Gene Expression Analysis in the Thalamus and Cerebrum of Horses Experimentally Infected with West Nile Virus

Bourgeois, Melissa; Denslow, Nancy D.; Seino, Kathy S.; Barber, David S.; Long, Maureen T.

doi:10.1371/journal.pone.0024371

Cited by 35 publications

(36 citation statements)

References 35 publications

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“…Although global gene induction in response to WNV infection has been reported previously [46]–[49], [66], [67], our results represent the first such analysis in DCs, which are a sentinel cell type coordinating the innate and adaptive antiviral immune responses, as well as among the first cells infected following a mosquito bite [8], [68]. Some of the genes we identified in mDCs also were detected in microarray analyses of WNV-infected MEFs [46], human kidney epithelial cells [48], or human retinal pigmented epithelium [47].…”

Section: Discussionmentioning

confidence: 97%

IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling

Lancaster²,

et al. 2013

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Although the transcription factors IRF-3 and IRF-7 are considered master regulators of type I interferon (IFN) induction and IFN stimulated gene (ISG) expression, Irf3−/−×Irf7−/− double knockout (DKO) myeloid dendritic cells (mDC) produce relatively normal levels of IFN-β after viral infection. We generated Irf3−/−×Irf5−/−×Irf7−/− triple knockout (TKO) mice to test whether IRF-5 was the source of the residual induction of IFN-β and ISGs in mDCs. In pathogenesis studies with two unrelated positive-sense RNA viruses (West Nile virus (WNV) and murine norovirus), TKO mice succumbed at rates greater than DKO mice and equal to or approaching those of mice lacking the type I IFN receptor (Ifnar−/−). In ex vivo studies, after WNV infection or exposure to Toll-like receptor agonists, TKO mDCs failed to produce IFN-β or express ISGs. In contrast, this response was sustained in TKO macrophages following WNV infection. To define IRF-regulated gene signatures, we performed microarray analysis on WNV-infected mDC from wild type (WT), DKO, TKO, or Ifnar−/− mice, as well as from mice lacking the RIG-I like receptor adaptor protein MAVS. Whereas the gene induction pattern in DKO mDC was similar to WT cells, remarkably, almost no ISG induction was detected in TKO or Mavs−/− mDC. The relative equivalence of TKO and Mavs−/− responses suggested that MAVS dominantly regulates ISG induction in mDC. Moreover, we showed that MAVS-dependent induction of ISGs can occur through an IRF-5-dependent yet IRF-3 and IRF-7-independent pathway. Our results establish IRF-3, -5, and -7 as the key transcription factors responsible for mediating the type I IFN and ISG response in mDC during WNV infection and suggest a novel signaling link between MAVS and IRF-5.

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Section: Discussionmentioning

confidence: 97%

IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling

Lancaster²,

et al. 2013

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“…Similarly, a global transcriptional analysis of human glioblastoma cells infected with WNV reported differential expression of 173 host genes, among which a subset participated in the regulation of diverse physiologic processes, such as immunity, apoptosis, the ubiquitin cycle and the regulation of transcription [23]. Recently, gene expression profiles in the central nervous system from horses infected with WNV were compared [24]. Significant changes were detected according to WNV exposure and/or vaccination, particularly in neurological, immunological and apoptotic pathways.…”

Section: Introductionmentioning

confidence: 99%

Altered Protein Networks and Cellular Pathways in Severe West Nile Disease in Mice

Fraisier¹,

Camoin²,

Lim³

et al. 2013

PLoS ONE

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BackgroundThe recent West Nile virus (WNV) outbreaks in developed countries, including Europe and the United States, have been associated with significantly higher neuropathology incidence and mortality rate than previously documented. The changing epidemiology, the constant risk of (re-)emergence of more virulent WNV strains, and the lack of effective human antiviral therapy or vaccines makes understanding the pathogenesis of severe disease a priority. Thus, to gain insight into the pathophysiological processes in severe WNV infection, a kinetic analysis of protein expression profiles in the brain of WNV-infected mice was conducted using samples prior to and after the onset of clinical symptoms.Methodology/Principal FindingsTo this end, 2D-DIGE and gel-free iTRAQ labeling approaches were combined, followed by protein identification by mass spectrometry. Using these quantitative proteomic approaches, a set of 148 proteins with modified abundance was identified. The bioinformatics analysis (Ingenuity Pathway Analysis) of each protein dataset originating from the different time-point comparisons revealed that four major functions were altered during the course of WNV-infection in mouse brain tissue: i) modification of cytoskeleton maintenance associated with virus circulation; ii) deregulation of the protein ubiquitination pathway; iii) modulation of the inflammatory response; and iv) alteration of neurological development and neuronal cell death. The differential regulation of selected host protein candidates as being representative of these biological processes were validated by western blotting using an original fluorescence-based method.Conclusion/SignificanceThis study provides novel insights into the in vivo kinetic host reactions against WNV infection and the pathophysiologic processes involved, according to clinical symptoms. This work offers useful clues for anti-viral research and further evaluation of early biomarkers for the diagnosis and prevention of severe neurological disease caused by WNV.

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“…Prior gene expression studies have also identified DR-associated genes that are differentially regulated following WNV infection. For example, (i) Daxx is upregulated in the spleens of mice infected with neuroinvasive strains of WNV compared to noninvasive strains (23); (ii) the death receptor-associated genes encoding cIAP2, TRAIL, TNF, and TRAF1 are upregulated in WNV-infected human retinal pigment epithelium (24), and (iii) multiple pathways involved in apoptosis, including induction of apoptosis by HIV-1, were identified in the brains of horses with exposure to WNV (25). In addition, we previously performed microarray analysis on RNA extracted from the brains of reovirus-infected mice (26).…”

Section: Discussionmentioning

confidence: 99%

Death Receptor-Mediated Apoptotic Signaling Is Activated in the Brain following Infection with West Nile Virus in the Absence of a Peripheral Immune Response

Clarke

Leser

Quick

et al. 2014

J Virol

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Apoptosis is an important mechanism of West Nile virus (WNV) pathogenesis within the central nervous system (CNS).N euronal apoptosis is an important mechanism of virus-induced pathogenesis within the central nervous system (CNS) (1). During West Nile virus (WNV) encephalitis, the proapoptotic executioner caspase, caspase 3, is activated, and mice lacking caspase 3 have reduced neuronal death and tissue injury following West Nile virus infection (2). Despite the importance of apoptosis in WNV pathogenesis, the exact pathways involved in triggering apoptotic cell death in the CNS have not yet been defined.Activation of initiator caspases 8 (3, 4) and 9 (3) occurs in cultured neuronal cells infected with WNV, and inhibition of these initiator caspases leads to reduced cleavage of the caspase 3 substrate poly(ADP-ribose) polymerase (PARP) (3, 4). These studies indicate that both extrinsic and intrinsic apoptotic signaling pathways are activated in vitro following WNV infection and are consistent with in vitro studies demonstrating that mitochondrial apoptotic signaling protein Bax is upregulated in neuronal cells following WNV infection (5) and that cytochrome c is released from the mitochondria (3). However, it remains to be seen whether the same apoptotic pathways are also activated in the intact brain during WNV encephalitis.Innate and adaptive immune responses also influence WNV pathogenesis within the CNS. Toll-like receptors 3 and 7 (TLR3 and TLR7) and the cytoplasmic proteins encoded by retinoic acidinducible gene I (RIG-I) and melanoma-differentiation-associated gene 5 (MDA5) are important for detection of WNV within the CNS, and defects in these, or additional, components of the interferon (IFN) response show enhanced viral burden and increased lethality (6). Although IFN restricts infection, pathogenic WNV strains attenuate IFN function at several steps of the induction and signaling cascade, allowing the virus to establish infection (6). Studies performed in mice (7-11) and humans (12-14) have also highlighted the role of CD8 ϩ T cells and the associated importance of pathways involving Fas ligand (10) and tumor necrosis factor (TNF)-related apoptosis-inducing factor ligand (TRAIL) (15) effector mechanisms in containing WNV CNS infection.In this report, we demonstrate that genes involved in death receptor (DR) apoptotic signaling are upregulated in the mouse brain following WNV infection. We also show for the first time that the activity of the DR-associated initiator caspase, caspase 8, is increased in the brain following WNV infection. WNV-induced activation of caspase 8 in the CNS is associated with cleavage of the proapoptotic Bcl-2 family protein Bid and with activation of caspase 9, suggesting that the caspase 8-dependent cleavage of Bid promotes intrinsic apoptotic signaling within the brains of infected animals. Utilization of WNV-infected ex vivo brain slice cultures (BSC), a novel model of WNV encephalitis, revealed that inhibition of caspase 8 decreased virus-induced activation of caspase 3 an...

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Gene Expression Analysis in the Thalamus and Cerebrum of Horses Experimentally Infected with West Nile Virus

Cited by 35 publications

References 35 publications

IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling

IRF-3, IRF-5, and IRF-7 Coordinately Regulate the Type I IFN Response in Myeloid Dendritic Cells Downstream of MAVS Signaling

Altered Protein Networks and Cellular Pathways in Severe West Nile Disease in Mice

Death Receptor-Mediated Apoptotic Signaling Is Activated in the Brain following Infection with West Nile Virus in the Absence of a Peripheral Immune Response

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