scholarly journals Toll-Like Receptor 3 Has a Protective Role against West Nile Virus Infection

2008 ◽  
Vol 82 (21) ◽  
pp. 10349-10358 ◽  
Author(s):  
Stephane Daffis ◽  
Melanie A. Samuel ◽  
Mehul S. Suthar ◽  
Michael Gale ◽  
Michael S. Diamond
Keyword(s):  
West Nile Virus ◽  
Viral Replication ◽  
West Nile Virus Infection ◽  
Protective Role ◽  
Toll Like Receptor ◽  
Wild Type ◽  
West Nile ◽  
Viral Loads

ABSTRACT Protection against West Nile virus (WNV) infection requires rapid viral sensing and the generation of an interferon (IFN) response. Mice lacking IFN regulatory factor 3 (IRF-3) show increased vulnerability to WNV infection with enhanced viral replication and blunted IFN-stimulated gene (ISG) responses. IRF-3 functions downstream of several viral sensors, including Toll-like receptor 3 (TLR3), RIG-I, and MDA5. Cell culture studies suggest that host recognizes WNV in part, through the cytoplasmic helicase RIG-I and to a lesser extent, MDA5, both of which activate ISG expression through IRF-3. However, the role of TLR3 in vivo in recognizing viral RNA and activating antiviral defense pathways has remained controversial. We show here that an absence of TLR3 enhances WNV mortality in mice and increases viral burden in the brain. Compared to congenic wild-type controls, TLR3−/− mice showed relatively modest changes in peripheral viral loads. Consistent with this, little difference in multistep viral growth kinetics or IFN-α/β induction was observed between wild-type and TLR3−/− fibroblasts, macrophages, and dendritic cells. In contrast, a deficiency of TLR3 was associated with enhanced viral replication in primary cortical neuron cultures and greater WNV infection in central nervous system neurons after intracranial inoculation. Taken together, our data suggest that TLR3 serves a protective role against WNV in part, by restricting replication in neurons.

scholarly journals Toll-like receptor 7-induced immune response to cutaneous West Nile virus infection

2009 ◽  
Vol 90 (11) ◽  
pp. 2660-2668 ◽  
Author(s):  
Thomas Welte ◽  
Krystle Reagan ◽  
Hao Fang ◽  
Carlos Machain-Williams ◽  
Xin Zheng ◽  
...  
Keyword(s):  
Immune Response ◽  
West Nile Virus ◽  
Interleukin 1 ◽  
West Nile Virus Infection ◽  
Intradermal Injection ◽  
Infected Mosquito ◽  
Toll Like Receptor ◽  
Wild Type ◽  
West Nile ◽  
Peripheral Tissues

The Toll-like receptor (TLR) 7 response represents a vital host-defence mechanism in a murine model of systemic West Nile virus (WNV) infection. Here, we investigated the role of the TLR7-induced immune response following cutaneous WNV infection. We found that there was no difference in susceptibility to WNV encephalitis between wild-type and TLR7−/− mice upon intradermal injection or infected mosquito feeding. Viral load analysis revealed similar levels of WNV RNA in the peripheral tissues and brains of these two groups of mice following intradermal infection. There was a higher level of cytokines in the blood of wild-type mice at early stages of infection; however, this difference was diminished in the blood and brains at later stages. Langerhans cells (LCs) are permissive to WNV infection and migrate from the skin to draining lymph nodes upon intradermal challenge. Our data showed that WNV infection of TLR7−/− keratinocytes was significantly higher than that of wild-type keratinocytes. Infection of wild-type keratinocytes induced higher levels of alpha interferon and interleukin-1β (IL-1β), IL-6 and IL-12, which might promote LC migration from the skin. Co-culture of naïve LCs of wild-type mice with WNV-infected wild-type keratinocytes resulted in the production of more IL-6 and IL-12 than with TLR7−/− keratinocytes or by cultured LCs alone. Moreover, LCs in the epidermis were reduced in wild-type mice, but not in TLR7−/− mice, following intradermal WNV infection. Overall, our results suggest that the TLR7 response following cutaneous infection promotes LC migration from the skin, which might compromise its protective effect in systemic infection.

scholarly journals A Molecular Determinant of West Nile Virus Secretion and Morphology as a Target for Viral Attenuation

2020 ◽  
Vol 94 (12) ◽  
Author(s):  
Justine Basset ◽  
Julien Burlaud-Gaillard ◽  
Maxence Feher ◽  
Philippe Roingeard ◽  
Félix A. Rey ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Rational Design ◽  
Surface Membrane ◽  
Public Health Problem ◽  
M Protein ◽  
Membrane Glycoprotein ◽  
Wild Type ◽  
West Nile ◽  
Viral Attenuation

ABSTRACT West Nile virus (WNV), a member of the Flavivirus genus and currently one of the most common arboviruses worldwide, is associated with severe neurological disease in humans. Its high potential to reemerge and rapidly disseminate makes it a bona fide global public health problem. The surface membrane glycoprotein (M) has been associated with Flavivirus-induced pathogenesis. Here, we identified a key amino acid residue at position 36 of the M protein whose mutation impacts WNV secretion and promotes viral attenuation. We also identified a compensatory site at position M-43 whose mutation stabilizes M-36 substitution both in vitro and in vivo. Moreover, we found that introduction of the two mutations together confers a full attenuation phenotype and protection against wild-type WNV lethal challenge, eliciting potent neutralizing-antibody production in mice. Our study thus establishes the M protein as a new viral target for rational design of attenuated WNV strains. IMPORTANCE West Nile virus (WNV) is a worldwide (re)emerging mosquito-transmitted Flavivirus causing fatal neurological diseases in humans. However, no human vaccine has been yet approved. One of the most effective live-attenuated vaccines was empirically obtained by serial passaging of wild-type yellow fever Flavivirus. However, such an approach is not acceptable nowadays, and the development of a rationally designed vaccine is necessary. Generating molecular infectious clones and mutating specific residues known to be involved in Flavivirus virulence constitute a powerful tool to promote viral attenuation. WNV membrane glycoprotein is thought to carry such essential determinants. Here, we identified two residues of this protein whose substitutions are key to the full and stable attenuation of WNV in vivo, most likely through inhibition of secretion and possible alteration of morphology. Applied to other flaviviruses, this approach should help in designing new vaccines against these viruses, which are an increasing threat to global human health.

WEST NILE VIRUS INFECTION OF PRIMARY MOUSE NEURONAL AND NEUROGLIAL CELLS: THE ROLE OF ASTROCYTES IN CHRONIC INFECTION

2006 ◽  
Vol 75 (4) ◽  
pp. 691-696 ◽  
Author(s):  
JOSE A. P. DINIZ ◽  
HILDA GUZMAN ◽  
VSEVOLOD L. POPOV ◽  
PEDRO F. C. VASCONCELOS ◽  
FANGLING XU ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Virus Infection ◽  
Chronic Infection ◽  
West Nile Virus Infection ◽  
West Nile ◽  
Primary Mouse

scholarly journals Early Production of Type I Interferon during West Nile Virus Infection: Role for Lymphoid Tissues in IRF3-Independent Interferon Production

2007 ◽  
Vol 81 (17) ◽  
pp. 9100-9108 ◽  
Author(s):  
Nigel Bourne ◽  
Frank Scholle ◽  
Maria Carlan Silva ◽  
Shannan L. Rossi ◽  
Nathan Dewsbury ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Type I Interferon ◽  
High Titer ◽  
West Nile Virus Infection ◽  
Lymphoid Tissues ◽  
Genome Replication ◽  
Type I ◽  
West Nile

ABSTRACT Infection of cells with flaviviruses in vitro is reduced by pretreatment with small amounts of type I interferon (IFN-α/β). Similarly, pretreatment of animals with IFN and experiments using mice defective in IFN signaling have indicated a role for IFN in controlling flavivirus disease in vivo. These data, along with findings that flavivirus-infected cells block IFN signaling, suggest that flavivirus infection can trigger an IFN response. To investigate IFN gene induction by the very first cells infected during in vivo infection with the flavivirus West Nile virus (WNV), we infected mice with high-titer preparations of WNV virus-like particles (VLPs), which initiate viral genome replication in cells but fail to spread. These studies demonstrated a brisk production of IFN in vivo, with peak levels of over 1,000 units/ml detected in sera between 8 and 24 h after inoculation by either the intraperitoneal or footpad route. The IFN response was dependent on genome replication, and WNV genomes and WNV antigen-positive cells were readily detected in the popliteal lymph nodes (pLN) of VLP-inoculated mice. High levels of IFN mRNA transcripts and functional IFN were also produced in VLP-inoculated IFN regulatory factor 3 null (IRF3−/−) mice, indicating that IFN production was independent of the IRF3 pathways to IFN gene transcription, consistent with the IFN type produced (predominantly α).

scholarly journals Comparison of a human neuronal model proteome upon Japanese encephalitis or West Nile Virus infection and potential role of mosquito saliva in neuropathogenesis

PLoS ONE ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. e0232585 ◽  
Author(s):  
Benoit Besson ◽  
Justine Basset ◽  
Sandrine Gatellier ◽  
Hélène Chabrolles ◽  
Thibault Chaze ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Virus Infection ◽  
Japanese Encephalitis ◽  
Potential Role ◽  
West Nile Virus Infection ◽  
Neuronal Model ◽  
West Nile ◽  
Mosquito Saliva

scholarly journals The role of IgG avidity determination in diagnosis of West Nile virus infection

2019 ◽  
Vol 79 ◽  
pp. 116-117 ◽  
Author(s):  
I. Tabain ◽  
T. Vilibic-Cavlek ◽  
B. Kristofic ◽  
V. Savic ◽  
P.B. Kolaric ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Virus Infection ◽  
West Nile Virus Infection ◽  
West Nile ◽  
Igg Avidity

scholarly journals A Critical Role for Induced IgM in the Protection against West Nile Virus Infection

2003 ◽  
Vol 198 (12) ◽  
pp. 1853-1862 ◽  
Author(s):  
Michael S. Diamond ◽  
Elizabeth M. Sitati ◽  
Lindzy D. Friend ◽  
Stephen Higgs ◽  
Bimmi Shrestha ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
West Nile Virus ◽  
Critical Role ◽  
West Nile Virus Infection ◽  
The Elderly ◽  
Wild Type ◽  
West Nile ◽  
Lethal Infection ◽  
The Central Nervous System

In humans, the elderly and immunocompromised are at greatest risk for disseminated West Nile virus (WNV) infection, yet the immunologic basis for this remains unclear. We demonstrated previously that B cells and IgG contributed to the defense against disseminated WNV infection (Diamond, M.S., B. Shrestha, A. Marri, D. Mahan, and M. Engle. 2003. J. Virol. 77:2578–2586). In this paper, we addressed the function of IgM in controlling WNV infection. C57BL/6J mice (sIgM−/−) that were deficient in the production of secreted IgM but capable of expressing surface IgM and secreting other immunoglobulin isotypes were vulnerable to lethal infection, even after inoculation with low doses of WNV. Within 96 h, markedly higher levels of infectious virus were detected in the serum of sIgM−/− mice compared with wild-type mice. The enhanced viremia correlated with higher WNV burdens in the central nervous system, and was also associated with a blunted anti-WNV IgG response. Passive transfer of polyclonal anti-WNV IgM or IgG protected sIgM−/− mice against mortality, although administration of comparable amounts of a nonneutralizing monoclonal anti-WNV IgM provided no protection. In a prospective analysis, a low titer of anti-WNV IgM antibodies at day 4 uniformly predicted mortality in wild-type mice. Thus, the induction of a specific, neutralizing IgM response early in the course of WNV infection limits viremia and dissemination into the central nervous system, and protects against lethal infection.

Sign in / Sign up

Export Citation Format

Share Document