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1.
JCI Insight ; 2020 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-31910161

RESUMEN

Dengue (DENV) and Zika viruses (ZIKV) are closely related mosquito-borne flaviviruses that co-circulate in tropical regions and constitute major threats to global human health. Whether preexisting immunity to one virus affects disease caused by the other during primary or secondary infections is unknown but is critical in preparing for future outbreaks and predicting vaccine safety. Using a human skin explant model, we show that DENV-3 immune sera increased recruitment and infection of Langerhans cells, macrophages and dermal dendritic cells following inoculation with DENV-2 or ZIKV. Similarly, ZIKV immune sera enhanced infection with DENV-2. Immune sera increased migration of infected Langerhans cells to dermis and emigration of infected cells out of skin. Heterotypic immune sera increased viral RNA in dermis almost tenfold and reduced the amount of virus required to infect a majority of myeloid cells by 100 to 1,000 fold. Enhancement was associated with cross-reactive IgG and induction of IL-10 expression and was mediated by both CD32 and CD64 Fcγ receptors. These findings reveal that preexisting heterotypic immunity greatly enhances DENV and ZIKV infection, replication and spread in human skin. This relevant tissue model will be valuable in assessing the efficacy and risk of dengue and Zika vaccines in humans.

2.
J Virol ; 2020 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-31915280

RESUMEN

Dengue virus (DENV) is a mosquito-borne flavivirus responsible for dengue disease, a major human health concern for which no specific therapies are available. Like other viruses, DENV relies heavily on the host cellular machinery for productive infection. Here, we performed a genome-wide CRISPR-Cas9 screen using haploid HAP1 cells to identify host genes important for DENV infection. We identified DPM1 and 3, two subunits of the ER resident DPM synthase (DPMS) complex, as host dependency factors for DENV and other related flaviviruses such as Zika virus (ZIKV). DPMS complex catalyzes the synthesis of dolichol-phosphate mannose (DPM) which serves as mannosyl donor in pathways leading to N-glycosylation, GPI anchor biosynthesis and C- or O-mannosylation of proteins in the ER lumen. Mutation in the DXD motif of DPM1, which is essential for its catalytic activity, abolished DPMS-mediated DENV infection. Similarly, genetic ablation of ALG3, a mannosyltransferase that transfers mannose to lipid-linked oligosaccharide (LLO), rendered cells poorly susceptible to DENV. We also established that in cells deficient for DPMS activity, viral RNA amplification is hampered and truncated oligosaccharides are transferred to the viral prM and E glycoproteins, affecting their proper folding. Overall, our study provides new insights into the host dependent mechanisms of DENV infection and supports current therapeutic approaches using glycosylation inhibitors to treat DENV infection.IMPORTANCE Dengue disease, which is caused by dengue virus (DENV), has emerged as the most important mosquito-borne viral disease in humans and is a major global health concern. DENV encodes only few proteins and relies on the host cell machinery to accomplish its life cycle. The identification of the host factors important for DENV infection is needed to propose new targets for antiviral intervention. Using a genome-wide CRISPR-Cas9 screen, we identified DPM1 and 3, two subunits of the DPMS complex, as important host factors for the replication of DENV as well as others related viruses such as Zika virus. We established that DPMS complex plays a dual role during viral infection, both regulating viral RNA replication and promoting viral structural glycoproteins folding/stability. These results provide insights into the host molecules exploited by DENV and other flaviviruses to facilitate their life cycle.

3.
Clin Exp Dermatol ; 2020 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-31916616

RESUMEN

Skin disorders are frequent in travelers, but data vary according to different studies. Our objectives were to describe imported dermatoses in the Bordeaux Geosentinel prospective database. between August 2015 and March 2018. During the study period, 1,025 travelers were seen in the clinic, 201 of them with dermatoses. Patients with skin disorders were more likely to be > 60 (OR 1.88, 95% CI [1.22-2.89]), tourists (OR 3.04, 95% CI [2.03-4.55]), travelers to South America (OR 2.18, 95% CI [1.29-3.67]) and less likely to be seen in pre-travel encounters (OR 0.53, 95% CI [0.31-0.91]). Skin bacterial infections (19.4%) and Zika virus infections (18.4%) were the most common dermatoses. Dengue fever and bacterial skin infections were the leading causes of hospitalization. The contribution of tropical diseases among imported dermatoses remains important. Lack of pre-travel advice puts tourists at risk of significant diseases such as dengue fever, Zika or bacterial infections.

4.
Neuroradiol J ; : 1971400919896264, 2020 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-31896285

RESUMEN

BACKGROUND: Many original articles and case series have been published emphasizing the neuroimaging findings of congenital Zika virus (ZIKV) infection. The majority of these studies do not follow a neuroradiological methodology to describe malformations and brain abnormalities resulting from ZIKV infection. The cause-and-effect correlation between the gestational period of maternal infection and the severity of encephalic changes at birth has rarely been reported. A systematic literature review was conducted on the neuroimaging findings in children affected with microcephaly due to ZIKV. METHODS: PubMed, Cochrane Library and Web of Science were searched for full-text articles published up to July 2019. Duplicate entries were removed. Two independent reviewers performed a quality assessment of all the studies included. RESULTS: A total of 2214 publications were identified. Of these 2170 were excluded by analysis of titles and abstracts, resulting in the inclusion of only eight articles. Chi-square and Fisher's exact tests were performed with a 95% confidence interval to verify the statistically significant differences in the neuroradiological findings between the cases of ZIKV infection in the first or second trimester of gestation. The studies published so far have described image abnormalities at random, without utilizing any pre-established neuroradiological criteria, and imaging modalities with different sensitivity and accuracy have been used, which jeopardizes a reliable and adequate statistical analysis. CONCLUSIONS: Neuroimaging abnormalities are much more prevalent and severe when the infection by ZIKV is contracted in the first or second trimester of pregnancy.

5.
Biol Reprod ; 2020 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-31901091

RESUMEN

Zika virus infection (ZIKV) is associated with adverse pregnancy outcomes in humans, and infection in the first trimester can lead to miscarriage and stillbirth. Vertical and sexual transmission of ZIKV have been demonstrated, yet the impact of infection during the initial stages of pregnancy remains unexplored. Here we defined the impact of ZIKV on early embryonic and placental development with a rhesus macaque model. During in vitro fertilization (IVF), macaque gametes were inoculated with a physiologically relevant dose of 5.48log10 plaque-forming units (PFU) of Zika virus/H.sapiens-tc/PUR/2015/PRVABC59_v3c2. Exposure at fertilization did not alter blastocyst formation rates compared to controls. To determine the impact of ZIKV exposure at implantation, hatched blastocysts were incubated with 3.26log10, 4.26log10, or 5.26log10 PFU, or not exposed to ZIKV, followed by extended embryo culture for 10 days. ZIKV exposure negatively impacted attachment, growth, and survival in comparison to controls, with exposure to 5.26log10 PFU ZIKV resulting in embryonic degeneration by day 2. Embryonic secretion of pregnancy hormones was lower in ZIKV-exposed embryos. Increasing levels of infectious virus were detected in the culture media post-exposure, suggesting that the trophectoderm is susceptible to productive ZIKV infection. These results demonstrate that ZIKV exposure severely impacts the zona-free blastocyst, whereas exposure at the time of fertilization does not hinder blastocyst formation. Overall, early stages of pregnancy may be profoundly sensitive to infection and pregnancy loss, and the negative impact of ZIKV infection on pregnancy outcomes may be underestimated.

7.
JAMA Pediatr ; 2020 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-31904798

RESUMEN

Importance: The number of children who were born to mothers with Zika virus (ZIKV) infection during pregnancy but who did not have apparent disability at birth is large, warranting the study of the risk for neurodevelopmental impairment in this population without congenital Zika syndrome (CZS). Objective: To investigate whether infants without CZS but who were exposed to ZIKV in utero have normal neurodevelopmental outcomes until 18 months of age. Design, Setting, and Participants: This cohort study prospectively enrolled a group of pregnant women with ZIKV in Atlántico Department, Colombia, and in Washington, DC. With this cohort, we performed a longitudinal study of infant neurodevelopment. Infants born between August 1, 2016, and November 30, 2017, were included if they were live born, had normal fetal brain findings on magnetic resonance imaging and ultrasonography, were normocephalic at birth, and had normal examination results without clinical evidence of CZS. Seventy-seven infants born in Colombia, but 0 infants born in the United States, met the inclusion criteria. Exposures: Prenatal ZIKV exposure. Main Outcomes and Measures: Infant development was assessed by the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA) and the Alberta Infant Motor Scale (AIMS) at 1 or 2 time points between 4 and 18 months of age. The WIDEA and AIMS scores were converted to z scores compared with normative samples. Longitudinal mixed-effects regression models based on bootstrap resampling methods estimated scores over time, accounting for gestational age at maternal ZIKV infection and infant age at assessment. Results were presented as slope coefficients with 2-tailed P values based on z statistics that tested whether the coefficient differed from 0 (no change). Results: Of the 77 Colombian infants included in this cohort study, 70 (91%) had no CZS and underwent neurodevelopmental assessments. Forty infants (57%) were evaluated between 4 and 8 months of age at a median (interquartile range [IQR]) age of 5.9 (5.3-6.5) months, and 60 (86%) underwent assessment between 9 and 18 months of age at a median (IQR) age of 13.0 (11.2-16.4) months. The WIDEA total score (coefficients: age = -0.227 vs age2 = 0.006; P < .003) and self-care domain score (coefficients: age = -0.238 vs age2 = 0.01; P < .008) showed curvilinear associations with age. Other domain scores showed linear declines with increasing age based on coefficients for communication (-0.036; P = .001), social cognition (-0.10; P < .001), and mobility (-0.14; P < .001). The AIMS scores were similar to the normative sample over time (95% CI, -0.107 to 0.037; P = .34). Nineteen of 57 infants (33%) who underwent postnatal cranial ultrasonography had a nonspecific, mild finding. No difference was found in the decline of WIDEA z scores between infants with and those without cranial ultrasonography findings except for a complex interactive relationship involving the social cognition domain (P < .049). The AIMS z scores were lower in infants with nonspecific cranial ultrasonography findings (-0.49; P = .07). Conclusions and Relevance: This study found that infants with in utero ZIKV exposure without CZS appeared at risk for abnormal neurodevelopmental outcomes in the first 18 months of life. Long-term neurodevelopmental surveillance of all newborns with ZIKV exposure is recommended.

10.
J AAPOS ; 2020 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-31926367

RESUMEN

PURPOSE: To follow the visual acuity development of children exposed to or infected with the Zika virus (ZIKV) during gestation and to relate potential visual acuity deficits to their clinical condition. METHODS: In this prospective study, visual acuity was measured via Teller Acuity Cards in three groups of children: (1) those with confirmed ZIKV exposure (ZE) through the mother only, (2) those with confirmed infection (ZI), and (3) unaffected controls. Visual acuity was measured 2-4 times in each child during the first 30 months of age. RESULTS: The study included 22 children in the ZE group, 11 in the ZI group, and 27 controls. Visual acuity developed normally in both patient groups, including infected patients (ZI) that did not manifest clinical symptoms. In a small subgroup of patients with characteristics consistent with congenital Zika syndrome (CZS), visual acuity was within normative values, with the exception of single child with chorioretinal atrophy. CONCLUSIONS: In this southeastern Brazil study cohort, visual acuity development seemed to progress normally in infected children without CZS symptoms.

11.
Environ Res ; 182: 109114, 2020 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-31927301

RESUMEN

BACKGROUND: Globally, dengue, Zika virus, and chikungunya are important viral mosquito-borne diseases that infect millions of people annually. Their geographic range includes not only tropical areas but also sub-tropical and temperate zones such as Japan and Italy. The relative severity of these arboviral disease outbreaks can vary depending on the setting. In this study we explore variation in the epidemiologic potential of outbreaks amongst these climatic zones and arboviruses in order to elucidate potential reasons behind such differences. METHODOLOGY: We reviewed the peer-reviewed literature (PubMed) to obtain basic reproduction number (R0) estimates for dengue, Zika virus, and chikungunya from tropical, sub-tropical and temperate regions. We also computed R0 estimates for temperate and sub-tropical climate zones, based on the outbreak curves in the initial outbreak phase. Lastly we compared these estimates across climate zones, defined by latitude. RESULTS: Of 2115 studies, we reviewed the full text of 128 studies and included 65 studies in our analysis. Our results suggest that the R0 of an arboviral outbreak depends on climate zone, with lower R0 estimates, on average, in temperate zones (R0 = 2.03) compared to tropical (R0 = 3.44) and sub-tropical zones (R0 = 10.29). The variation in R0 was considerable, ranging from 0.16 to 65. The largest R0 was for dengue (65) and was estimated by the Ross-Macdonald model in the tropical zone, whereas the smallest R0 (0.16) was for Zika virus and was estimated statistically from an outbreak curve in the sub-tropical zone. CONCLUSIONS: The results indicate climate zone to be an important determinant of the basic reproduction number, R0, for dengue, Zika virus, and chikungunya. The role of other factors as determinants of R0, such as methods, environmental and social conditions, and disease control, should be further investigated. The results suggest that R0 may increase in temperate regions in response to global warming, and highlight the increasing need for strengthening preparedness and control activities.

12.
Emerg Microbes Infect ; 9(1): 111-123, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31906823

RESUMEN

The Zika virus (ZIKV) is a mosquito-borne flavivirus that causes neonatal abnormalities and other disorders. Antibodies to the ZIKV envelope (E) protein can block infection. In this study, next-generation sequencing (NGS) of immunoglobulin heavy chain (IgH) mRNA transcripts was combined with single-cell PCR cloning of E-binding monoclonal antibodies for analysing antibody response in a patient from the early stages of infection to more than one year after the clearance of the virus. The patient's IgH repertoire 14 and 64 days after symptom onset showed dramatic dominant clonal expansion but low clonal diversity. IgH repertoire 6 months after disease-free status had few dominant clones but increased diversity. E-binding antibodies appeared abundantly in the repertoire during the early stages of infection but quickly declined after clearance of the virus. Certain VH genes such as VH5-10-1 and VH4-39 appeared to be preferentially enlisted for a rapid antibody response to ZIKV infection. Most of these antibodies require relatively few somatic hypermutations to acquire the ability to bind to the E protein, pointing to a possible mechanism for rapid defence against ZIKV infection. This study provides a unique and holistic view of the dynamic changes and characteristics of the antibody response to ZIKV infection.

13.
Cell Host Microbe ; 27(1): 14-24, 2020 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-31917957

RESUMEN

Humoral immunity is an essential component of the protective immune response to flavivirus infection. Typically, primary infection generates a robust neutralizing antibody response that mediates viral control and protection. It is becoming increasingly apparent that secondary infection with a closely related flavivirus strain can result in immunological cross-reactivity; however, the consequences to infection outcome remain controversial. Since its introduction to Brazil in 2015, Zika virus (ZIKV) has caused an epidemic of fetal congenital malformations within the Americas. Because ZIKV is a mosquito-borne flavivirus with a high degree of sequence and structural homology to Dengue virus (DENV), the role of immunological cross-reactivity in ZIKV and DENV infections has become a great concern. In this review, we highlight contemporary findings that implicate a role for flavivirus antibodies in mediating protection, contributing to pathogenesis, and seeding the human placenta.

14.
Infect Genet Evol ; : 104180, 2020 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-31918041

RESUMEN

Zika virus (ZIKV) is a negative sense RNA virus from the Flaviviridae family, which was relatively unknown until the first human epidemic in Micronesia, in 2007. Since its spread to French Polynesia and the Americas. Recife, the capital of Pernambuco state and epicenter of the Zika epidemic in Brazil, experienced a large number of microcephaly cases and other congenital abnormalities associated to the ZIKV infection from, 2015 to 16. Evidences suggest that both Aedes aegypti and Culex quinquefasciatus mosquitoes from Recife are capable of replicating and transmitting the virus. Here, we conducted high throughput sequencing of ZIKV genomes directly from Ae. aegypti and Cx. quinquefasciatus mosquitoes collected during the ZIKV epidemics in Recife, in order to investigate the variability and evolution of the virus. We obtained 11 draft ZIKV genomes derived from 5 pools from each Ae. aegypti and Cx. quinquefasciatus species. Genome coverage breadth ranged from 16 to 100% and average depth from 45 to 46,584×. Two of these genomes were obtained from pools of unfed Cx. quinquefasciatus females. Amino acid substitutions found here were not species-specific, which could indicate species specific virus adaptation. In addition, molecular clock dating estimated that ZIKV draft genomes obtained here were co-circulating in the region during the epidemics. Overall results highlight that viral mutations and even minor variants can be detected in genomes directly sequenced from mosquito samples and insights about natural viral genomic variability and viral evolution can be useful when designing tools for mosquito control programs.

15.
J Biol Chem ; 2020 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-31919100

RESUMEN

The genus Flavivirus in the family Flaviviridae comprises many medically important viruses, such as dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV). The quest for therapeutic targets to combat flavivirus infections requires a better understanding of the kinetics of virus-host interactions during infections with native viral strains. However, this is precluded by limitations of current cell-based systems for monitoring flavivirus infection in living cells. In the present study, we report the construction of fluorescence activatable sensors to detect the activities of flavivirus NS2B-NS3 serine proteases in living cells. The system consists of GFP-based reporters that become fluorescent upon cleavage by recombinant DENV-2/ZIKV proteases in vitro. A version of this sensor containing the flavivirus internal NS3 cleavage site linker reported the highest fluorescence activation in stably transduced mammalian cells upon DENV-2/ZIKV infection. Moreover, the onset of fluorescence correlated with viral protease activity. A far-red version of this flavivirus sensor had the best signal-to-noise ratio in a fluorescent Dulbecco's plaque assay, leading to the construction of a multi-reporter platform combining the flavivirus sensor with reporter dyes for detection of chromatin condensation and cell death, enabling studies of viral plaque formation with single-cell resolution. Finally, the application of this platform enabled the study of cell-population kinetics of infection and cell death by DENV-2, ZIKV, and YFV. We anticipate that future studies of viral infection kinetics with this reporter system will enable basic investigations of virus-host interactions and facilitate future applications in antiviral drug research to manage flavivirus infections.

16.
J Biomol Struct Dyn ; : 1-13, 2020 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-31920173

RESUMEN

Zika virus (ZIKV), belongs to the flavivirus genus and Flaviviridae family that associated with serious diseased conditions like microcephaly and other neurological disorders (Guillan-Barré syndrome). As there is no vaccine or therapies available against ZIKV to date. Hence, it is an unmet need to find potential drug candidates and target sites against Zika virus infection. NS2B-NS3 protease making an attractive target for therapeutic intervention in ZIKV infections because of its critical role in hydrolysis of a single polyprotein encoded by Zika virus. Recently, there are some experimental evidence about the flavonoids as Zika virus NS2B-NS3 protease inhibitors. However, molecular interaction between protease complex and inhibitors at atomic levels has not been explored. Here, we have taken the experimentally validated thirty-eight flavonoids inhibitors against NS2B-NS3 protease to examine the molecular interaction using molecular docking and molecular dynamics simulations. We found out few flavonoids such as EGCG and its two derivatives, isoquercetin, rutin and sanggenon O showing interaction with catalytic triad (His51, Asp75, and Ser135) of the active site of NS2B-NS3 protease and found to be stable throughout the simulation. Therefore it is evident that interaction with the catalytic triad playing a vital role in the inhibition of the enzyme activity as a result inhibition of the virus propagation. However these compounds can be explored further for understanding the mechanism of action of these compounds targeting NS2B-NS3 protease for inhibition of Zika virus.

17.
Viruses ; 12(1)2020 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-31936013

RESUMEN

The aim of this study is to evaluate the performance characteristics of the LIAISON XL Zika Capture IgM II. For this purpose we tested 128 samples obtained from recent infections caused by the Zika (ZIKV; 74 samples), dengue (DENV; 10 samples), chikungunya (CHIK V; 11 samples), rubella (RUBV; 10 samples) and measles (MeV; 10 samples) viruses, as well as human parvovirus B19 (HPVB19; 13 samples). The results of the assay under evaluation are compared with those obtained from an indirect immunofluorescence (IIF) assay, and the discrepancies are resolved by considering other laboratory results (PCR and a plaque-reduction neutralization test). The LIAISON showed excellent sensitivity (100%). The specificity (91.25%) was hampered by some false-positive results in recent dengue virus, chikungunya virus, measles virus and human parvovirus B19 infections. The method evaluated is adequate, but the low specificity makes it necessary to consider the clinical and epidemiological contexts of patients, as well as other laboratory results.

18.
Viruses ; 12(1)2020 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-31936159

RESUMEN

In 2015 Zika virus (ZIKV) emerged for the first time in South America. The following ZIKV epidemic resulted in the appearance of a clinical phenotype with microcephaly and other severe malformations in newborns. So far, mechanisms of ZIKV induced damage to the fetus are not completely understood. Previous data suggest that ZIKV may bypass the placenta to reach the fetus. Thus, animal models for ZIKV infection are important to facilitate studies about ZIKV infection during pregnancy. Here, we used ultrasound based imaging (USI) to characterize ZIKV induced pathogenesis in the pregnant Type I interferon receptor-deficient (IFNAR-/-) mouse model. Based on USI we suggest the placenta to be a primary target organ of ZIKV infection enabling ZIKV spreading to the fetus. Moreover, in addition to direct infection of the fetus, the placental ZIKV infection may cause an indirect damage to the fetus through reduced uteroplacental perfusion leading to intrauterine growth retardation (IUGR) and fetal complications as early as embryonic day (ED) 12.5. Our data confirmed the capability of USI to characterize ZIKV induced modifications in mouse fetuses. Data from further studies using USI to monitor ZIKV infections will contribute to a better understanding of ZIKV infection in pregnant IFNAR-/- mice.

19.
Cells ; 9(1)2020 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-31936331

RESUMEN

The Zika virus (ZIKV) is a mosquito-borne Flavivirus and can be transmitted through an infected mosquito bite or through human-to-human interaction by sexual activity, blood transfusion, breastfeeding, or perinatal exposure. After the 2015-2016 outbreak in Brazil, a strong link between ZIKV infection and microcephaly emerged. ZIKV specifically targets human neural progenitor cells, suggesting that proteins encoded by ZIKV bind and inactivate host cell proteins, leading to microcephaly. Here, we present a systematic annotation of interactions between human proteins and the seven non-structural ZIKV proteins corresponding to a Brazilian isolate. The interaction network was generated by combining tandem-affinity purification followed by mass spectrometry with yeast two-hybrid screens. We identified 150 human proteins, involved in distinct biological processes, as interactors to ZIKV non-structural proteins. Our interacting network is composed of proteins that have been previously associated with microcephaly in human genetic disorders and/or animal models. Further, we show that the protein inhibitor of activated STAT1 (PIAS1) interacts with NS5 and modulates its stability. This study builds on previously published interacting networks of ZIKV and genes related to autosomal recessive primary microcephaly to generate a catalog of human cellular targets of ZIKV proteins implicated in processes related to microcephaly in humans. Collectively, these data can be used as a resource for future characterization of ZIKV infection biology and help create a basis for the discovery of drugs that may disrupt the interaction and reduce the health damage to the fetus.

20.
Cells ; 9(1)2020 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-31936642

RESUMEN

Viral disease is one of the greatest burdens for human health worldwide, with an urgent need for efficacious antiviral strategies. While antiviral drugs are available, in many cases, they are prone to the development of drug resistance. A way to overcome drug resistance associated with common antiviral therapies is to develop antivirals targeting host cellular co-factors critical to viral replication, such as DEAD-box helicase 3 X-linked (DDX3X), which plays key roles in RNA metabolism and the antiviral response. Here, we use biochemical/biophysical approaches and infectious assays to show for the first time that the small molecule RK-33 has broad-spectrum antiviral action by inhibiting the enzymatic activities of DDX3X. Importantly, we show that RK-33 is efficacious at low micromolar concentrations in limiting infection by human parainfluenza virus type 3 (hPIV-3), respiratory syncytial virus (RSV), dengue virus (DENV), Zika virus (ZIKV) or West Nile virus (WNV)-for all of which, no Food and Drug Administration (FDA)-approved therapeutic is widely available. These findings establish for the first time that RK-33 is a broad-spectrum antiviral agent that blocks DDX3X's catalytic activities in vitro and limits viral replication in cells.

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