Cellular microRNA-155 Regulates Virus-Induced Inflammatory Response and Protects against Lethal West Nile Virus Infection

West Nile virus (WNV) is a flavivirus that has disseminated globally as a significant cause of viral encephalitis in humans. MircoRNA-155 (miR-155) regulates various aspects of innate and adaptive immune responses. We previously reported that WNV infection induces upregulation of miR-155 in mice brains. In the current study, we demonstrate the critical role of miR-155 in restricting the pathogenesis of WNV infection in mice. Compared to wild-type (WT) mice, miR-155 knockout mice exhibited significantly higher morbidity and mortality after infection with either a lethal strain, WNV NY99, or a non-lethal strain, WNV Eg101. Increased mortality in miR-155−/− mice was associated with significantly high WNV burden in the serum and brains. Protein levels of interferon (IFN)-α in the serum and brains were higher in miR-155−/− mice. However, miR-155−/− mice exhibited significantly lower protein levels of anti-viral interleukin (IL)-1β, IL-12, IL-6, IL-15, and GM-CSF despite the high viral load. Primary mouse cells lacking miR-155 were more susceptible to infection with WNV compared to cells derived from WT mice. Besides, overexpression of miR-155 in human neuronal cells modulated anti-viral cytokine response and resulted in significantly lower WNV replication. These data collectively indicate that miR-155 restricts WNV production in mouse and human cells and protects against lethal WNV infection in mice.

Download Full-text

Differential Expression of Interferon (IFN) Regulatory Factors and IFN-Stimulated Genes at Early Times after West Nile Virus Infection of Mouse Embryo Fibroblasts

Journal of Virology ◽

10.1128/jvi.01359-07 ◽

2007 ◽

Vol 81 (21) ◽

pp. 12005-12018 ◽

Cited By ~ 36

Author(s):

Svetlana V. Scherbik ◽

Bronislava M. Stockman ◽

Margo A. Brinton

Keyword(s):

West Nile Virus ◽

Mouse Embryo ◽

Stress Responses ◽

Host Response ◽

West Nile Virus Infection ◽

West Nile ◽

Protein Levels ◽

Mouse Embryo Fibroblasts ◽

Primary Mouse ◽

Embryo Fibroblasts

ABSTRACT Although lineage I West Nile virus (WNV) strain Eg101 induced beta interferon (IFN-β) production as early as 12 h after infection in primary mouse embryo fibroblasts and did not inhibit the JAK-STAT signaling pathway, it was still able to replicate efficiently. To gain insights about possible viral countermeasures used by this virus to suppress the host response, the cell transcriptional profile and the kinetics of IFN regulatory factor (IRF) expression and activation were examined at early times after infection. By 12 h after WNV infection, the majority of the up-regulated genes were ones involved in IFN pathways. However, comparison of IFN-stimulated gene (ISG) expression levels in mock-infected, IFN-treated, and virus-infected cells indicated that WNV infection suppressed the up-regulation of a subset of ISGs, including genes involved in transcriptional regulation, apoptosis, and stress responses, prior to 24 h after infection. Analysis of mRNA and protein levels for representative genes indicated that suppression was at the transcriptional and posttranscriptional levels. Translocation of IRF-3 to the nucleus was observed beginning at 8 h, IRF-7 expression was detected by 12 h, but IRF-1 expression was not detected until 24 h after infection. Virus-induced gene suppression was sufficient to overcome the effect of exogenous IFN pretreatment for 1 h but not for 4 h prior to infection. These data indicate that WNV can selectively counteract the host response at early times after infection by previously unreported mechanisms.

Download Full-text

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

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.2006.75.691 ◽

2006 ◽

Vol 75 (4) ◽

pp. 691-696 ◽

Cited By ~ 29

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

Download Full-text

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

Journal of Experimental Medicine ◽

10.1084/jem.20031223 ◽

2003 ◽

Vol 198 (12) ◽

pp. 1853-1862 ◽

Cited By ~ 218

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.

Download Full-text