotic Mosquito-Borne Flaviviruses in Saltwater Crocodiles (Crocodylus porosus) in Northern Australia

by Gervais Habarugira, Jasmin Moran, Jessica J. Harrison, Sally R. Isberg, Jody Hobson-Peters, Roy A. Hall and Helle Bielefeldt-Ohmann

Viruses 2022, 14(5), 1106; https://doi.org/10.3390/v14051106 - 21 May 2022

Cited by 4 | Viewed by 2887

Abstract

The risk of flavivirus infections among the crocodilian species was not recognised until West Nile virus (WNV) was introduced into the Americas. The first outbreaks caused death and substantial economic losses in the alligator farming industry. Several other WNV disease episodes have been [...] Read more.

The risk of flavivirus infections among the crocodilian species was not recognised until West Nile virus (WNV) was introduced into the Americas. The first outbreaks caused death and substantial economic losses in the alligator farming industry. Several other WNV disease episodes have been reported in crocodilians in other parts of the world, including Australia and Africa. Considering that WNV shares vectors with other flaviviruses, crocodilians are highly likely to also be exposed to flaviviruses other than WNV. A serological survey for flaviviral infections was conducted on saltwater crocodiles (Crocodylus porosus) at farms in the Northern Territory, Australia. Five hundred serum samples, collected from three crocodile farms, were screened using a pan-flavivirus-specific blocking ELISA. The screening revealed that 26% (n = 130/500) of the animals had antibodies to flaviviruses. Of these, 31.5% had neutralising antibodies to WNV_KUN (Kunjin strain), while 1.5% had neutralising antibodies to another important flavivirus pathogen, Murray Valley encephalitis virus (MVEV). Of the other flaviviruses tested for, Fitzroy River virus (FRV) was the most frequent (58.5%) in which virus neutralising antibodies were detected. Our data indicate that farmed crocodiles in the Northern Territory are exposed to a range of potentially zoonotic flaviviruses, in addition to WNV_KUN. While these flaviviruses do not cause any known diseases in crocodiles, there is a need to investigate whether infected saltwater crocodiles can develop a viremia to sustain the transmission cycle or farmed crocodilians can be used as sentinels to monitor the dynamics of arboviral infections in tropical areas. Full article

(This article belongs to the Special Issue Flaviviruses and Flavivirus Vaccines)

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14 pages, 1383 KiB

Open AccessArticle

Increased Ifng and Il10 Expression Correlate with Disease in Rodent Models Experimentally Infected with Modoc Virus

by Tyler J. Sherman, Douglas Petty, Tony Schountz, Natasha Hodges and Ann C. Hawkinson

Viruses 2022, 14(5), 1026; https://doi.org/10.3390/v14051026 - 11 May 2022

Viewed by 2088

Abstract

Flaviviruses present an ongoing threat to global public health, although the factors that contribute to the disease remain incompletely understood. We examined an acute Modoc virus (MODV) infection of two rodent models. Viral RNA was detected in the kidneys, spleen, liver, brain, urine, [...] Read more.

Flaviviruses present an ongoing threat to global public health, although the factors that contribute to the disease remain incompletely understood. We examined an acute Modoc virus (MODV) infection of two rodent models. Viral RNA was detected in the kidneys, spleen, liver, brain, urine, and sera of experimentally infected deer mice, a reservoir host of MODV, and Syrian hamsters, a known disease model. As expected, clinical outcomes differed between species, and the levels of viral RNA recovered from various tissues demonstrated signs of differential replication and tissue tropism. Multivariate analysis indicated significance in the profile of expressed genes between species when analyzed across tissues and over time (p = 0.02). Between-subject effects with corrected models revealed a significance specific to the expression of Ifng (p = 0.01). the expression of Ifng was elevated in hamsters as compared to deer mice in brain tissues at all timepoints. As the over-expression of Ifng has been shown to correlate with decreased vascular integrity, the findings presented here offer a potential mechanism for viral dissemination into the CNS. The expression of IL10 also differed significantly between species at certain timepoints in brain tissues; however, it is uncertain how increased expression of this cytokine may influence the outcome of MODV-induced pathology. Full article

(This article belongs to the Special Issue Flaviviruses and Flavivirus Vaccines)

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15 pages, 3279 KiB

Open AccessArticle

Excretion of Cell-Free and Cell-Associated Zika Virus into Breast Milk of Infected Dams and Identification of Antiviral Factors

by Sophie Desgraupes, Patricia Jeannin, Antoine Gessain, Pierre-Emmanuel Ceccaldi and Aurore Vidy

Viruses 2022, 14(5), 851; https://doi.org/10.3390/v14050851 - 20 Apr 2022

Cited by 1 | Viewed by 2178

Abstract

Zika virus (ZIKV) is a mosquito-borne RNA virus belonging to the Flavivirus genus of the Flaviviridae family. During the 60 years following its discovery in 1947, ZIKV caused little concern for public health as the associated infection was reported as mostly asymptomatic or [...] Read more.

Zika virus (ZIKV) is a mosquito-borne RNA virus belonging to the Flavivirus genus of the Flaviviridae family. During the 60 years following its discovery in 1947, ZIKV caused little concern for public health as the associated infection was reported as mostly asymptomatic or inducing mild symptoms. However, since 2013, severe neurological symptoms have been associated with ZIKV infection, compelling the World Health Organization to declare a Public Health Emergency of International Concern. Among those symptoms, neurological birth defects may affect children born to mothers infected during pregnancy. Additionally, during the past 8 years, ZIKV transmission through breastfeeding has repeatedly been suggested in epidemiological studies and demonstrated on a mouse model by our team. To better understand the biological factors controlling ZIKV transmission through breastfeeding, we investigated the nature of the viral entities excreted in the breast milk of infected dams and evaluated viral transmission to breastfed pups. We show that both cell-free and cell-associated virus is excreted into breast milk and that ZIKV is efficiently transmitted to the breastfed pups. Additionally, we studied murine breast milk cell types, and identified a majority of mammary luminal cells. Finally, we investigated the effect on ZIKV infectivity of several breast milk components that are antiviral against different viruses such as lactoferrin (LF) and lactalbumin (LA), or free fatty acids (FFA). We showed no effect of LF and LA, whereas FFA inactivated the virus. These results bring new insight concerning the mechanisms of ZIKV transmission during breastfeeding and identify biological factors modulating it. These elements should be considered in risk assessment of ZIKV mother-to-child transmission. Full article

(This article belongs to the Special Issue Flaviviruses and Flavivirus Vaccines)

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12 pages, 2085 KiB

Open AccessArticle

Construction of a Recombinant Japanese Encephalitis Virus with a Hemagglutinin-Tagged NS2A: A Model for an Analysis of Biological Characteristics and Functions of NS2A during Viral Infection

by Xiaochun Ma, Chenxi Li, Qiqi Xia, Yan Zhang, Yang Yang, Abdul Wahaab, Ke Liu, Zongjie Li, Beibei Li, Yafeng Qiu, Jianchao Wei and Zhiyong Ma

Viruses 2022, 14(4), 706; https://doi.org/10.3390/v14040706 - 29 Mar 2022

Cited by 2 | Viewed by 2231

Abstract

Nonstructural protein 2A (NS2A) of the Japanese encephalitis virus (JEV) contributes to viral replication and pathogenesis; however, a lack of NS2A-specific antibodies restricts studies on the underlying mechanisms. In this study, we constructed a recombinant JEV with a hemagglutinin (HA)-tagged NS2A (JEV-HA/NS2A/∆NS1’) to [...] Read more.

Nonstructural protein 2A (NS2A) of the Japanese encephalitis virus (JEV) contributes to viral replication and pathogenesis; however, a lack of NS2A-specific antibodies restricts studies on the underlying mechanisms. In this study, we constructed a recombinant JEV with a hemagglutinin (HA)-tagged NS2A (JEV-HA/NS2A/∆NS1’) to overcome this challenge. An HA-tag was fused to the N-terminus of NS2A (HA-NS2A) at the intergenic junction between NS1 and NS2A. A peptide linker, “FNG”, was added to the N-terminus of HA-tag to ensure correct cleavage between the C-terminus of NS1 and the N-terminus of HA-NS2A. To avoid the side effects of an unwanted NS1’ tagged with HA (HA-NS1’), an alanine-to-proline (A30P) substitution was introduced at residue 30 of NS2A to abolish HA-NS1’ production. The HA-tag insertion and A30P substitution were stably present in JEV-HA/NS2A/∆NS1’ after six passages and did not exhibit any significant effects on viral replication and plaque morphology. Taking advantage of HA-NS2A, we examined the activities of NS2A during JEV infection in vitro using anti-HA antibodies. NS2A was observed to be localized to the endoplasmic reticulum and interact with viral NS2B and NS3 during virus infection. These data suggest that JEV-HA/NS2A/∆NS1’ can serve as a model for the analysis of the biological characteristics and functions of NS2A in vitro during JEV infection. Full article

(This article belongs to the Special Issue Flaviviruses and Flavivirus Vaccines)

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Review

Jump to: Research

16 pages, 720 KiB

Open AccessReview

Mosquito-Borne Flaviviruses and Current Therapeutic Advances

by Xijing Qian and Zhongtian Qi

Viruses 2022, 14(6), 1226; https://doi.org/10.3390/v14061226 - 5 Jun 2022

Cited by 20 | Viewed by 4092

Abstract

Mosquito-borne flavivirus infections affect approximately 400 million people worldwide each year and are global threats to public health. The common diseases caused by such flaviviruses include West Nile, yellow fever, dengue, Zika infection and Japanese encephalitis, which may result in severe symptoms and [...] Read more.

Mosquito-borne flavivirus infections affect approximately 400 million people worldwide each year and are global threats to public health. The common diseases caused by such flaviviruses include West Nile, yellow fever, dengue, Zika infection and Japanese encephalitis, which may result in severe symptoms and disorders of multiple organs or even fatal outcomes. Till now, no specific antiviral agents are commercially available for the treatment of the diseases. Numerous strategies have been adopted to develop novel and promising inhibitors against mosquito-borne flaviviruses, including drugs targeting the critical viral components or essential host factors during infection. Research advances in antiflaviviral therapy might optimize and widen the treatment options for flavivirus infection. This review summarizes the current developmental progresses and involved molecular mechanisms of antiviral agents against mosquito-borne flaviviruses. Full article

(This article belongs to the Special Issue Flaviviruses and Flavivirus Vaccines)

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13 pages, 711 KiB

Open AccessReview

Cross-Reactive Immunity among Five Medically Important Mosquito-Borne Flaviviruses Related to Human Diseases

by Baohua Hou, Hui Chen, Na Gao and Jing An

Viruses 2022, 14(6), 1213; https://doi.org/10.3390/v14061213 - 2 Jun 2022

Cited by 17 | Viewed by 2969

Abstract

Flaviviruses cause a spectrum of potentially severe diseases. Most flaviviruses are transmitted by mosquitoes or ticks and are widely distributed all over the world. Among them, several mosquito-borne flaviviruses are co-epidemic, and the similarity of their antigenicity creates abundant cross-reactive immune responses which [...] Read more.

Flaviviruses cause a spectrum of potentially severe diseases. Most flaviviruses are transmitted by mosquitoes or ticks and are widely distributed all over the world. Among them, several mosquito-borne flaviviruses are co-epidemic, and the similarity of their antigenicity creates abundant cross-reactive immune responses which complicate their prevention and control. At present, only effective vaccines against yellow fever and Japanese encephalitis have been used clinically, while the optimal vaccines against other flavivirus diseases are still under development. The antibody-dependent enhancement generated by cross-reactive immune responses against different serotypes of dengue virus makes the development of the dengue fever vaccine a bottleneck. It has been proposed that the cross-reactive immunity elicited by prior infection of mosquito-borne flavivirus could also affect the outcome of the subsequent infection of heterologous flavivirus. In this review, we focused on five medically important flaviviruses, and rearranged and recapitulated their cross-reactive immunity in detail from the perspectives of serological experiments in vitro, animal experiments in vivo, and human cohort studies. We look forward to providing references and new insights for the research of flavivirus vaccines and specific prevention. Full article

(This article belongs to the Special Issue Flaviviruses and Flavivirus Vaccines)

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