Concept: West Nile virus
Mosquito-borne disease is an annual problem in Australia, with endemic pathogens such as Ross River virus infecting thousands of people each year. The recent emergence of Zika virus in South America and the Pacific, together with ongoing outbreaks of dengue viruses in Southeast Asia, generated great community interest in the most effective strategies to avoid mosquito bites. Large-scale mosquito control programs are not common in Australia and are limited in New South Wales (NSW). The use of topical insect repellents is a key recommendation by health authorities to prevent mosquito-borne disease. All products sold in Australia purporting to repel mosquitoes must be registered with the Australian Pesticides and Veterinary Medicines Authority. Despite around 100 commercial products registered as repelling mosquitoes, there are relatively few active ingredients used across these formulations. The most common are diethyltoluamide (DEET), picaridin, p-menthane-3,8-diol (PMD) and a range of plant-derived products (e.g. melaleuca, eucalyptus, citronella oils). Research has shown that each of these active ingredients varies in the duration of protection provided against biting mosquitoes. Recommendations by health authorities are informed by this research, but inconsistencies between recommendations and available repellent formulations and their concentration of active ingredients can cause confusion in the community. There are conflicts between the data resulting from scholarly research, marketing promotion by manufacturers and recommendations provided by overseas health authorities. A review was undertaken of NSW Health’s current recommendations on choosing and using insect repellents, taking into consideration recent research and currently registered topical repellents.
Although the outcome of flavivirus infection can vary from asymptomatic to lethal, environmental factors modulating disease severity are poorly defined. Here, we observed increased susceptibility of mice to severe West Nile (WNV), Dengue, and Zika virus infections after treatment with oral antibiotics (Abx) that depleted the gut microbiota. Abx treatment impaired the development of optimal T cell responses, with decreased levels of WNV-specific CD8+T cells associated with increased infection and immunopathology. Abx treatments that resulted in enhanced WNV susceptibility generated changes in the overall structure of the gut bacterial community and in the abundance of specific bacterial taxa. As little as 3 days of treatment with ampicillin was sufficient to alter host immunity and WNV outcome. Our results identify oral Abx therapy as a potential environmental determinant of systemic viral disease, and they raise the possibility that perturbation of the gut microbiota may have deleterious consequences for subsequent flavivirus infections.
Mosquito feeding behaviour determines the degree of vector-host contact and may have a serious impact on the risk of West Nile virus (WNV) epidemics. Feeding behaviour also interacts with other biotic and abiotic factors that affect virus amplification and transmission.
Entomologic Investigations during an Outbreak of West Nile Virus Disease in Maricopa County, Arizona, 2010
- The American journal of tropical medicine and hygiene
- Published over 6 years ago
Abstract. Entomologic investigations were conducted during an intense outbreak of West Nile virus (WNV) disease in Maricopa County, Arizona during July 31-August 9, 2010. The investigations compared the East Valley outbreak area, and a demographically similar control area in northwestern metropolitan Phoenix where no human cases were reported. Five mosquito species were identified in each area, and species composition was similar in both areas. Significantly more Culex quinquefasciatus females were collected by gravid traps at Outbreak sites (22.2 per trap night) than at control sites (8.9 per trap night), indicating higher Cx. quinquefasciatus abundance in the outbreak area. Twenty-eight WNV TaqMan reverse transcription-polymerase chain reaction-positive mosquito pools were identified, including 24 of Cx. quinquefasciatus, 3 of Psorophora columbiae, and 1 of Culex sp. However, Cx. quinquefasciatus WNV infection rates did not differ between outbreak and control sites. At outbreak sites, 30 of 39 engorged Cx. quinquefasciatus had fed on birds, 8 of 39 on humans, and 1 of 39 on a lizard. At control sites, 20 of 20 identified blood meals were from birds. Data suggest that Cx. quinquefasciatus was the primary enzootic and epidemic vector of this outbreak. The most important parameters in the outbreak were vector abundance and blood meal analysis, which suggested more frequent contact between Cx. quinquefasciatus and human hosts in the outbreak area compared with the control area.
BACKGROUND: The genus Flavivirus includes several pathogenic agents that cause severe illness in humans. Re-emergence of West Nile virus in Europe and continuous spread of certain flaviviruses such as dengue, yellow fever and Japanese encephalitis viruses represent a global danger to public health. Therefore, a rapid and accurate molecular method is required for diagnostics and epidemiological surveillance of flaviviruses. METHODS: A Pan-Flavi quantitative RT-PCR assay using a Locked-Nucleic Acid probe targeting the flavivirus NS5 gene was developed and optimized to detect a wide range of flaviviruses simultaneously. The specificity and sensitivity of the Pan-Flavi assay were tested using RNA of different flaviviruses and non-flaviviruses. Furthermore, the assay was compared directly to flavivirus species-specific assays for the ability to detect flaviviruses sensitively. RESULTS: Two degenerate primers and one Locked-Nucleic Acids probe were designed to amplify most of the flaviviruses. To increase the specificity and fluorescence signal of the Pan-Flavi assay for detection of yellow fever virus and dengue virus 4, additional primers and probes were included. Viral RNA of thirty different flaviviruses was detected, verifying the broad range specificity. The testing of this assay was successful, using standard plasmid and RNA dilutions of yellow fever virus vaccine strain, dengue virus 1 and tick-borne encephalitis virus, with a sensitivity limit of 10–100 genome copies/reaction. Also comparatively good results were achieved for detecting different flaviviruses by the Pan-Flavi assay when compared to the flavivirus species-specific assays. CONCLUSION: The assay is rapid, broad-range flavivirus-specific and highly sensitive making it a valuable tool for rapid detection of flaviviruses in livestock samples, epidemiological studies or as useful complement to single flavivirus-specific assays for clinical diagnosis.
The outbreak of West Nile virus (WNV) in 1999 in the USA, and its continued spread throughout the Americas, parts of Europe, the Middle East and Africa, underscored the need for WNV antiviral development. Here, we review the current status of WNV drug discovery. A number of approaches have been used to search for inhibitors of WNV, including viral infection-based screening, enzyme-based screening, structure-based virtual screening, structure-based rationale design, and antibody-based therapy. These efforts have yielded inhibitors of viral or cellular factors that are critical for viral replication. For small molecule inhibitors, no promising preclinical candidate has been developed; most of the inhibitors could not even be advanced to the stage of hit-to-lead optimization due to their poor drug-like properties. However, several inhibitors developed for related members of the family Flaviviridae, such as dengue virus and hepatitis C virus, exhibited cross-inhibition of WNV, suggesting the possibility to re-purpose these antivirals for WNV treatment. Most promisingly, therapeutic antibodies have shown excellent efficacy in mouse model; one of such antibodies has been advanced into clinical trial. The knowledge accumulated during the past fifteen years has provided better rationale for the ongoing WNV and other flavivirus antiviral development.
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.
Glioblastoma is a highly lethal brain cancer that frequently recurs in proximity to the original resection cavity. We explored the use of oncolytic virus therapy against glioblastoma with Zika virus (ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile virus indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a mouse-adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs; thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients.
The recent rapid spread of Zika virus and its unexpected linkage to birth defects and an autoimmune-neurological syndrome has generated worldwide concern. Zika virus is a flavivirus like dengue, yellow fever and West Nile viruses. We present the 3.8Å resolution structure of mature Zika virus determined by cryo-electron microscopy. The structure of Zika virus is similar to other known flavivirus structures except for the ~10 amino acids that surround the Asn154 glycosylation site found in each of the 180 envelope glycoproteins that make up the icosahedral shell. The carbohydrate moiety associated with this residue, recognizable in the cryo-EM electron density, may function as an attachment site of the virus to host cells. This region varies not only among Zika virus strains but also in other flaviviruses and suggests that changes in this region influence virus transmission and disease.
AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses
- Proceedings of the National Academy of Sciences of the United States of America
- Published over 2 years ago
Although a causal relationship between Zika virus (ZIKV) and microcephaly has been established, it remains unclear why ZIKV, but not other pathogenic flaviviruses, causes congenital defects. Here we show that when viruses are produced in mammalian cells, ZIKV, but not the closely related dengue virus (DENV) or West Nile virus (WNV), can efficiently infect key placental barrier cells that directly contact the fetal bloodstream. We show that AXL, a receptor tyrosine kinase, is the primary ZIKV entry cofactor on human umbilical vein endothelial cells (HUVECs), and that ZIKV uses AXL with much greater efficiency than does DENV or WNV. Consistent with this observation, only ZIKV, but not WNV or DENV, bound the AXL ligand Gas6. In comparison, when DENV and WNV were produced in insect cells, they also infected HUVECs in an AXL-dependent manner. Our data suggest that ZIKV, when produced from mammalian cells, infects fetal endothelial cells much more efficiently than other pathogenic flaviviruses because it binds Gas6 more avidly, which in turn facilitates its interaction with AXL.