A broadly protective antibody that targets the flavivirus NS1 protein

There are no approved flaviviral therapies and the development of vaccines against flaviruses has the potential of being undermined by antibody-dependent enhancement (ADE). The flavivirus nonstructural protein 1 (NS1) is a promising vaccine antigen with low ADE risk but has yet to be explored as a broad-spectrum therapeutic antibody target. Here, we provide the structural basis of NS1 antibody cross-reactivity through cocrystallization of the antibody 1G5.3 with NS1 proteins from dengue and Zika viruses. The 1G5.3 antibody blocks multi-flavivirus NS1-mediated cell permeability in disease-relevant cell lines, and therapeutic application of 1G5.3 reduces viremia and improves survival in dengue, Zika, and West Nile virus murine models. Finally, we demonstrate that 1G5.3 protection is independent of effector function, identifying the 1G5.3 epitope as a key site for broad-spectrum antiviral development.
Source: ScienceNOW - Category: Science Authors: Tags: Biochemistry, Microbiology reports Source Type: news

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any Usutu virus (USUV), a mosquito-borne zoonotic flavivirus discovered in South Africa in 1959, has spread to many European countries over the last 20 years. The virus is currently a major concern for animal health due to its expanding host range and the growing number of avian mass mortality events. Although human infections with USUV are often asymptomatic, they are occasionally accompanied by neurological complications reminiscent of those due to West Nile virus (another flavivirus closely related to USUV). Whilst USUV actually appears less threatening than some other emergent arboviruses, the lessons learned from ...
Source: Viruses - Category: Virology Authors: Tags: Review Source Type: research
West Nile (WN) virus infection of humans is frequently asymptomatic, but can also lead to WN fever or neuroinvasive disease. CD4 T cells and B cells are critical in the defense against WN virus, and neutralizing antibodies, which are directed against the viral glycoprotein E, are an accepted correlate of protection. For the efficient production of these antibodies, B cells interact directly with CD4 helper T cells that recognize peptides from E or the two other structural proteins (capsid-C and membrane-prM/M) of the virus. However, the specific protein sites yielding such helper epitopes remain unknown. Here, we explored ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
CONCLUSIONS: The co-circulation of those viruses in the same area represents a risk for the development of severe infections if they spread throughout the country. Successive flavivirus infections may have an impact on disease pathogenesis, as well as on the development of safe vaccine strategies. PMID: 31411310 [PubMed - in process]
Source: Memorias do Instituto Oswaldo Cruz - Category: Infectious Diseases Authors: Tags: Mem Inst Oswaldo Cruz Source Type: research
Dengue virus (DENV) is a member of the Flavivirus family that includes Zika virus (ZIKV), West Nile virus, Japanese encephalitis virus, and yellow fever virus. As the most prevalent of the flaviviruses, DENV is responsible for tens of millions of infections each year. The clinical manifestations of infection with one of the four DENV serotypes (DENV1–4) range from no symptoms to hemorrhagic fever and shock (“severe dengue”), which is fatal in ~25,000 patients annually. Many factors contribute to the development of severe dengue, including the DENV serotype and host expression of certain HLA alleles; howev...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
María Maximina B. Moreno-Altamirano1*, Simon E. Kolstoe2 and Francisco Javier Sánchez-García1* 1Laboratorio de Inmunorregulación, Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico 2School of Health Sciences, University of Portsmouth, Portsmouth, United Kingdom Over the last decade, there has been significant advances in the understanding of the cross-talk between metabolism and immune responses. It is now evident that immune cell effector function strongly depends on the metabolic pathway in w...
Source: Frontiers in cellular and infection microbiology - Category: Microbiology Source Type: research
In this study, we exposed apically well-differentiated human NECs cultured at the ALI to the related flaviviruses ZIKV, JEV, WNV, and Usutu virus (USUV). We selected these viruses due to the recent increasing evidences of potential threat to humans (Cadar et al., 2017; Simonin et al., 2018). We show that NECs are particularly susceptible to JEV and WNV infection and to other flaviviruses included in this study. Infection with each virus led to shedding of infectious virus particles through the apical and basolateral surfaces and triggered host mechanisms at the level of inflammatory and antiviral mediators. Given...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
Abstract Many viruses belonging to the Flaviviridae family are transmitted by invertebrate vectors. Among those transmitted by mosquitos, there are many human pathogens of great medical importance, such as Japanese encephalitis virus, West Nile virus, dengue virus, Zika virus, or yellow fever virus. Millions of people contract mosquito-borne diseases each year, leading to thousands of deaths. Co-circulation of genetically similar flaviviruses in the same areas result in the generation of crossreactive antibodies, which is of serious concern for the development of effective vaccines and diagnostic tests. This revie...
Source: Trends in Biotechnology - Category: Biotechnology Authors: Tags: Trends Biotechnol Source Type: research
In this study, we evaluated ATA as a potential antiviral drug against ZIKV replication. The antiviral activity of ATA against ZIKV replication in vitro showed median inhibitory concentrations (IC50) of 13.87 ± 1.09 μM and 33.33 ± 1.13 μM in Vero and A549 cells, respectively; without showing any cytotoxic effect in both cell lines (median cytotoxic concentration (CC50)> 1,000 μM). Moreover, ATA protected both cell types from ZIKV-induced cytopathic effect (CPE) and apoptosis in a time- and concentration-dependent manner. In addition, pre-treatment of Vero cells with ATA for up to 72 h also resulted...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
Conclusions Apart West Nile virus (78), thousands of congenital microcephaly cases, fetal brain tissue damage and neurological syndromes have been associated with ZIKV infection. Unfortunately, the epidemics of this mosquito born, and a relative stable virus is on a rise. Although congenital microcephaly is a rare disorder however, due to lack of standardized diagnostic test facilities, the incidence in the geographically widespread ZIKV epidemic regions is higher. Animals studies showed that ZIKV is a neurotropic virus. It directly targets the developing embryonic brain cells by inducing apoptosis, cell-cycle arrest, and...
Source: Frontiers in Neurology - Category: Neurology Source Type: research
Authors: Merle H, Donnio A, Jean-Charles A, Guyomarch J, Hage R, Najioullah F, Césaire R, Cabié A Abstract Arboviruses are viral diseases transmitted by mosquitoes and tics bites. They are a major cause of morbidity and sometimes mortality. Their expansion is constant and due in part to climate change and globalization. Mostly found in tropical regions, arboviruses are sometimes the source of epidemics in Europe. Recently, the Chikungunya virus and the Zika virus were responsible for very large epidemics impacting populations that had never been in contact with those viruses. There are currently no ef...
Source: Journal Francais d Ophtalmologie - Category: Opthalmology Tags: J Fr Ophtalmol Source Type: research
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