-
PLoS Neglected Tropical Diseases Aug 2016West Nile virus (WNV) replicates in a wide variety of avian species, which serve as reservoir and amplification hosts. WNV strains isolated in North America, such as the...
West Nile virus (WNV) replicates in a wide variety of avian species, which serve as reservoir and amplification hosts. WNV strains isolated in North America, such as the prototype strain NY99, elicit a highly pathogenic response in certain avian species, notably American crows (AMCRs; Corvus brachyrhynchos). In contrast, a closely related strain, KN3829, isolated in Kenya, exhibits a low viremic response with limited mortality in AMCRs. Previous work has associated the difference in pathogenicity primarily with a single amino acid mutation at position 249 in the helicase domain of the NS3 protein. The NY99 strain encodes a proline residue at this position, while KN3829 encodes a threonine. Introduction of an NS3-T249P mutation in the KN3829 genetic background significantly increased virulence and mortality; however, peak viremia and mortality were lower than those of NY99. In order to elucidate the viral genetic basis for phenotype variations exclusive of the NS3-249 polymorphism, chimeric NY99/KN3829 viruses were created. We show herein that differences in the NS1-2B region contribute to avian pathogenicity in a manner that is independent of and additive with the NS3-249 mutation. Additionally, NS1-2B residues were found to alter temperature sensitivity when grown in avian cells.
Topics: Animals; Bird Diseases; Birds; Kenya; Mutation; North America; Polymorphism, Genetic; Temperature; Viral Nonstructural Proteins; Viremia; Virulence; Virus Replication; West Nile Fever; West Nile virus
PubMed: 27548738
DOI: 10.1371/journal.pntd.0004938 -
PloS One May 2010Most acute infections with RNA viruses are transient and subsequently cleared from the host. Recent evidence, however, suggests that the RNA virus, West Nile virus...
Most acute infections with RNA viruses are transient and subsequently cleared from the host. Recent evidence, however, suggests that the RNA virus, West Nile virus (WNV), not only causes acute disease, but can persist long term in humans and animal models. Our goal in this study was to develop a mouse model of WNV persistence. We inoculated immunocompetent mice subcutaneously (s.c.) with WNV and examined their tissues for infectious virus and WNV RNA for 16 months (mo) post-inoculation (p.i.). Infectious WNV persisted for 1 mo p.i. in all mice and for 4 mo p.i. in 12% of mice, and WNV RNA persisted for up to 6 mo p.i. in 12% of mice. The frequency of persistence was tissue dependent and was in the following order: skin, spinal cord, brain, lymphoid tissues, kidney, and heart. Viral persistence occurred in the face of a robust antibody response and in the presence of inflammation in the brain. Furthermore, persistence in the central nervous system (CNS) and encephalitis were observed even in mice with subclinical infections. Mice were treated at 1 mo p.i. with cyclophosphamide, and active viral replication resulted, suggesting that lymphocytes are functional during viral persistence. In summary, WNV persisted in the CNS and periphery of mice for up to 6 mo p.i. in mice with subclinical infections. These results have implications for WNV-infected humans. In particular, immunosuppressed patients, organ transplantation, and long term sequelae may be impacted by WNV persistence.
Topics: Animals; Antibody Formation; Antibody Specificity; Central Nervous System; Cyclophosphamide; Immunosuppression Therapy; Longevity; Mice; Organ Specificity; RNA, Viral; Recurrence; West Nile Fever; West Nile virus
PubMed: 20498839
DOI: 10.1371/journal.pone.0010649 -
Journal of Virology Sep 2021Dengue virus (DENV) and West Nile virus (WNV) are arthropod-transmitted flaviviruses that cause systemic vascular leakage and encephalitis syndromes, respectively, in...
Dengue virus (DENV) and West Nile virus (WNV) are arthropod-transmitted flaviviruses that cause systemic vascular leakage and encephalitis syndromes, respectively, in humans. However, the viral factors contributing to these specific clinical disorders are not completely understood. Flavivirus nonstructural protein 1 (NS1) is required for replication, expressed on the cell surface, and secreted as a soluble glycoprotein, reaching high levels in the blood of infected individuals. Extracellular DENV NS1 and WNV NS1 interact with host proteins and cells, have immune evasion functions, and promote endothelial dysfunction in a tissue-specific manner. To characterize how differences in DENV NS1 and WNV NS1 might function in pathogenesis, we generated WNV NS1 variants with substitutions corresponding to residues found in DENV NS1. We discovered that the substitution NS1-P101K led to reduced WNV infectivity in the brain and attenuated lethality in infected mice, although the virus replicated efficiently in cell culture and peripheral organs and bound at wild-type levels to brain endothelial cells and complement components. The P101K substitution resulted in reduced NS1 antigenemia in mice, and this was associated with reduced WNV spread to the brain. Because exogenous administration of NS1 protein rescued WNV brain infectivity in mice, we conclude that circulating WNV NS1 facilitates viral dissemination into the central nervous system and impacts disease outcomes. Flavivirus NS1 serves as an essential scaffolding molecule during virus replication but also is expressed on the cell surface and is secreted as a soluble glycoprotein that circulates in the blood of infected individuals. Although extracellular forms of NS1 are implicated in immune modulation and in promoting endothelial dysfunction at blood-tissue barriers, it has been challenging to study specific effects of NS1 on pathogenesis without disrupting its key role in virus replication. Here, we assessed WNV NS1 variants that do not affect virus replication and evaluated their effects on pathogenesis in mice. Our characterization of WNV NS1-P101K suggests that the levels of NS1 in the circulation facilitate WNV dissemination to the brain and affect disease outcomes. Our findings facilitate understanding of the role of NS1 during flavivirus infection and support antiviral strategies for targeting circulating forms of NS1.
Topics: Animals; Brain; Dengue Virus; Endothelial Cells; Female; Flavivirus; Immune Evasion; Male; Mice; Mice, Inbred C57BL; Viral Nonstructural Proteins; Virus Replication; West Nile Fever; West Nile virus
PubMed: 34346770
DOI: 10.1128/JVI.00844-21 -
Viruses Jul 2022There are at least five common mosquito-borne viruses (MBVs) recorded in Egypt, including dengue virus (DENV), Rift Valley fever virus (RVFV), West Nile virus (WNV),... (Review)
Review
There are at least five common mosquito-borne viruses (MBVs) recorded in Egypt, including dengue virus (DENV), Rift Valley fever virus (RVFV), West Nile virus (WNV), Chikungunya virus, and Sindbis virus. Unexpected outbreaks caused by MBVs reflect the deficiencies of the MBV surveillance system in Egypt. This systematic review characterized the epidemiology of MBV prevalence in Egypt. Human, animal, and vector prevalence studies on MBVs in Egypt were retrieved from Web of Science, PubMed, and Bing Scholar, and 33 eligible studies were included for further analyses. The monophyletic characterization of the RVFV and WNV strains found in Egypt, which spans about half a century, suggests that both RVFV and WNV are widely transmitted in this nation. Moreover, the seropositive rates of DENV and WNV in hosts were on the rise in recent years, and spillover events of DENV and WNV to other countries from Egypt have been recorded. The common drawback for surveillance of MBVs in Egypt is the lack of seroprevalence studies on MBVs, especially in this century. It is necessary to evaluate endemic transmission risk, establish an early warning system for MBVs, and develop a sound joint system for medical care and public health for managing MBVs in Egypt.
Topics: Animals; Culicidae; Egypt; Humans; Rift Valley fever virus; Seroepidemiologic Studies; West Nile Fever; West Nile virus
PubMed: 35891557
DOI: 10.3390/v14071577 -
The Journal of Clinical Investigation Apr 2004West Nile virus was first detected in North America in 1999 and has subsequently spread throughout the United States and Canada and into Mexico and the Caribbean. This... (Review)
Review
West Nile virus was first detected in North America in 1999 and has subsequently spread throughout the United States and Canada and into Mexico and the Caribbean. This review describes the epidemiology and ecology of West Nile virus in North America and the prospects for effective treatments and vaccines.
Topics: Animals; Ecology; Humans; Viral Vaccines; West Nile Fever; West Nile virus
PubMed: 15085186
DOI: 10.1172/JCI21623 -
Journal of Virology Mar 2011West Nile virus (WNV) is the most widely distributed of the encephalitic flaviviruses and is a major cause of encephalitis, with isolates obtained from all continents,...
West Nile virus (WNV) is the most widely distributed of the encephalitic flaviviruses and is a major cause of encephalitis, with isolates obtained from all continents, apart from Antarctica. Subsequent to its divergence from the other members of the Japanese encephalitis virus complex, presumably in Africa, WNV has diverged into individual lineages that mostly correspond with geographic distribution. Here we elucidate the phylogeography and evolutionary history of isolates from lineage 1 of WNV. Interestingly, there are many examples of the same amino acid having evolved independently on multiple occasions. In Africa, WNV exists in an endemic cycle, whereas it is epidemic in Europe, being reintroduced regularly from Africa either directly (in western Europe) or via the Middle East (in eastern Europe). Significantly, introduction into other geographic areas has occurred on one occasion only in each region, leading to subsequent establishment and expansion of the virus in these areas. Only one endemic genotype each is present in India and Australia, suggesting that WNV was successfully introduced into these locations once only. Each introduction occurred many centuries ago, probably due to trade and exploration during the 19th century. Likewise, in the Americas, WNV was successfully introduced in 1999 and subsequently became endemic across most temperate regions of North America (NA). In contrast to previous suggestions, an isolate from the epidemic in Israel in 1998 was not the direct progenitor of the NA epidemic; rather, both epidemics originated from the same (unknown) location.
Topics: Animals; Evolution, Molecular; Humans; Molecular Sequence Data; Phylogeography; RNA, Viral; Sequence Analysis, DNA; West Nile Fever; West Nile virus
PubMed: 21159871
DOI: 10.1128/JVI.01963-10 -
Applied and Environmental Microbiology Jul 2017In November and December of 2013, a large mortality event involving 15,000 to 20,000 eared grebes () occurred at the Great Salt Lake (GSL), UT. The onset of the outbreak...
In November and December of 2013, a large mortality event involving 15,000 to 20,000 eared grebes () occurred at the Great Salt Lake (GSL), UT. The onset of the outbreak in grebes was followed by a mortality event in >86 bald eagles (). During the die-off, West Nile virus (WNV) was detected by reverse transcription-PCR (RT-PCR) or viral culture in the carcasses of grebes and eagles submitted to the National Wildlife Health Center. However, no activity of mosquitoes, the primary vectors of WNV, was detected by the State of Utah's WNV monitoring program. The transmission of WNV has rarely been reported during the winter in North America in the absence of known mosquito activity; however, the size of this die-off, the habitat in which it occurred, and the species involved are unique. We experimentally investigated whether WNV could survive in water with a high salt content, as found at the GSL, and whether brine shrimp, the primary food of migrating eared grebes on the GSL, could have played a role in the transmission of WNV to feeding birds. We found that WNV can survive up to 72 h at 4°C in water containing 30 to 150 ppt NaCl, and brine shrimp incubated with WNV in 30 ppt NaCl may adsorb WNV to their cuticle and, through feeding, infect epithelial cells of their gut. Both mechanisms may have potentiated the WNV die-off in migrating eared grebes on the GSL. Following a major West Nile virus die-off of eared grebes and bald eagles at the Great Salt Lake (GSL), UT, in November to December 2013, this study assessed the survival of West Nile virus (WNV) in water as saline as that of the GSL and whether brine shrimp, the major food for migrating grebes, could have played a role as a vector for the virus. While mosquitoes are the major vector of WNV, under certain circumstances, transmission may occur through contaminated water and invertebrates as food.
Topics: Animals; Artemia; Bird Diseases; Birds; Culicidae; Lakes; Seasons; Sodium Chloride; Utah; West Nile Fever; West Nile virus
PubMed: 28500043
DOI: 10.1128/AEM.00705-17 -
Journal of Virology Mar 2011For intracellular survival it is imperative that viruses have the capacity to manipulate various cellular responses, including metabolic and biosynthetic pathways. The...
For intracellular survival it is imperative that viruses have the capacity to manipulate various cellular responses, including metabolic and biosynthetic pathways. The unfolded protein response (UPR) is induced by various external and internal stimuli, including the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Our previous studies have indicated that the replication and assembly of the flavivirus West Nile virus strain Kunjin virus (WNV(KUN)) is intimately associated with the ER. Thus, we sought to determine whether the UPR was induced during WNV(KUN) infection. WNV(KUN) induces UPR signaling during replication, which is coordinated with peak replication. Interestingly, signaling is biased toward the ATF6/IRE-1 arm of the response, with high levels of Xbp-1 activation but negligible eukaryotic translation initiation factor 2α phosphorylation and downstream transcription. We show that the PERK-mediated response may partially regulate replication, since external UPR stimulation had a limiting effect on early replication events and cells deficient for PERK demonstrated increased replication and virus release. Significantly, we show that the WNV(KUN) hydrophobic nonstructural proteins NS4A and NS4B are potent inducers of the UPR, which displayed a high correlation in inhibiting Jak-STAT signaling in response to alpha interferon (IFN-α). Sequential removal of the transmembrane domains of NS4A showed that reducing hydrophobicity decreased UPR signaling and restored IFN-α-mediated activation. Overall, these results suggest that WNV(KUN) can stimulate the UPR to facilitate replication and that the induction of a general ER stress response, regulated by hydrophobic WNV(KUN) proteins, can potentiate the inhibition of the antiviral signaling pathway.
Topics: Endoplasmic Reticulum; Host-Pathogen Interactions; Immune Evasion; Interferon-alpha; Unfolded Protein Response; Viral Nonstructural Proteins; Virus Replication; West Nile virus
PubMed: 21191014
DOI: 10.1128/JVI.02050-10 -
Journal of Innate Immunity 2009As a first line of defense after viral infection, host cells develop an intrinsic immune response to control virus dissemination and protect against serious infection.... (Review)
Review
As a first line of defense after viral infection, host cells develop an intrinsic immune response to control virus dissemination and protect against serious infection. Recent experiments have shown a dominant role of the IFN-alpha/beta response in protection against lethal West Nile virus (WNV) by limiting the cellular and tissue tropism of infection. This review will focus on advances in identifying the host sensors that detect WNV and the adaptor molecules and signaling pathways that regulate the induction of IFN-alpha/beta defenses that limit WNV replication, spread and pathogenesis.
Topics: Animals; Antiviral Agents; Humans; Immunity, Innate; Interferon-alpha; Interferon-beta; Mice; Pattern Recognition, Automated; Signal Transduction; West Nile Fever; West Nile virus
PubMed: 20375601
DOI: 10.1159/000226248 -
BMC Ecology and Evolution Sep 2021The West Nile virus is a highly contagious agent for a wide range of hosts. Its spread in the Mediterranean region raises several questions about its origin and the risk...
BACKGROUND
The West Nile virus is a highly contagious agent for a wide range of hosts. Its spread in the Mediterranean region raises several questions about its origin and the risk factors underlying the virus's dispersal.
MATERIALS AND METHODS
The present study aims to reconstruct the temporal and spatial phylodynamics of West Nile virus lineage 2 in the Mediterranean region using 75 complete genome sequences from different host species retrieved from international databases.
RESULTS
This data set suggests that current strains of WNV-2 began spreading in South Africa or nearby regions in the early twentieth century, and it migrated northwards via at least one route crossing the Mediterranean to reach Hungary in the early 2000s, before spreading throughout Europe. Another introduction event, according to the data set collected and analyses performed, is inferred to have occurred in around 1978. Migratory birds constitute, among others, additional risk factors that enhance the geographical transmission of the infection.
CONCLUSION
Our data underline the importance of the spatial-temporal tracking of migratory birds and phylodynamic reconstruction in setting up an efficient surveillance system for emerging and reemerging zoonoses in the Mediterranean region.
Topics: Animals; Birds; Europe; Phylogeography; West Nile Fever; West Nile virus
PubMed: 34579648
DOI: 10.1186/s12862-021-01902-w