Dengue Virus Research Articles

Comparative Diagnostic Value of Dengue Infection Using ELFA and Two Commercial Immuno-Chromatography Tests

Dengue Virus (DEN-V) can lead to a broad spectrum of clinical presentations, from mild symptoms to mortality. Based on the presence of antibodies, dengue infection is categorized into primary and secondary dengue. Early diagnosis is crucial for effective treatment of DEN-V infection. Non-Structural Antigen 1 (NS1) and dengue antibodies like immunoglobulin M (IgM) and immunoglobulin G (IgG) anti-dengue are standard assays used for dengue diagnosis. Various immunoassay methods, including Enzyme-Linked Fluorescent Assay (ELFA) and Immuno-Chromatographic Tests (ICT), are employed to detect these antigens and antibodies. This study aimed to compare the diagnostic value between ELFA and two commercial ICTs for detecting NS1 antigen, IgM/IgG anti-dengue. Seventy suspected dengue patients with fever lasting two to seven days at Premier Hospital, Surabaya were enrolled in this study. Blood serum samples from the individuals were tested for NS1 antigen and IgM/IgG anti-dengue using VIDAS® and two commercial ICTs (Boson and SD Bioline). The sensitivity of NS1 antigen assays using ELFA and two ICTs was calculated, as well as the agreement rate between ELFA and both ICTs. ELFA demonstrated high sensitivity (77.97%) for NS1 antigen detection in diagnosing dengue infection compared to two ICTs (76.27% and 45.45%). Using an automated system in ELFA can offer more excellent diagnostic value and objective results and determine the cut-off ratio of IgM/IgG antibodies. All of this comes at a cost comparable to ICT.

Detecting the impacts of humidity, rainfall, temperature, and season on chikungunya, dengue and Zika viruses in Aedes albopictus mosquitoes from selected sites in Cebu city, Philippines

BackgroundAedes albopictus is the secondary vector for dengue virus (DENV) in the Philippines, and also harbors chikungunya (CHIKV) and Zika (ZIKV) viruses. This study aimed to determine the minimum infection rates (MIRs) of CHIKV, DENV serotypes, and ZIKV in Ae. albopictus collected from selected two-site categories by altitude (highland [H] and lowland [L] sites) in Cebu city, Philippines during the wet (WS) and dry seasons (DS) of 2021–2022, and to explore the relationships between these arboviral MIRs and the local weather.MethodsThe viral RNA extracts in pooled and reared adult Ae. albopictus collected during the DS and WS from two-site categories were subjected to RT-PCR to amplify and detect gene loci specific for CHIKV, DENV-1 to DENV-4, and ZIKV and analyzed with the weather data.ResultsThe range of CHIKV MIRs was higher in the WS (13.61–107.38 infected individuals per 1,000 mosquitoes) than in the DS (13.22–44.12), but was similar between the two-site categories. Rainfall (RF) influenced the CHIKV MIR. The MIR ranges of both DENV-2 (WS: H = 0, L = 0; DS: H = 0–5.92; L = 0–2.6) and DENV-4 (WS: H = 0, L = 0–2.90; DS: H = 2.96–6.13, L = 0–15.63) differed by season but not between the two-site categories. Relative humidity (RH), RF, and temperature did not influence DENVs’ MIRs. The MIR range of ZIKV was similar in both seasons (WS: 11.36–40.27; DS: 0–46.15) and two-site categories (H = 0–90.91, L = 0–55.56). RH and temperature influenced ZIKV MIR.ConclusionsRF influenced CHIKV MIR in Ae. albopictus, whereas RH and temperature influenced that of ZIKV. Season influenced the MIRs of CHIKV and DENVs but not in ZIKV. Ae. albopictus were co-infected with CHIKV, DENVs, and ZIKV in both highland and lowland sites in Cebu city. Recommendations include all-year-round implementation of the Philippine Department of Health’s 4S enhanced strategy and installation of water pipelines in rural highlands for vector and disease control. Our findings are relevant to protect public health in the tropics in this climate change.

Zika Virus-A Reemerging Neurotropic Arbovirus Associated with Adverse Pregnancy Outcomes and Neuropathogenesis.

Zika virus (ZIKV) is a reemerging flavivirus that is primarily spread through bites from infected mosquitos. It was first discovered in 1947 in sentinel monkeys in Uganda and has since been the cause of several outbreaks, primarily in tropical and subtropical areas. Unlike earlier outbreaks, the 2015-2016 epidemic in Brazil was characterized by the emergence of neurovirulent strains of ZIKV strains that could be sexually and perinatally transmitted, leading to the Congenital Zika Syndrome (CZS) in newborns, and Guillain-Barre Syndrome (GBS) along with encephalitis and meningitis in adults. The immune response elicited by ZIKV infection is highly effective and characterized by the induction of both ZIKV-specific neutralizing antibodies and robust effector CD8+ T cell responses. However, the structural similarities between ZIKV and Dengue virus (DENV) lead to the induction of cross-reactive immune responses that could potentially enhance subsequent DENV infection, which imposes a constraint on the development of a highly efficacious ZIKV vaccine. The isolation and characterization of antibodies capable of cross-neutralizing both ZIKV and DENV along with cross-reactive CD8+ T cell responses suggest that vaccine immunogens can be designed to overcome these constraints. Here we review the structural characteristics of ZIKV along with the evidence of neuropathogenesis associated with ZIKV infection and the complex nature of the immune response that is elicited by ZIKV infection.

Dengue Cases Presenting to the Emergency Department of a Tertiary Care Hospital in Late 2021: A Cross-Sectional Study in Karachi.

Objectives: Dengue Fever (DF) is an arboviral disease caused by the Dengue virus (DENV). This study aims to assess the association of dengue prevalence with patients' residential areas and hematological laboratory findings (Total platelet count, immunoglobulins, and dengue antigens) during COVID-19 pandemic. Methods: A retrospective study was conducted at the Emergency department of Jinnah Postgraduate Medical Center, Karachi from October to December 2021. All the patients irrespective of their ages presenting to the ED with either of the following complaints: fever; GIT problems; vomiting; body ache; bleeding were included in our study. Results: Our study comprised 189 patients in total in which the females (n = 172) outnumbered the males (n = 17). Out of all, 84.7% of the patients were febrile having a low-grade fever on average. Korangi district had the most dengue cases, while Keamari had the fewest. There was no significant association reported between mean platelet count, mean TLC, and mean hemoglobin levels with dengue positivity. Conclusion: There is a concerning rise in DF cases in Karachi, particularly in the Korangi district. Despite the COVID-19 pandemic, DF demands urgent attention.

Implementation of Fuzzy K-Nearest Neighbor Method in Dengue Disiase Classification

Dengue hemorrhagic fever (DHF) is a condition brought on by infection with the dengue virus. DHF is a severe illness with hemorrhagic clinical signs that can result in shock and death. One of the four viral serotypes of the genus Flavivirus is responsible for DHF. DHF symptoms include fever, joint pain, red skin patches, and others that are similar to those of other illnesses. So that there are no errors in illness prediction, strong accuracy and accuracy are required when classifying DHF patients or not. The Fuzzy K-Nearest Neighbor (FKNN) method is used in this study to classify dengue sickness in order to obtain the best classification outcomes. In this investigation, k was searched for eight times, with values of 3,5,7,9,11,13,15, and 20. Each K's accuracy statistics are 75.15, 75.16, 77.58%, 79.51%, 85.01%, 78.14%, and 75.20 percent. K = 13, which has an accuracy score of 85.01%, yields the highest accuracy.

Comprehensive evaluation on progressive development strategies in DENV surveillance and monitoring infection rate among vector population.

The elevated rise in dengue infection rate has been a health burden worldwide and it will continue to impact global health for years to come. Accumulated literature holds accountable the geographical expansion of the mosquito species transmitting the dengue virus DENV. The frequency of this viral disease outbreaks has increased rapidly in the recent years, owing to various geo-climatic and anthropological activities. Due to scarcity of any effective control measures, there has been a continuous traceable rise in mortality and morbidity rates. However, it has been reported that the spate of incidences is directly related to density of the virus infected vector (mosquito) population in a given region. In such a scenario, systems capable of detecting virus infected vector population would aid in estimating prediction of outbreak, as well as provide time to deploy suitable management strategies for vector control, and to break the vector-human transmission chain. This would also help in identifying areas, where much improvement is needed for vector management. To this context, we illustrate an exhaustive overview of both gold standards and as well as emerging advents for sensitive and specific mosquito population strategized viral detection technologies. We summarize the cutting-edge technologies and the challenges faced in pioneering to field application. Regardless the proven popularity of the gold standards for detection purpose, they offer certain limitations. Thus with the surge in the infection rate globally, approaches for development of newer advancements and technique upgradation to arrest the infection escalation and for early detection as a part of vector management should be prioritized.

Tanreqing injection inhibits dengue virus encephalitis by suppressing the activation of NLRP3 inflammasome

BackgroundEncephalitis caused by dengue virus (DENV) is considered a manifestation of severe dengue. Tanreqing injection (TRQ) is a well-known Chinese patented medicine, which has been used to treat brain-related disorders by inhibiting inflammation. Nevertheless, the effects of TRQ on DENV encephalitis have not been studied. The aim of this study was to evaluate the effects of TRQ on DENV encephalitis and to explore its potential mechanisms.MethodsThe cytotoxicity of TRQ was examined by MTT assay, and the anti-DENV activities of TRQ in BHK-21 baby hamster kidney fibroblast were evaluated through CCK-8 and plaque assays. The expression levels of NO, IL1B/IL-1β, TNFα and IL6 were measured by qRT‒PCR and ELISA in the BV2 murine microglial cell line. The inhibitory effects of TRQ on NLRP3 inflammasome activation in BV2 cells were examined by Western blotting, qRT‒PCR and ELISA. The effects of TRQ on HT22 mouse hippocampal neuronal cells were examined by CCK-8 assay, morphology observation and flow cytometry. Moreover, a DENV-infected ICR suckling mouse model was developed to investigate the protective role of TRQ in vivo.ResultsTRQ decreased the release of NO, IL6, TNFα and IL1B from BV2 cells and inhibited the activation of NLRP3. The presence of the NLRP3 agonist nigericin reversed the anti-inflammatory activities of TRQ. Furthermore, TRQ inhibited the death of HT22 cells by decreasing IL1B in DENV-infected BV2 cells. In addition, TRQ significantly attenuated weight loss, reduced clinical scores and extended the survival in DENV-infected ICR suckling mice. Critically, TRQ ameliorated pathological changes in ICR suckling mice brain by inhibiting microglia and NLRP3 activation and decreasing the production of inflammatory factors and the number of dead neurons.ConclusionTRQ exerts potent inhibitory effects on dengue encephalitis in vitro and in vivo by reducing DENV-2-induced microglial activation and subsequently decreasing the inflammatory response, thereby protecting neurons. These findings demonstrate the potential of TRQ in the treatment of dengue encephalitis.

Multiplex Serology for Sensitive and Specific Flavivirus IgG Detection: Addition of Envelope Protein Domain III to NS1 Increases Sensitivity for Tick-Borne Encephalitis Virus IgG Detection.

Tick-borne encephalitis is a vaccine-preventable disease of concern for public health in large parts of Europe, with EU notification rates increasing since 2018. It is caused by the orthoflavivirus tick-borne encephalitis virus (TBEV) and a diagnosis of infection is mainly based on serology due to its short viremic phase, often before symptom onset. The interpretation of TBEV serology is hampered by a history of orthoflavivirus vaccination and by previous infections with related orthoflaviviruses. Here, we sought to improve TBEV sero-diagnostics using an antigen combination of in-house expressed NS1 and EDIII in a multiplex, low-specimen-volume set-up for the detection of immune responses to TBEV and other clinically important orthoflaviviruses (i.e., West Nile virus, dengue virus, Japanese encephalitis virus, Usutu virus and Zika virus). We show that the combined use of NS1 and EDIII results in both a specific and sensitive test for the detection of TBEV IgG for patient diagnostics, vaccination responses and in seroprevalence studies. This novel approach potentially allows for a low volume-based, simultaneous analysis of IgG responses to a range of orthoflaviviruses with overlapping geographic circulations and clinical manifestations.

Prior dengue virus serotype 3 infection modulates subsequent plasmablast responses to Zika virus infection in rhesus macaques.

The Zika virus epidemic of 2015-2016 in the Americas revealed that this mosquito-transmitted virus could be congenitally transmitted during pregnancy and cause birth defects in newborns. Currently, there are no interventions to mitigate this disease and Zika virus is likely to re-emerge. Understanding how protective antibody responses are generated against Zika virus can help in the development of a safe and effective vaccine. One main challenge is that Zika virus co-circulates with related viruses like dengue, such that prior exposure to one can generate cross-reactive antibodies against the other which may enhance infection and disease from the second virus. In this study, we sought to understand how prior dengue virus infection impacts subsequent immunity to Zika virus by single-cell sequencing of antibody producing cells in a second Zika virus infection. Identifying specific qualities of Zika virus immunity that are modulated by prior dengue virus immunity will enable optimal immunization strategies.

Progress in epidemiological characteristics and surveillance and early warning of dengue fever in China

Dengue fever is an acute mosquito-borne infectious disease caused by dengue virus and widely spread worldwide. Many factors, such as pathogens, vector organisms, climate, and social environment, affect its transmission and prevalence. The local dengue fever epidemic caused by imported cases in China shows a trend of increasing epidemic latitude and more widespread epidemic areas. However, the traditional monitoring and early warning models of dengue fever mainly focus on researching a single factor and a single area. Establishing a multi-factor forecast and early warning system is urgent to strengthen the early warning capability for the dengue fever epidemic. This paper mainly discusses the epidemic characteristics, the influencing factors, and the surveillance and early warning models of dengue fever in China to provide a reference for the effective prevention and control of dengue fever in China.

Unraveling Dengue Dynamics: In-Depth Epidemiological and Entomological Analyses in Bengaluru, India.

In view of the increased number of detected dengue cases in Bengaluru, a request for situation analysis was received from local health authorities in the selected area. The study included epidemiological and entomological assessments to understand the same. The immature forms collected were allowed to emerge, pooled, and processed for vector incrimination. In the surveyed population (347), 20 (5.8%) reported fever cases and 12 (3.5%) were confirmed as dengue cases among the 102 families. Stegomyia indices were high. Vector incrimination studies revealed pools positive for the presence of dengue virus in flower pots, fridge trays, plastic barrels, and rubber tires habitats. This study highlights the increased risk of dengue fever incidence in communities wherepoor intra and peri-domestic sanitation practices are prevailing and recommendsregular entomological surveillance of denguevirus in its vector population..

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

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.

Plant Extracts and Phytochemicals from the Asteraceae Family with Antiviral Properties.

Asteraceae (Compositae), commonly known as the sunflower family, is one of the largest plant families in the world and includes several species with pharmacological properties. In the search for new antiviral candidates, an in vitro screening against dengue virus (DENV) was performed on a series of dichloromethane and methanolic extracts prepared from six Asteraceae species, including Acmella bellidioides, Campuloclinium macrocephalum, Grindelia pulchella, Grindelia chiloensis, Helenium radiatum, and Viguiera tuberosa, along with pure phytochemicals isolated from Asteraceae: mikanolide (1), eupatoriopicrin (2), eupahakonenin B (3), minimolide (4), estafietin (5), 2-oxo-8-deoxyligustrin (6), santhemoidin C (7), euparin (8), jaceidin (9), nepetin (10), jaceosidin (11), eryodictiol (12), eupatorin (13), and 5-demethylsinensetin (14). Results showed that the dichloromethane extracts of C. macrocephalum and H. radiatum and the methanolic extracts prepared from C. macrocephalum and G. pulchella were highly active and selective against DENV-2, affording EC50 values of 0.11, 0.15, 1.80, and 3.85 µg/mL, respectively, and SIs of 171.0, 18.8, >17.36, and 64.9, respectively. From the pool of phytochemicals tested, compounds 6, 7, and 8 stand out as the most active (EC50 = 3.7, 3.1, and 6.8 µM, respectively; SI = 5.9, 6.7, and >73.4, respectively). These results demonstrate that Asteraceae species and their chemical constituents represent valuable sources of new antiviral molecules.

Seroprevalence of dengue, Japanese encephalitis and Zika among long-term expatriates in Thailand.

Travel to Southeast Asia increases the likelihood of acquiring mosquito-borne Flavivirus infections such as dengue (DENV), Japanese encephalitis (JEV) and Zika viruses (ZIKV). Expatriates are long-term travellers who have a higher risk of mosquito-borne illness at their destination country. The purpose of this study was to evaluate the seroprevalence of DENV, JEV and ZIKV infections and the determinants contributing to seropositivity among expatriates living in Thailand. A cross-sectional study was performed from December 2017 to February 2020. Expatriates from non-Flavivirus endemic countries were recruited. 5mL of blood was collected for DENV 1-4, JEV and ZIKV antibody testing by plaque reduction neutralization test (PRNT50). Individuals with vaccination histories or diagnoses for dengue, Japanese encephalitis, yellow fever and tick-borne encephalitis were excluded. Among 254 participants, most participants (83.1%) were male, the mean age was 65years and the median duration of stay in Thailand was 6years. Seroprevalence rate of any Flavivirus, non-specific DENV, DENV1-4, JEV and ZIKV were 34.3, 30.7, 20.5, 18.1, 18.9, 10.6, 4.7 and 2.8%, respectively. The presence of neutralizing antibodies against DENV1-4 positively correlates with the duration of stay in Thailand. DENV seropositivity was associated with living in urban areas (aOR 2.75, 95% CI 1.36-5.57). Expatriates were unlikely to have detectable anti-JEV antibodies regardless of time spent in a JEV-endemic area. No risk factors were identified that were significantly associated with JEV or ZIKV seropositivity. Only 48.4% received pre-travel counselling services, while only 18.9% visited a travel medicine specialist. A high proportion (34.3%) of long-term expatriates living in Thailand were seropositive for flavivirus, mainly from dengue (30.7%). To minimize risk, travel medicine practitioners should provide adequate pre-travel health risk information on mosquito-borne flavivirus infection and offer advice on mosquito bite prevention strategies. Dengue vaccine might be considered in high-risk travellers such as long-term expatriate.

Seroprevalence of dengue IgG and associated risk factors in symptomatic and asymptomatic adults in Posadas (Misiones, Argentina), 2017-2019

BackgroundDengue represents a major public health problem in the Americas in general, and in Posadas (Misiones, Argentina) in particular. This study aimed to assess the seroprevalence of dengue virus infection, analyze associated factors, and determine the proportion of asymptomatic cases. MethodsThis prospective cross-sectional study took place from November 2017 to April 2019 in the High Complexity Laboratory of Misiones, at the School Hospital Dr. Ramón Madariaga in Posadas. A random sample of 301 adults (≥ 15 years) was selected from the electoral registry and stratified by geographical area of residence. Sociodemographic, clinical, and laboratory data were collected by means of a survey and serology. Results were analyzed using multivariable logistic regression. ResultsThe median age of the sample was 33 years; 66% were women, and 46.5% had completed at least secondary school. Anti-dengue IgG antibodies were present in 40.2% of the sample (95% confidence interval [CI] 34.5–45.9%), including 90% of those who reported dengue and 20.5% who did not (odds ratio [OR] 33.25, 95% CI 15.46–71.51, p < 0.001). In the multivariable analysis, adjusted for age, group, gender, and vaccination against yellow fever, seropositivity was associated with having relatives with dengue (adjusted OR 3.96, 95% CI 2.18–7.23; p < 0.001). ConclusionSeroprevalence for dengue in Posadas was higher than estimates based on the notification records, and there was a high proportion of asymptomatic cases. Educational level and having a family member who had suffered from dengue were associated with positive serology.

Investigating the Association Between ABO Blood Groups and Rhesus Factors with Dengue and Chikungunya Virus Infections During the 2017 Outbreak in Bangladesh.

This retrospective study was conducted in 2017 during the dual dengue and chikungunya outbreak in Bangladesh. Febrile participants underwent blood tests for chikungunya, dengue, and ABO groups and rhesus (Rh) factors. Blood grouping information was gathered from healthy donors. Males and those aged between 18 and 49 years had a higher risk of contracting dengue and chikungunya. Blood group O exhibited the highest infection rates at ∼50%, whereas group AB had the lowest at ∼9% among the participants in the study. Yet, when considering the general population's blood group distribution, the combined odds of infection were 2.0, 3.5, and 1.4 times higher in groups B, O, and AB, respectively, than in group A. Infection rates were greater in Rh-negative people. Blood groups B, O, and AB showed higher susceptibility than blood group A according to adjusted odds ratios. Blood groups ABO and Rh factor hold significance in disease susceptibility and vaccine effectiveness. Keeping these implications in mind, further investigations are necessary to understand the mechanisms underlying these connections and their effects on the efficacy of dengue and chikungunya vaccines.

Macrophages derived from human induced pluripotent stem cells (iPSCs) serve as a high-fidelity cellular model for investigating HIV-1, dengue, and influenza viruses.

Macrophages have complex relationships with viruses: while macrophages aid in the removal of pathogenic viruses from the body, macrophages are also manipulated by some viruses to serve as vessels for viral replication, dissemination, and long-term persistence. Here, we show that iPSC-derived macrophages are an excellent model that can be exploited in virology.

Sofosbuvir Suppresses the Genome Replication of DENV1 in Human Hepatic Huh7 Cells.

Dengue virus (DENV) causes dengue fever and dengue hemorrhagic fever, and DENV infection kills 20,000 people annually worldwide. Therefore, the development of anti-DENV drugs is urgently needed. Sofosbuvir (SOF) is an effective drug for HCV-related diseases, and its triphosphorylated metabolite inhibits viral RNA synthesis by the RNA-dependent RNA polymerase (RdRp) of HCV. (2'R)-2'-Deoxy-2'-fluoro-2'-methyluridine (FMeU) is the dephosphorylated metabolite produced from SOF. The effects of SOF and FMeU on DENV1 replication were analyzed using two DENV1 replicon-based methods that we previously established. First, a replicon-harboring cell assay showed that DENV1 replicon replication in human hepatic Huh7 cells was decreased by SOF but not by FMeU. Second, a transient replicon assay showed that DENV1 replicon replication in Huh7 cells was decreased by SOF; however, in hamster kidney BHK-21 cells, it was not suppressed by SOF. Additionally, the replicon replication in Huh7 and BHK-21 cells was not affected by FMeU. Moreover, we assessed the effects of SOF on infectious DENV1 production. SOF suppressed infectious DENV1 production in Huh7 cells but not in monkey kidney Vero cells. To examine the substrate recognition of the HCV and DENV1 RdRps, the complex conformation of SOF-containing DENV1 RdRp or HCV RdRp was predicted using AlphaFold 2. These results indicate that SOF may be used as a treatment for DENV1 infection.

An obligate microsporidian parasite modulates defense against opportunistic bacterial infection in the yellow fever mosquito, Aedes aegypti.

The microsporidium Edhazardia aedis is a parasite of the yellow fever mosquito, Aedes aegypti. This mosquito transmits multiple viruses to humans in the United States and around the world, including dengue, yellow fever, and Zika viruses. Hundreds of millions of people worldwide will become infected with one of these viruses each year. E. aedis infection significantly reduces the lifespan of Ae. aegypti and is therefore a promising novel biocontrol agent. Here, we show that when the mosquito is infected with this parasite, it is also significantly more susceptible to infection by an opportunistic bacterial pathogen, Serratia marcescens. This novel discovery suggests the mosquito's ability to control infection by other microbes is impacted by the presence of the parasite.

ISG15/USP18/STAT2 is a molecular hub regulating IFN I-mediated control of Dengue and Zika virus replication.

The establishment of a virus infection is the result of the pathogen's ability to replicate in a hostile environment generated by the host's immune system. Here, we found that ISG15 restricts Dengue and Zika viruses' replication through the stabilization of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signaling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the STAT2's stability and restrict virus growth, suggesting that the IFNAR-mediated ISG15 activity is also antiviral. Our results add a novel layer of complexity in the virus/host interaction interface and suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing host's IFN-I mediated response and promoting virus replication.