The IFITMs Inhibit Zika Virus Replication Savidis, George; Perreira, Jill M.; Portmann, Jocelyn M. ...
Cell reports (Cambridge),
06/2016, Letnik:
15, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Zika virus has emerged as a severe health threat with a rapidly expanding range. The IFITM family of restriction factors inhibits the replication of a broad range of viruses, including the closely ...related flaviruses West Nile virus and dengue virus. Here, we show that IFITM1 and IFITM3 inhibit Zika virus infection early in the viral life cycle. Moreover, IFITM3 can prevent Zika-virus-induced cell death. These results suggest that strategies to boost the actions and/or levels of the IFITMs might be useful for inhibiting a broad range of emerging viruses.
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•IFITM3 and IFITM1 inhibit Zika virus infection•IFITM3 can prevent Zika-virus-induced cell death•The IFITMs can halt Zika virus early in the viral life cycle
Savidis et al. find that the IFITMs block Zika virus replication, including that of a recently isolated strain from Cambodia. Importantly, this protection translates into a large reduction in Zika-virus-induced cell death. The authors develop an imaging assay and determine that IFITM3 blocks the very earliest stages of Zika virus infection.
PURPOSE OF REVIEWThe continued emergence of dengue virus infection and its severe disease manifestation, dengue hemorrhagic fever, is a growing public health problem. The majority of severe ...infections occur upon secondary encounters with heterologous dengue virus serotypes, suggesting an immune-mediated process.
RECENT FINDINGSSignificant findings in the past year include a greater understanding of dengue virus interactions with target cells such as dendritic cells, hepatocytes and endothelial cells. Infection of these cells results in the production of immune mediators that then shape the adaptive humoral and cellular immune response. The circulation of high levels of secreted NS1 in the presence of pre-existing heterologous non-neutralizing antibody may mediate complement activation and trigger plasma leakage. The role of enhancing antibodies in disease pathogenesis remains unclear. Recent studies demonstrate low avidity crossreactive T cells, which may produce an altered profile of cytokines leading to plasma leakage. Ongoing prospective studies that include epidemiological, virological and immunological risk factors are crucial to our understanding of the mechanisms of immunopathogenesis of dengue hemorrhagic fever.
SUMMARYThe immune mechanisms that lead to dengue hemorrhagic fever are complex and need to be elucidated further for the development of therapeutics as well as safe and efficacious dengue vaccines.
The flaviviruses dengue virus (DENV) and Zika virus (ZIKV) are severe health threats with rapidly expanding ranges. To identify the host cell dependencies of DENV and ZIKV, we completed orthologous ...functional genomic screens using RNAi and CRISPR/Cas9 approaches. The screens recovered the ZIKV entry factor AXL as well as multiple host factors involved in endocytosis (RAB5C and RABGEF), heparin sulfation (NDST1 and EXT1), and transmembrane protein processing and maturation, including the endoplasmic reticulum membrane complex (EMC). We find that both flaviviruses require the EMC for their early stages of infection. Together, these studies generate a high-confidence, systems-wide view of human-flavivirus interactions and provide insights into the role of the EMC in flavivirus replication.
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•RNAi and CRISPR/Cas9 screens were used to find flavivirus dependencies•The screens recovered host factors involved in endocytosis and heparin sulfation•The EMC is required by DENV and ZIKV in the early stages of replication•These studies give a systems-wide view of human-flavivirus interactions
Savidis et al. identify DENV and ZIKV dependencies using orthologous RNAi and CRISPR/Cas9 approaches. Multiple host factors involved in endocytosis and transmembrane protein processing, including the endoplasmic reticulum membrane complex (EMC), are important for flaviviral replication. Together, their studies generate a systems-wide view of human-flavivirus interactions.
It is unclear whether dengue serotypes differ in their propensity to cause severe disease. We analyzed differences in serotype-specific disease severity in children presenting for medical attention ...in Bangkok, Thailand.
Prospective studies were conducted from 1994 to 2006. Univariate and multivariate logistic and multinomial logistic regressions were used to determine if dengue hemorrhagic fever (DHF) and signs of severe clinical disease (pleural effusion, ascites, thrombocytopenia, hemoconcentration) were associated with serotype. Crude and adjusted odds ratios were calculated. There were 162 (36%) cases with DENV-1, 102 (23%) with DENV-2, 123 (27%) with DENV-3, and 64 (14%) with DENV-4. There was no significant difference in the rates of DHF by serotype: DENV-2 (43%), DENV-3 (39%), DENV-1 (34%), DENV-4 (31%). DENV-2 was significantly associated with increased odds of DHF grade I compared to DF (OR 2.9 95% CI 1.1, 8.0), when using DENV-1 as the reference. Though not statistically significant, DENV-2 had an increased odds of total DHF and DHF grades II, III, and IV. Secondary serologic response was significantly associated with DHF (OR 6.2) and increased when considering more severe grades of DHF. DENV-2 (9%) and -4 (3%) were significantly less often associated with primary disease than DENV-1 (28%) and -3 (33%). Restricting analysis to secondary cases, we found DENV-2 and DENV-3 to be twice as likely to result in DHF as DEN-4 (p = 0.05). Comparing study years, we found the rate of DHF to be significantly less in 1999, 2000, 2004, and 2005 than in 1994, the study year with the highest percentage of DHF cases, even when controlling for other variables.
As in other studies, we find secondary disease to be strongly associated with DHF and with more severe grades of DHF. DENV-2 appears to be marginally associated with more severe dengue disease as evidenced by a significant association with DHF grade I when compared to DENV-1. In addition, we found non-significant trends with other grades of DHF. Restricting the analysis to secondary disease we found DENV-2 and -3 to be twice as likely to result in DHF as DEN-4. Differences in severity by study year may suggest that other factors besides serotype play a role in disease severity.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dengue viruses are a major cause of morbidity in tropical and subtropical regions of the world. Inapparent dengue is an important component of the overall burden of dengue infection. It provides a ...source of infection for mosquito transmission during the course of an epidemic, yet by definition is undetected by health care providers. Previous studies of inapparent or subclinical infection have reported varying ratios of symptomatic to inapparent dengue infection.
In a prospective study of school children in Northern Thailand, we describe the spatial and temporal variation of the symptomatic to inapparent (S:I) dengue illness ratio. Our findings indicate that there is a wide fluctuation in this ratio between and among schools in a given year and within schools over several dengue seasons. The most important determinants of this S:I ratio for a given school were the incidence of dengue infection in a given year and the incidence of infection in the preceding year. We found no association between the S:I ratio and age in our population.
Our findings point to an important aspect of virus-host interactions at either a population or individual level possibly due to an effect of heterotypic cross-reactive immunity to reduce dengue disease severity. These findings have important implications for future dengue vaccines.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Transmission of dengue viruses (DENV), the leading cause of arboviral disease worldwide, is known to vary through time and space, likely owing to a combination of factors related to the human host, ...virus, mosquito vector, and environment. An improved understanding of variation in transmission patterns is fundamental to conducting surveillance and implementing disease prevention strategies. To test the hypothesis that DENV transmission is spatially and temporally focal, we compared geographic and temporal characteristics within Thai villages where DENV are and are not being actively transmitted.
Cluster investigations were conducted within 100 m of homes where febrile index children with (positive clusters) and without (negative clusters) acute dengue lived during two seasons of peak DENV transmission. Data on human infection and mosquito infection/density were examined to precisely (1) define the spatial and temporal dimensions of DENV transmission, (2) correlate these factors with variation in DENV transmission, and (3) determine the burden of inapparent and symptomatic infections. Among 556 village children enrolled as neighbors of 12 dengue-positive and 22 dengue-negative index cases, all 27 DENV infections (4.9% of enrollees) occurred in positive clusters (p < 0.01; attributable risk AR = 10.4 per 100; 95% confidence interval 1-19.8 per 100. In positive clusters, 12.4% of enrollees became infected in a 15-d period and DENV infections were aggregated centrally near homes of index cases. As only 1 of 217 pairs of serologic specimens tested in positive clusters revealed a recent DENV infection that occurred prior to cluster initiation, we attribute the observed DENV transmission subsequent to cluster investigation to recent DENV transmission activity. Of the 1,022 female adult Ae. aegypti collected, all eight (0.8%) dengue-infected mosquitoes came from houses in positive clusters; none from control clusters or schools. Distinguishing features between positive and negative clusters were greater availability of piped water in negative clusters (p < 0.01) and greater number of Ae. aegypti pupae per person in positive clusters (p = 0.04). During primarily DENV-4 transmission seasons, the ratio of inapparent to symptomatic infections was nearly 1:1 among child enrollees. Study limitations included inability to sample all children and mosquitoes within each cluster and our reliance on serologic rather than virologic evidence of interval infections in enrollees given restrictions on the frequency of blood collections in children.
Our data reveal the remarkably focal nature of DENV transmission within a hyperendemic rural area of Thailand. These data suggest that active school-based dengue case detection prompting local spraying could contain recent virus introductions and reduce the longitudinal risk of virus spread within rural areas. Our results should prompt future cluster studies to explore how host immune and behavioral aspects may impact DENV transmission and prevention strategies. Cluster methodology could serve as a useful research tool for investigation of other temporally and spatially clustered infectious diseases.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Early recognition of dengue, particularly patients at risk for plasma leakage, is important to clinical management. The objective of this study was to build predictive models for dengue, dengue ...hemorrhagic fever (DHF), and dengue shock syndrome (DSS) using structural equation modelling (SEM), a statistical method that evaluates mechanistic pathways.
We performed SEM using data from 257 Thai children enrolled within 72 h of febrile illness onset, 156 with dengue and 101 with non-dengue febrile illnesses. Models for dengue, DHF, and DSS were developed based on data obtained three and one day(s) prior to fever resolution (fever days -3 and -1, respectively). Models were validated using data from 897 subjects who were not used for model development. Predictors for dengue and DSS included age, tourniquet test, aspartate aminotransferase, and white blood cell, % lymphocytes, and platelet counts. Predictors for DHF included age, aspartate aminotransferase, hematocrit, tourniquet test, and white blood cell and platelet counts. The models showed good predictive performances in the validation set, with area under the receiver operating characteristic curves (AUC) at fever day -3 of 0.84, 0.67, and 0.70 for prediction of dengue, DHF, and DSS, respectively. Predictive performance was comparable using data based on the timing relative to enrollment or illness onset, and improved closer to the critical phase (AUC 0.73 to 0.94, 0.61 to 0.93, and 0.70 to 0.96 for dengue, DHF, and DSS, respectively).
Predictive models developed using SEM have potential use in guiding clinical management of suspected dengue prior to the critical phase of illness.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
West Nile virus (WNV), a category B pathogen endemic in parts of Africa, Asia and Europe, emerged in North America in 1999, and spread rapidly across the continental U.S. Outcomes of infection with ...WNV range from asymptomatic to severe neuroinvasive disease manifested as encephalitis, paralysis, and/or death. Neuroinvasive WNV disease occurs in less than one percent of cases, and although host genetic factors are thought to influence risk for symptomatic disease, the identity of these factors remains largely unknown. We tested 360 common haplotype tagging and/or functional SNPs in 86 genes that encode key regulators of immune function in 753 individuals infected with WNV including: 422 symptomatic WNV cases and 331 cases with asymptomatic infections. After applying a Bonferroni correction for multiple tests and controlling for population stratification, SNPs in IRF3 (OR 0.54, p = 0.035) and MX1, (OR 0.19, p = 0.014) were associated with symptomatic WNV infection and a single SNP in OAS1 (OR 9.79, p = 0.003) was associated with increased risk for West Nile encephalitis and paralysis (WNE/P). Together, these results suggest that genetic variation in the interferon response pathway is associated with both risk for symptomatic WNV infection and WNV disease progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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