Yellow Fever Virus Research Articles

Nifuroxazide Prevents Chikungunya Virus Infection Both In Vitro and In Vivo via Suppressing Viral Replication.

Chikungunya virus (CHIKV) is a reemerging arbovirus causing disease on a global scale, and the potential for its epidemics remains high. CHIKV has caused millions of cases and heavy economic burdens around the world, while there are no available approved antiviral therapies to date. In this study, nifuroxazide, an FDA-approved antibiotic for acute diarrhea or colitis, was found to significantly inhibit a variety of arboviruses, although its antiviral activity varied among different target cell types. Nifuroxazide exhibited relatively high inhibitory efficiency in yellow fever virus (YFV) infection of the hepatoma cell line Huh7, tick-borne encephalitis virus (TBEV) and west nile virus (WNV) infection of the vascular endothelial cell line HUVEC, and CHIKV infection of both Huh7 cells and HUVECs, while it barely affected the viral invasion of neurons. Further systematic studies on the action stage of nifuroxazide showed that nifuroxazide mainly inhibited in the viral replication stage. In vivo, nifuroxazide significantly reduced the viral load in muscles and protected mice from CHIKV-induced footpad swelling, an inflammation injury within the arthrosis of infected mice. These results suggest that nifuroxazide has a potential clinical application as an antiviral drug, such as in the treatment of CHIKV infection.

Aptamer and aptasensor technology for diagnosis of infectious diseases: A mini review

BackgroundAptamers are not so new a concept, however, it is scarcely discussed by medical fraternity. Aptamers are potent, new identification molecules set to rope in a new technique in the diagnostic arena. Aptamers have started almost a revolution in diagnostic assays since their discovery in the 90s. (Radu S. Current and previous disease outbreaks around the world, U.S. News & World Report. 2020 Mar 13 [cited 2024 Jun 17]. Available from: https://www.usnews.com/news/best-countries/slideshows/20-pandemic-and-epidemic-diseases-according-to-who) provides an overview of pandemics and epidemics as reported by the WHO. It is interesting to note that several endemic and epidemic diseases viz. Chikungunya, Cholera, Crimean-Congo haemorrhagic fever, Ebola virus disease, Hendra virus infection, Influenza, Lassa fever, Marburg virus disease, Meningitis, MERS-CoV (Middle East Respiratory Syndrome Corona Virus), Monkeypox, Nipah virus infection, Novel coronavirus, Plague, Rift Valley fever, SARS (Severe Acute Respiratory Syndrome), Smallpox, Tularaemia, Yellow fever, and Zika virus disease have been identified by the WHO and are being explored for applicability of aptamer technology in their identification. ObjectivesOne of the most important necessities to control epidemic or pandemic diseases is early diagnosis. However, the majority of the diagnostic tests for these diseases are available only in tertiary care centres. The objective of this review is to discuss the potential of aptamer technology to provide undemanding, simple, specific, sensitive, and cost-effective diagnostic assays that are useable in remote and field conditions. ContentHere, we discuss recent advances and approaches in aptamer and aptamer engineering useful in the diagnosis of infectious and non-infectious conditions. This review also discusses a few sensing discoveries which are a gift of advanced engineering and technology using optical and electrochemical aptasensors. It's still a long way to go, and we need to take into account the technological challenges being faced by aptamer-aptasensor technology.

Homonymous hemianopia following yellow fever vaccination: a case of acute disseminated encephalomyelitis.

A 42-year-old Caucasian man developed left homonymous hemianopia sixteen days after receipt of a live-attenuated 17D-204 yellow fever virus vaccine. MRI imaging of the brain revealed right occipital and left parieto-occipital lesions with marked hyperintensity consistent with demyelination, and a diagnosis of yellow fever vaccine-associated acute disseminated encephalomyelitis was made.

Epidemiological Modelling of Yellow Fever Dynamics

Aims: Yellow fever is a severe and often fatal viral illness caused by the yellow fever virus Despite being largely overlooked, yellow fever continues to silently claim lives in many parts of the world. The study focuses on the epidemiological modelling of yellow fever dynamics between a host (human) and vector (mosquito) populations The human population was divided into five main compartments: Susceptible, Exposed, Infected, Isolated, and Recovered. The vector population was also divided into two compartments: Susceptible and Infected. Nonlinear differential equations describing these compartments were formulated. Stability analysis and numerical simulations were then performed based on the formulated equations. From the stability analysis, it was observed that the disease-free equilibrium is both locally and globally asymptotically stable. Similarly, the endemic equilibrium was found to be locally and globally asymptotically stable. The simulation also revealed a direct correlation between the transmission rate and disease spread.

First detection of V410L kdr mutation in Aedes aegypti populations of Argentina supported by toxicological evidence

BackgroundAedes aegypti (L.) is the main vector of dengue, yellow fever, Zika, and chikungunya viruses in many parts of the world, impacting millions of people worldwide each year. Insecticide-based interventions have been effective in controlling Aedes mosquito populations for several years, but in recent times, resistance to these compounds has developed, posing a global threat to the control of this mosquito.MethodsOvitraps were used to collect A. aegypti eggs in the cities of Tartagal and San Ramón de la Nueva Orán (Salta), Puerto Iguazú (Misiones), and Clorinda (Formosa). World Health Organization (WHO)-impregnated papers with the discriminating concentration (DC) of permethrin, 5X, 10X and pirimiphos methyl were used for the toxicological bioassays. We also genotyped each sample for the three kdr single nucleotide polymorphisms (SNP): V410L, V1016I, and F1534C in individual TaqMan quantitative PCR (qPCR) reactions.ResultsAll investigated A. aegypti populations were highly resistant to permethrin, as the mortality percentage with the permethrin 10×DC remained below 98%. However, all populations were 100% susceptible to pirimiphos-methyl. Kdr genotyping demonstrated the presence of the V410L mutation for the first time in Argentina in all the populations studied. A prevalence of the triple mutant genotype (LL + II + CC) was observed in the northeastern cities of Clorinda (83.3%) and Puerto Iguazú (55.6%).ConclusionsThis study demonstrates for the first time the presence and intensity of resistance to permethrin in different populations from Argentina, and correlates the observed phenotype with the presence of kdr mutations (genotype).Graphical

Identification of specific IgG class antibodies to certain flaviviruses in the population of the Republic of Guinea

One of the most common arboviruses in the world are representatives of the genus Orthoflavivirus (family Flaviviridae). On the territory of the Republic of Guinea, the circulation of such representatives of this family as the yellow fever virus (YFV), West Nile virus (WNV) and dengue virus (DENV) has been confirmed. The aim of the study was to determine the level of specific IgG class antibodies to YFV, DENV and WNV in residents of various landscape– geographical zones of the Republic of Guinea by the ELISA method. Materials and methods. For the study, a panel of 1559 blood serums from practically healthy people was compiled, which were collected in all landscape and geographical zones of the Republic of Guinea. The detection of specific IgG class antibodies to DENV and WNV was carried out with commercial diagnostic drugs, and for YFV — with an experimental ELISA test system based on an analogue of the third domain of protein E obtained at the State Research Center for Virology and Biotechnology “Vector” of Rospotrebnadzor. Results. When testing blood sera in 28.5% (95% CI: 26.3–30.7) of cases, IgG antibodies to YFV, to DENV — in 11.8%, (95% CI: 10.3–13.5) and to WNV — in 27.0% (95% CI: 24.8–29.3) were detected. Antibodies to three viruses simultaneously (YFV, DENV and WNV) were detected in 30 cases, to YFV and DENV — 14, YFV and WNV — 44, DENV and WNV — 56. Conclusion. The detection of antibodies to WNV and DENV confirms the fact of the continued circulation of these pathogens in the territory of the Republic of Guinea, which poses a health risk to the local population. A detailed study of the molecular genetic and antigenic properties of flaviviruses circulating in this area will allow the development of more specific diagnostic tools.

Viral hijacking of hnRNPH1 unveils a G-quadruplex-driven mechanism of stress control

Viral genomes are enriched with G-quadruplexes (G4s), non-canonical structures formed in DNA or RNA upon assembly of four guanine stretches into stacked quartets. Because of their critical roles, G4s are potential antiviral targets, yet their function remains largely unknown. Here, we characterize the formation and functions of a conserved G4 within the polymerase coding region of orthoflaviviruses of the Flaviviridae family. Using yellow fever virus, we determine that this G4 promotes viral replication and suppresses host stress responses via interactions with hnRNPH1, a host nuclear protein involved in RNA processing. G4 binding to hnRNPH1 causes its cytoplasmic retention with subsequent impacts on G4-containing tRNA fragments (tiRNAs) involved in stress-mediated reductions in translation. As a result, these host stress responses and associated antiviral effects are impaired. These data reveal that the interplay between hnRNPH1 and both host and viral G4 targets controls the integrated stress response and viral replication.

A reporter virus particle seroneutralization assay for tick-borne encephalitis virus overcomes ELISA limitations.

Tick-borne encephalitis (TBE) virus is the most prevalent tick-transmitted orthoflavivirus in Europe. Due to the nonspecific nature of its symptoms, TBE is primarily diagnosed by ELISA-based detection of specific antibodies in the patient serum. However, cross-reactivity between orthoflaviviruses complicates the diagnosis. Specificity issues may be mitigated by serum neutralization assays (SNT), although the handling of clinically relevant orthoflaviviruses requires biosafety level (BSL) 3 conditions and they have highly divergent viral kinetics and cell tropisms. In the present study, we established a reporter virus particle (RVP)-based SNT in which the infectivity is measured by luminescence and that can be performed under BSL-2 conditions. The RVP-based SNT for TBEV exhibited a highly significant correlation with the traditional virus-based SNT (R2 = 0.8637, p < 0.0001). The RVP-based assay demonstrated a sensitivity of 92.3% (95% CI: 79.7%-97.4%) and specificity of 100% (95% CI: 81.6%-100%). We also tested the cross-reactivity of serum samples in RVP-based assays against other orthoflaviviruses (yellow fever virus, dengue virus type 2, Zika virus, West Nile virus and Japanese encephalitis virus). Interestingly, all serum samples which had tested TBEV-positive by ELISA but negative by RVP-based SNT were reactive for antibodies against other orthoflaviviruses. Thus, the RVP-based seroneutralization assay provides an added value in clinical diagnostics as well as in epidemiological studies.

Novel Pyrazino[1,2-a]indole-1,3(2H,4H)-dione Derivatives Targeting the Replication of Flaviviridae Viruses: Structural and Mechanistic Insights.

Infections with Flaviviridae viruses, such as hepatitis C (HCV), dengue (DENV), and yellow fever (YFV) viruses, are major public health problems worldwide. In the case of HCV, treatment is associated with drug resistance and high costs, while there is no clinically approved therapy for DENV and YFV. Consequently, there is still a need for new chemotherapies with alternative modes of action. We have previously identified novel 2-hydroxypyrazino[1,2-a]indole-1,3(2H,4H)-diones as metal-chelating inhibitors targeting HCV RNA replication. Here, by utilizing a structure-based approach, we rationally designed a second series of compounds by introducing various substituents at the indole core structure and at the imidic nitrogen, to improve specificity against the RNA-dependent RNA polymerase (RdRp). The resulting derivatives were evaluated for their potency against HCV genotype 1b, DENV2, and YFV-17D using stable replicon cell lines. The most favorable substitution was nitro at position 6 of the indole ring (compound 36), conferring EC50 1.6 μM against HCV 1b and 2.57 μΜ against HCV 1a, with a high selectivity index. Compound 52, carrying the acetohydroxamic acid functionality (-CH2CONHOH) on the imidic nitrogen, and compound 78, the methyl-substituted molecule at the position 4 indolediketopiperazine counterpart, were the most effective against DENV and YFV, respectively. Interestingly, compound 36 had a high genetic barrier to resistance and only one resistance mutation was detected, T181I in NS5B, suggesting that the compound target HCV RdRp is in accordance with our predicted model.

The Flavivirus Non-Structural Protein 5 (NS5): Structure, Functions, and Targeting for Development of Vaccines and Therapeutics.

Flaviviruses, including dengue (DENV), Zika (ZIKV), West Nile (WNV), Japanese encephalitis (JEV), yellow fever (YFV), and tick-borne encephalitis (TBEV) viruses, pose a significant global emerging threat. With their potential to cause widespread outbreaks and severe health complications, the development of effective vaccines and antiviral therapeutics is imperative. The flaviviral non-structural protein 5 (NS5) is a highly conserved and multifunctional protein that is crucial for viral replication, and the NS5 protein of many flaviviruses has been shown to be a potent inhibitor of interferon (IFN) signalling. In this review, we discuss the functions of NS5, diverse NS5-mediated strategies adopted by flaviviruses to evade the host antiviral response, and how NS5 can be a target for the development of vaccines and antiviral therapeutics.

Immunogenicity and Protective Efficacy of Aerosolized Live-Attenuated Yellow Fever 17D Vaccine in Mice.

Yellow fever (YF), caused by the yellow fever virus (YFV), continually spreads and causes epidemics worldwide, posing a great threat to human health. The live-attenuated YF 17D vaccine (YF-17D) has been licensed for preventing YFV infection and administrated via the intramuscular (i.m.) route. In this study, we sought to determine the immunogenicity and protective efficacy of aerosolized YF-17D via the intratracheal (i.t.) route in mice. YF-17D stocks in liquids were successfully aerosolized into particles of 6 μm. Further in vitro phenotype results showed the aerosolization process did not abolish the infectivity of YF-17D. Meanwhile, a single i.t. immunization with aerosolized YF-17D induced robust humoral and cellular immune responses in A129 mice, which is comparable to that received i.p. immunization. Notably, the aerosolized YF-17D also triggered specific secretory IgA (SIgA) production in bronchoalveolar lavage. Additionally, all immunized animals survived a lethal dose of YFV challenge in mice. In conclusion, our results support further development of aerosolized YF-17D in the future.

Structural Insights into the Dynamic Assembly of a YFV sNS1 Tetramer.

Yellow fever virus (YFV) infections can cause severe diseases in humans, resulting in mass casualties in Africa and the Americas each year. Secretory NS1 (sNS1) is thought to be used as a diagnostic marker of flavivirus infections, playing an essential role in the flavivirus life cycle, but little is known about the composition and structure of YFV sNS1. Here, we present that the recombinant YFV sNS1 exists in a heterogeneous mixture of oligomerizations, predominantly in the tetrameric form. The cryoEM structures show that the YFV tetramer of sNS1 is stacked by the hydrophobic interaction between β-roll domains and greasy fingers. According to the 3D variability analysis, the tetramer is in a semi-stable state that may contain multiple conformations with dynamic changes. We believe that our study provides critical insights into the oligomerization of NS1 and will aid the development of NS1-based diagnoses and therapies.

Mosquito vectors of yellow fever virus in areas of epidemiological risk in northeastern Argentina

Mosquito vectors of yellow fever virus in areas of epidemiological risk in northeastern Argentina

Comparative Evaluation of Select Serological Assays for Zika Virus Using Blinded Reference Panels.

In response to the 2015 Zika virus (ZIKV) epidemic that occurred in Brazil, numerous commercial serological assays have been developed for clinical and research applications. Diagnosis of recent infection in pregnant women remains challenging. Having standardized, comparative studies of ZIKV tests is important for implementing optimal diagnostic testing and disease surveillance. This is especially important for serology tests used to detect ZIKV infection given that antibodies against ZIKV can cross-react with other arboviruses in the same virus family, such as dengue virus (DENV), yellow fever virus (YFV) and West Nile virus (WNV). We looked at the sensitivity and specificity of tests detecting ZIKV antibodies (IgM, IgG) from multiple manufacturers using panels of samples previously collected with known exposure to ZIKV and other arboviruses. We found that performance of the IgM tests was highly variable, with only one test (Inbios 2.0 IgM capture ELISA) having both high sensitivity and specificity. All IgG tests showed good sensitivity; however, specificity was highly variable, with some assays giving false-positive results on samples infected by another flavivirus. Overall, the results confirmed that accurate ZIKV antibody testing is challenging, especially in specimens from regions endemic for multiple other flaviviruses, and highlight the importance of available and suitable reference samples to evaluate ZIKV diagnostics.

Establishment of a multisite umbrella cohort study protocol to describe the epidemiology and aetiologies of acute undifferentiated febrile illness in Latin America

IntroductionAcute undifferentiated febrile illnesses (AUFIs) impose a large burden in the tropics. Understanding of AUFI’s epidemiology is limited. Insufficient diagnostic capacity hinders the detection of outbreaks. The lack of interconnection...

The GA-Hecate Peptide inhibits the ZIKV Replicative Cycle in Different Steps and can Inhibit the Flavivirus NS2B-NS3 Protease after Cell Infection.

Peptide drugs are advantageous because they are subject to rational design and exhibit highly diverse structures and broad biological activities. The NS2B-NS3 protein is a particularly promising flavivirus therapeutic target, with extensive research on the development of inhibitors as therapeutic candidates, and was used as a model in this work to determine the mechanism by which GA-Hecate inhibits ZIKV replication. The present study aimed to evaluate the potential of GA-Hecate, a new antiviral developed by our group, against the Brazilian Zika virus and to evaluate the mechanism of action of this compound on the flavivirus NS2B-NS3 protein. Solid-phase peptide Synthesis, High-Performance Liquid Chromatography, and Mass Spectrometry were used to obtain, purify, and characterize the synthesized compound. Real-time and enzymatic assays were used to determine the antiviral potential of GA-Hecate against ZIKV. The RT-qPCR results showed that GA-Hecate decreased the number of ZIKV RNA copies in the virucidal, pre-treatment, and post-entry assays, with 5- to 6-fold fewer RNA copies at the higher nontoxic concentration in Vero cells (HNTC: 10 μM) than in the control cells. Enzymatic and kinetic assays indicated that GA-Hecate acts as a competitive ZIKV NS2B-NS3 protease inhibitor with an IC50 of 32 nM and has activity against the yellow fever virus protease. The results highlight the antiviral potential of the GA-Hecate bioconjugate and open the door for the development of new antivirals.

Detection and population genetic analysis of Aedes albopictus (Diptera: Culicidae) based on knockdown resistance (kdr) mutations in the Yangtze River basin of China

BackgroundAedes albopictus is an important vector of chikungunya, dengue, yellow fever and Zika viruses. Insecticides are often the most effective tools for rapidly decreasing the density of vector populations, especially during arbovirus disease outbreaks. However, the intense use of insecticides, particularly pyrethroids, has led to the selection of resistant mosquito populations worldwide. Mutations in the voltage-gated sodium channel (VGSC) gene are one of the main drivers of insecticide resistance in Ae. albopictus and are also known as “knockdown resistance” (kdr) mutations. Knowledge about genetic mutations associated with insecticide resistance is a prerequisite for developing techniques for rapid resistance diagnosis. Here, we report studies on the origin and dispersion of kdr haplotypes in samples of Ae. albopictus from the Yangtze River Basin, China; MethodsHere, we report the results of PCR genotyping of kdr mutations in 541 Ae. albopictus specimens from 22 sampling sites in 7 provinces and municipalities in the Yangtze River Basin. Partial DNA sequences of domain II and domain III of the VGSC gene were amplified. These DNA fragments were subsequently sequenced to discover the possible genetic mutations mediating knockdown resistance (kdr) to pyrethroids. The frequency and distribution of kdr mutations were assessed in 22 Ae. albopictus populations. Phylogenetic relationships among the haplotypes were used to infer whether the kdr mutations had a single or multiple origins; ResultsThe kdr mutation at the 1016 locus had 2 alleles with 3 genotypes: V/V (73.38%), V/G (26.43%) and G/G (0.18%). The 1016G homozygous mutation was found in only one case in the CQSL strain in Chongqing, and no 1016G mutations were detected in the SHJD (Shanghai), NJDX (Jiangsu) or HBQN (Hubei) strains. A total of 1532 locus had two alleles and three genotypes, I/I (88.35%), I/T (8.50%) and T/T (3.14%). A total of 1534 locus had four alleles and six genotypes: F/F (49.35%), F/S (19.96%), F/C (1.48%) and F/L (0.18%); S/S (23.66%); and C/C (5.36%). Haplotypes with the F1534C mutation were found only in Ae. albopictus populations in Chongqing and Hubei, and C1534C was found only in three geographic strains in Chongqing. Haplotypes with the 1534S mutation were found only in Ae. albopictus populations in Sichuan and Shanghai. F1534L was found only in HBYC. The Ae. albopictus populations in Shanghai were more genetically differentiated from those in the other regions (except Sichuan), and the genetic differentiation between the populations in Chongqing and those in the middle-lower reaches of the Yangtze River (Huber, Jiangsu, Jiangxi, and Anhui) was lower. Shanghai and Sichuan displayed low haplotype diversity and low nucleotide diversity. Phylogenetic analysis and sequence comparison revealed that the 1016 locus was divided into three branches, with the Clade A and Clade B branches bearing the 1016 mutation occurring mostly in Jiangsu and the Clade C branch bearing the 1016 mutation occurring mostly in Chongqing, suggesting at least two origins for 1016G. IIIS6 phylogenetic analysis and sequence comparison revealed that F1534S, F1534C and I1532T can be divided into two branches, indicating that IIIS6 has two origins; ConclusionsCombined with the distribution of kdr mutations and the analysis of population genetics, we infer that besides the local selection of pyrethroid resistance mutations, dispersal and colonization of Ae. albopictus from other regions may explain why kdr mutations are present in some Ae. albopictus populations in the Yangtze River Basin.

Serological Evidence of Zika Virus Infections in Sudan.

Little is known about the frequency of Zika virus (ZIKV) infections in Sudan. The aim of this study was to obtain data on the prevalence of ZIKV infections and the immunity of the population in the country. To this end, 198 sera obtained between December 2012 and January 2013 in different regions in Sudan were examined for neutralizing antibodies against ZIKV, dengue virus (DENV), and yellow fever virus (YFV). The sera were non-randomly selected. The neutralization titers were compared with each other and with the WHO 1st International Standard for anti-Asian lineage Zika virus antibody. Twenty-six sera neutralized ZIKV. One-third of these sera had higher neutralization titers against ZIKV than against DENV-2 and -3. Two sera showed higher neutralization titers than the WHO standard for ZIKV antibodies. These data suggest occasional ZIKV infections in Sudan. The low percentage of sera in this cohort that neutralized ZIKV indicates that, in the study period, the population was susceptible to ZIKV infection.

One-pot synthesis, characterization and antiviral properties of new benzenesulfonamide-based spirothiazolidinones

A novel series of benzenesulfonamide substituted spirothiazolidinone derivatives (3a–j) were synthesized, characterized and evaluated for their antiviral activity. The spirocyclic compounds were prepared by the condensation of 4-(aminosulfonyl)-2-methoxybenzohydrazide, appropriate cyclic ketones and 2-mercaptopropionic acid in a one-pot reaction. The structures of the new compounds were established by IR, 1H NMR, 13C NMR (APT), and elemental analysis. The new compounds were evaluated in vitro antiviral activity against influenza A/H1N1, A/H3N2 and B viruses, as well as herpes simplex virus type 1 (HSV-1), respiratory syncytial virus (RSV) and yellow fever virus (YFV). Two derivatives bearing propyl (3d) and tert-butyl (3e) substituents at position 8 of the spiro ring exhibited activity against influenza A/H1N1 virus with EC50 values in the range of 35–45 µM and no cytotoxicity at 100 μM, the highest concentration tested.

Nanosheets adsorption and antiviral activity of Favipiravir drug against envelope proteins of yellow fever virus: DFT and molecular docking simulation study

Our previous research investigated the delivery of Favipiravir (FAV) drug through the encapsulation of FAV into 1D nanomaterials (NMs), AlN, BN, and carbon nanotubes, now we evaluated the possibility of using 2D NMs carbon nanosheets (GPNS), boron nitride nanosheets (BNNS), and aluminum nitride nanosheets (AlNNS) as drug delivery systems. The adsorption of FAV drug in its two tautomeric forms over the surfaces of these NSs is conducted. The adsorption energies are in the range of − 0.681 to − 2.469 eV. FAV binds to BNNS and GPNS through stacking interactions, while it chemisorbs to AlNNS. NCI and QTAIM analyses confirmed the dominance of vdW interactions. The recovery times over NSs were shorter than those inside NTs, and they indicated that NSs are better for drug release while NTs bind better and have larger adsorption energies. MD simulations revealed that FAV showed a good level of resistance to yellow fever virus (YFV) infections.