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1.
Viruses ; 14(4)2022 04 04.
Article in English | MEDLINE | ID: covidwho-1875770

ABSTRACT

Among emerging arthropod-borne viruses (arbovirus), West Nile virus (WNV) is a flavivirus that can be associated with severe neuroinvasive infections in humans. In 2018, the European WNV epidemic resulted in over 2000 cases, representing the most important arboviral epidemic in the European continent. Characterization of inflammation and neuronal biomarkers released during WNV infection, especially in the context of neuronal impairments, could provide insight into the development of predictive tools that could be beneficial for patient outcomes. We first analyzed the inflammatory signature in the serum of WNV-infected mice and found increased concentrations of several inflammatory cytokines. We next analyzed serum and cerebrospinal-fluid (CSF) samples from a cohort of patients infected by WNV between 2018 and 2019 in Hungary to quantify a large panel of inflammatory cytokines and neurological factors. We found higher levels of inflammatory cytokines (e.g., IL4, IL6, and IL10) and neuronal factors (e.g., BDNF, GFAP, MIF, TDP-43) in the sera of WNV-infected patients with neuroinvasive disease. Furthermore, the serum inflammatory profile of these patients persisted for several weeks after initial infection, potentially leading to long-term sequelae and having a deleterious effect on brain neurovasculature. This work suggests that early signs of increased serum concentrations of inflammatory cytokines and neuronal factors could be a signature underlying the development of severe neurological impairments. Biomarkers could play an important role in patient monitoring to improve care and prevent undesirable outcomes.


Subject(s)
West Nile Fever , West Nile virus , Animals , Biomarkers , Cytokines , Humans , Mice , West Nile virus/physiology
2.
Acta Trop ; 231: 106470, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1864514

ABSTRACT

West Nile virus (WNV) infections have increased over recent years to the extent that WNV has become one of the most widespread arboviruses in the world, with potential consequences for both human and animal health. While much is known about WNV and the vectors that transmit it from their primary hosts across continental Europe, little is known about the epidemiology of the disease on the island of Cyprus. In this study, the aim was to investigate the prevalence of WNV infection in potential mosquito vectors for the first time in the Republic of Cyprus, using WNV surveillance of mosquitoes. Mosquitoes were collected in 2019, during which an outbreak in humans had occurred, and sampled mosquitoes were then examined for WNV infection by testing them for the presence of WNV RNA. Of 126 mosquito pools tested, one pool, containing Culex pipiens mosquitoes sampled from the Nicosia district, was found to be positive for the presence of WNV RNA. The positive pool found in this study represents the first demonstration of WNV in mosquitoes in Cyprus and confirms that human cases in Cyprus are likely the result of transmission via local Culex mosquitoes.


Subject(s)
Culex , Culicidae , West Nile Fever , West Nile virus , Animals , Culex/genetics , Cyprus/epidemiology , RNA , West Nile virus/genetics
3.
Acta Trop ; 230: 106391, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1803335

ABSTRACT

Since 2010 when West Nile virus (WNV) emerged in Greece, it causes seasonal outbreaks of human infections almost every year. During May-October of 2019-2021 a total number of 51,504 Culex pipiens mosquitoes were trapped in all seven regional units of Central Macedonia in northern Greece. They were grouped into 1099 pools and tested for WNV. The virus was detected in 5% of the mosquito pools (1.5%, 3.6% and 9.6% pools in 2019, 2020, and 2021, respectively), with significant rate differences among the regional units and years. The highest maximum likelihood estimation for WNV infection rates calculated per 1000 mosquitoes for 2019 and 2020 were 1.89 and 3.84 in Serres, and 7.08 for 2021 in Pella regional unit. Sixteen whole genome sequences were taken by applying a recently described PCR-based next generation sequencing protocol. Phylogenetic analysis showed that the sequences belonged to the Central European clade of WNV lineage 2, and that a virus strain introduced in Greece in 2019 continued to circulate and spread further during 2020-2021. The data are useful for public health and mosquito control programs' operational scheduling, while the whole genome sequences are an added value for molecular epidemiology and evolutionary studies.


Subject(s)
Culex , West Nile Fever , West Nile virus , Animals , Greece/epidemiology , Humans , Phylogeny , West Nile Fever/epidemiology , West Nile virus/genetics
4.
Aging Cell ; 21(4): e13582, 2022 04.
Article in English | MEDLINE | ID: covidwho-1788809

ABSTRACT

Older humans and animals often exhibit reduced immune responses to infection and vaccination, and this often directly correlates to the numbers and frequency of naive T (Tn) cells. We found such a correlation between reduced numbers of blood CD8+ Tn cells and severe clinical outcomes of West Nile virus (WNV) in both humans naturally exposed to, and mice experimentally infected with, WNV. To examine possible causality, we sought to increase the number of CD8 Tn cells by treating C57BL/6 mice with IL-7 complexes (IL-7C, anti-IL-7 mAb bound to IL-7), shown previously to efficiently increase peripheral T-cell numbers by homeostatic proliferation. T cells underwent robust expansion following IL-7C administration to old mice increasing the number of total T cells (>fourfold) and NS4b:H-2Db -restricted antigen-specific CD8 T cells (twofold). This improved the numbers of NS4b-specific CD8 T cells detected at the peak of the response against WNV, but not survival of WNV challenge. IL-7C-treated old animals also showed no improvement in WNV-specific effector immunity (neutralizing antibody and in vivo T-cell cytotoxicity). To test quantitative limits to which CD8 Tn cell restoration could improve protective immunity, we transferred graded doses of Ag-specific precursors into old mice and showed that injection of 5400 (but not of 1800 or 600) adult naive WNV-specific CD8 T cells significantly increased survival after WNV. These results set quantitative limits to the level of Tn reconstitution necessary to improve immune defense in older organisms and are discussed in light of targets of immune reconstitution.


Subject(s)
West Nile Fever , West Nile virus , Animals , CD8-Positive T-Lymphocytes , Cell Count , Interleukin-7 , Mice , Mice, Inbred C57BL
5.
PLoS One ; 17(4): e0266840, 2022.
Article in English | MEDLINE | ID: covidwho-1785207

ABSTRACT

In Hungary, West Nile virus (WNV) has been responsible for 459 laboratory confirmed human cases between 2004 and 2019, while the first human Usutu virus (USUV) infection was confirmed only in 2018. A comprehensive serosurvey was conducted among blood donors to assess the WNV and USUV seroprevalence in 2019, one year after the largest European WNV epidemic. Altogether, 3005 plasma samples were collected and screened for WNV and USUV specific Immunoglobulin G (IgG) antibodies by Enzyme-Linked Immunosorbent Assay (ELISA). All reactive samples were further tested for tick-borne encephalitis virus IgG antibodies by ELISA. Indirect immunofluorescence test and microneutralization assay were used as confirmatory methods. Overall, the WNV seroprevalence was 4.32%, and in five blood donors USUV seropositivity was confirmed. The highest seroprevalence was measured in Central, Eastern and Southern Hungary, while the Western part of the country proved to be less affected. There was a statistically strong association between the WNV seroprevalence of 2019 and the cumulative incidence in the period of 2004 and 2019 calculated for every NUTS 3 region. The last WNV serological screening was performed in 2016 and the prevalence of anti-WNV IgG proved to be 2.19%. One year after the 2018 WNV outbreak, a significant increase in seroprevalence was observed in the Hungarian population and evidence for USUV seropositivity was also obtained. The spatial pattern of seroprevalence can support the identification of high-risk areas raising awareness of the need for increased surveillance, such as screening vector, equine, and avian populations. The communication with general practitioners and other professionals in primary health care services can support the early identification of acute human cases. Education and awareness-raising on the importance of protection against mosquito vectors amongst residents are also important parts of preventive measures.


Subject(s)
Encephalitis Viruses, Tick-Borne , Flavivirus , West Nile Fever , West Nile virus , Animals , Antibodies, Viral , Blood Donors , Enzyme-Linked Immunosorbent Assay/veterinary , Horses , Humans , Hungary/epidemiology , Immunoglobulin G , Seroepidemiologic Studies
6.
Front Public Health ; 9: 628799, 2021.
Article in English | MEDLINE | ID: covidwho-1581140

ABSTRACT

West Nile virus infections have surged across the globe. South Texas, located on the path of bird migration, with Culex quinquefasciatus and other Culex species, and biotic primers that predispose the area to epidemics (floods, amplifying hosts, and lack of mosquito control and prevention) remains a highly endemic area for arbovirus spread. West Nile virus infection ranges from mild febrile illness to severe central nervous system involvement. The purpose of this report is to highlight complex presentations of WNV and how confounding presenting symptoms delay diagnosis. The secondary goal is to describe how pandemics, such as SARS-CoV-2, can overwhelm the system and result in medical decision bias errors.


Subject(s)
COVID-19 , Culex , West Nile Fever , West Nile virus , Animals , Humans , SARS-CoV-2 , West Nile Fever/diagnosis
7.
Transbound Emerg Dis ; 69(2): 221-226, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1546411

ABSTRACT

West Nile Virus (WNV) infections are increasingly detected in birds and horses in central Europe, with the first mosquito-borne autochthonous human infection detected in Germany in 2019. Human infections are typically asymptomatic, with occasional severe neurological disease. Because of a low number of cases in central Europe, awareness regarding potential cases is low and WNV diagnostic testing is not routine. We tested cerebrospinal fluid (CSF) samples from unsolved encephalitis and meningitis cases from Berlin from 2019 to 2020, and describe a WNV-encephalitis case in a 33-year-old kidney transplant recipient. The infectious course was resolved by serology, RT-PCR and sequencing of stored samples. Phylogenetic sequence analysis revealed a close relationship of the patient's WNV strain to German sequences from 2019 and 2020. A lack of travel history and patient self-isolation during the SARS-CoV-2 pandemic suggest the infection was acquired in the patient's home or garden. Serological tests of four people sharing the living space were negative. Retrospective RT-PCR and WNV-IgM testing of 671 CSF samples from unsolved encephalitis and meningitis cases from Berlin detected no additional infections. The recent increase of WNV cases illustrates the importance of considering WNV in cases of meningoencephalitis, especially in immunocompromised patients, as described here. Proper education and communication and a revised diagnostic strategy will help to raise awareness and to detect future WNV infections.


Subject(s)
Kidney Transplantation , West Nile Fever , West Nile virus , Adult , Humans , West Nile Fever/diagnosis
9.
J Virol ; 95(24): e0059621, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1443352

ABSTRACT

Cellular factors have important roles in all facets of the flavivirus replication cycle. Deciphering viral-host protein interactions is essential for understanding the flavivirus life cycle as well as development of effective antiviral strategies. To uncover novel host factors that are co-opted by multiple flaviviruses, a CRISPR/Cas9 genome wide knockout (KO) screen was employed to identify genes required for replication of Zika virus (ZIKV). Receptor for Activated Protein C Kinase 1 (RACK1) was identified as a novel host factor required for ZIKV replication, which was confirmed via complementary experiments. Depletion of RACK1 via siRNA demonstrated that RACK1 is important for replication of a wide range of mosquito- and tick-borne flaviviruses, including West Nile Virus (WNV), Dengue Virus (DENV), Powassan Virus (POWV) and Langat Virus (LGTV) as well as the coronavirus SARS-CoV-2, but not for YFV, EBOV, VSV or HSV. Notably, flavivirus replication was only abrogated when RACK1 expression was dampened prior to infection. Utilising a non-replicative flavivirus model, we show altered morphology of viral replication factories and reduced formation of vesicle packets (VPs) in cells lacking RACK1 expression. In addition, RACK1 interacted with NS1 protein from multiple flaviviruses; a key protein for replication complex formation. Overall, these findings reveal RACK1's crucial role to the biogenesis of pan-flavivirus replication organelles. IMPORTANCE Cellular factors are critical in all facets of viral lifecycles, where overlapping interactions between the virus and host can be exploited as possible avenues for the development of antiviral therapeutics. Using a genome-wide CRISPR knockout screening approach to identify novel cellular factors important for flavivirus replication we identified RACK1 as a pro-viral host factor for both mosquito- and tick-borne flaviviruses in addition to SARS-CoV-2. Using an innovative flavivirus protein expression system, we demonstrate for the first time the impact of the loss of RACK1 on the formation of viral replication factories known as 'vesicle packets' (VPs). In addition, we show that RACK1 can interact with numerous flavivirus NS1 proteins as a potential mechanism by which VP formation can be induced by the former.


Subject(s)
CRISPR-Cas Systems , Flavivirus/genetics , Neoplasm Proteins/genetics , Receptors for Activated C Kinase/genetics , Virus Replication , A549 Cells , Aedes , Animals , COVID-19 , Chlorocebus aethiops , Culicidae , Dengue Virus/genetics , Genome-Wide Association Study , HEK293 Cells , Host-Pathogen Interactions/genetics , Humans , RNA, Small Interfering/metabolism , RNA, Viral/metabolism , SARS-CoV-2 , Vero Cells , West Nile virus/genetics , Zika Virus/genetics , Zika Virus Infection/virology
10.
Front Immunol ; 12: 739025, 2021.
Article in English | MEDLINE | ID: covidwho-1417086

ABSTRACT

A rise in adiposity in the United States has resulted in more than 70% of adults being overweight or obese, and global obesity rates have tripled since 1975. Following the 2009 H1N1 pandemic, obesity was characterized as a risk factor that could predict severe infection outcomes to viral infection. Amidst the SARS-CoV-2 pandemic, obesity has remained a significant risk factor for severe viral disease as obese patients have a higher likelihood for developing severe symptoms and requiring hospitalization. However, the mechanism by which obesity enhances viral disease is unknown. In this study, we utilized a diet-induced obesity mouse model of West Nile virus (WNV) infection, a flavivirus that cycles between birds and mosquitoes and incidentally infects both humans and mice. Likelihood for severe WNV disease is associated with risk factors such as diabetes that are comorbidities also linked to obesity. Utilizing this model, we showed that obesity-associated chronic inflammation increased viral disease severity as obese female mice displayed higher mortality rates and elevated viral titers in the central nervous system. In addition, our studies highlighted that obesity also dysregulates host acute adaptive immune responses, as obese female mice displayed significant dysfunction in neutralizing antibody function. These studies highlight that obesity-induced immunological dysfunction begins at early time points post infection and is sustained through memory phase, thus illuminating a potential for obesity to alter the differentiation landscape of adaptive immune cells.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Cytokines/blood , Obesity/immunology , West Nile Fever/mortality , West Nile virus/immunology , Animals , COVID-19/pathology , Disease Models, Animal , Female , Humans , Inflammation/pathology , Liver/injuries , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Obesity/pathology , Severity of Illness Index , West Nile Fever/immunology , West Nile Fever/pathology
11.
J Insur Med ; 49(1): 37-45, 2021 Jan 01.
Article in English | MEDLINE | ID: covidwho-1237379

ABSTRACT

Severe acute respiratory syndrome (SARS) reminds us that sudden disease emergence is a permanent part of our world-and should be anticipated in our planning. Historically the emergence of new diseases has had little or no impact beyond a small, localized cluster of infections. However, given just the right conditions, a highly virulent pathogen can suddenly spread across time and space with massive consequences, as has occurred on several occasions in human history. In the wake of the SARS outbreak, we are now forced to confront the unpleasant fact that human activities are increasing the frequency and severity of these kinds of emergences. The idea of more frequent biological ''invasions'' with economic and societal impacts comparable to SARS, presents stakeholders in the global economy with unprecedented new risks, challenges and even opportunities. As a major contributor to economic stability, the insurance industry must follow these trends very closely and develop scenarios to anticipate these events.


Subject(s)
Epidemics , Insurance , Nipah Virus , Severe Acute Respiratory Syndrome , West Nile virus , Humans , Severe Acute Respiratory Syndrome/epidemiology
12.
ACS Infect Dis ; 7(2): 471-478, 2021 02 12.
Article in English | MEDLINE | ID: covidwho-1006383

ABSTRACT

A series of 7-deazaadenine ribonucleosides bearing alkyl, alkenyl, alkynyl, aryl, or hetaryl groups at position 7 as well as their 5'-O-triphosphates and two types of monophosphate prodrugs (phosphoramidates and S-acylthioethanol esters) were prepared and tested for antiviral activity against selected RNA viruses (Dengue, Zika, tick-borne encephalitis, West Nile, and SARS-CoV-2). The modified triphosphates inhibited the viral RNA-dependent RNA polymerases at micromolar concentrations through the incorporation of the modified nucleotide and stopping a further extension of the RNA chain. 7-Deazaadenosine nucleosides bearing ethynyl or small hetaryl groups at position 7 showed (sub)micromolar antiviral activities but significant cytotoxicity, whereas the nucleosides bearing bulkier heterocycles were still active but less toxic. Unexpectedly, the monophosphate prodrugs were similarly or less active than the corresponding nucleosides in the in vitro antiviral assays, although the bis(S-acylthioethanol) prodrug 14h was transported to the Huh7 cells and efficiently released the nucleoside monophosphate.


Subject(s)
Antiviral Agents/pharmacology , Prodrugs/pharmacology , Purines/pharmacology , RNA Viruses/drug effects , Ribonucleosides/pharmacology , COVID-19/drug therapy , COVID-19/virology , Cell Line, Tumor , Dengue Virus/drug effects , Encephalitis Viruses, Tick-Borne/drug effects , Humans , Phosphates/pharmacology , Purine Nucleosides , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/drug effects , West Nile virus/drug effects , Zika Virus/drug effects
15.
J Infect Dis ; 221(6): 882-889, 2020 03 02.
Article in English | MEDLINE | ID: covidwho-27190

ABSTRACT

BACKGROUND: Virus infections result in a range of clinical outcomes for the host, from asymptomatic to severe or even lethal disease. Despite global efforts to prevent and treat virus infections to limit morbidity and mortality, the continued emergence and re-emergence of new outbreaks as well as common infections such as influenza persist as a health threat. Challenges to the prevention of severe disease after virus infection include both a paucity of protective vaccines as well as the early identification of individuals with the highest risk that may require supportive treatment. METHODS: We completed a screen of mice from the Collaborative Cross (CC) that we infected with influenza, severe acute respiratory syndrome-coronavirus, and West Nile virus. RESULTS: The CC mice exhibited a range of disease manifestations upon infections, and we used this natural variation to identify strains with mortality after infection and strains exhibiting no mortality. We then used comprehensive preinfection immunophenotyping to identify global baseline immune correlates of protection from mortality to virus infection. CONCLUSIONS: These data suggest that immune phenotypes might be leveraged to identify humans at highest risk of adverse clinical outcomes upon infection, who may most benefit from intensive clinical interventions, in addition to providing insight for rational vaccine design.


Subject(s)
Mortality , RNA Virus Infections/immunology , RNA Virus Infections/mortality , Animals , Collaborative Cross Mice , Cytokines/metabolism , Disease Models, Animal , Female , Humans , Influenza A virus/immunology , Influenza, Human , Male , Mice , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/mortality , RNA , RNA Virus Infections/virology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/mortality , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Viral Vaccines/immunology , West Nile Fever/immunology , West Nile Fever/mortality , West Nile virus/immunology
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