A Systems Biology Approach Reveals that Tissue Tropism to West Nile Virus Is Regulated by Antiviral Genes and Innate Immune Cellular Processes

Suthar, Mehul S.; Brassil, Margaret M.; Blahnik, Gabriele; McMillan, Aimee; Ramos, Hilario J.; Proll, Sean; Belisle, Sarah E.; Katze, Michael G.; Gale, Michael

doi:10.1371/journal.ppat.1003168

Cited by 83 publications

(82 citation statements)

References 64 publications

(99 reference statements)

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“…However, the control of innate immune signaling varies according to tissue and virus (72)(73)(74)(75). Increased susceptibility of IRF-7-deficient mice to viruses such as West Nile virus, Chikungunya virus, and SINV demonstrates the central importance of IRF-7 in orchestrating IFN signaling (44,47,(76)(77)(78).…”

Section: Figmentioning

confidence: 99%

Differentiation of Neurons Restricts Arbovirus Replication and Increases Expression of the Alpha Isoform of IRF-7

Schultz

Vernon

Griffin

2015

J Virol

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Susceptibility to alphavirus infection is age dependent, and host maturation is associated with decreased virus replication and less severe encephalitis. To identify factors associated with maturation-dependent restriction of virus replication, we studied AP-7 rat olfactory bulb neuronal cells, which can differentiate in vitro. Differentiation was associated with a 150-to 1,000-fold decrease in replication of the alphaviruses Sindbis virus and Venezuelan equine encephalitis virus, as well as La Crosse bunyavirus. Differentiation delayed synthesis of SINV RNA and protein but did not alter the susceptibility of neurons to infection or virion maturation. Additionally, differentiation slowed virus-induced translation arrest and death of infected cells. Differentiation of uninfected AP-7 neurons was associated with changes in expression of antiviral genes. Expression of key transcription factors was increased, including interferon regulatory factor 3 and 7 (IRF-3 and IRF-7) and STAT-1, suggesting that neuronal maturation may enhance the capacity for antiviral signaling upon infection. IRF-7 produced by undifferentiated AP-7 neurons was exclusively the short dominant negative ␥-isoform, while that produced by differentiated neurons was the full-length ␣-isoform. A similar switch in IRF-7 isoforms also occurred in the brains of maturing C57BL/6J mice. Silencing of IRF expression did not improve virus multiplication in differentiated neurons. Therefore, neuronal differentiation is associated with upregulation of transcription factors that activate antiviral signaling, but this alone does not account for maturation-dependent restriction of virus replication. IMPORTANCEViral encephalomyelitis is an important cause of age-dependent morbidity and mortality. Because mature neurons are not readily regenerated, recovery from encephalitis suggests that mature neurons utilize unique antiviral mechanisms to block infection and/or clear virus. To identify maturational changes in neurons that may improve outcome, we compared immature and mature cultured neurons for susceptibility to three encephalitic arboviruses and found that replication of Old World and New World alphaviruses and a bunyavirus was reduced in mature compared to immature neurons. Neuronal maturation was associated with increased baseline expression of interferon regulatory factor 3 and 7 mRNAs and production of distinct isoforms of interferon regulatory factor 7 protein. Overall, our studies identified maturational changes in neurons that likely contribute to assembly of immunoregulatory factors prior to infection, a more rapid antiviral response, increased resistance to virus infection, and improved survival. Development of age-dependent resistance to fatal disease is a characteristic of many virus infections of the central nervous system (CNS) (1-9). We have used Sindbis virus (SINV), the prototype alphavirus in the family Togaviridae, as a model system to understand maturation-mediated restriction of virus multiplication in neurons. SINV preferentially i...

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Section: Figmentioning

confidence: 99%

Differentiation of Neurons Restricts Arbovirus Replication and Increases Expression of the Alpha Isoform of IRF-7

Schultz

Vernon

Griffin

2015

J Virol

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“…During WNV infection, the innate immune response serves to control tissue tropism of infection and restrict virus entry into the CNS (10,23,24). WNV and other RNA viruses trigger the innate host defense response upon non-self recognition by the RIG-I-like receptors (RLRs), including RIG-I and melanoma differentiation antigen 5 (MDA5) (25).…”

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confidence: 99%

The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection

Errett

Suthar

McMillan

et al. 2013

J Virol

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182

158

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Virus recognition and response by the innate immune system are critical components of host defense against infection. Activation of cell-intrinsic immunity and optimal priming of adaptive immunity against West Nile virus (WNV), an emerging vectorborne virus, depend on recognition by RIG-I and MDA5, two cytosolic pattern recognition receptors (PRRs) of the RIG-I-like receptor (RLR) protein family that recognize viral RNA and activate defense programs that suppress infection. We evaluated the individual functions of RIG-I and MDA5 both in vitro and in vivo in pathogen recognition and control of WNV. Lack of RIG-I or MDA5 alone results in decreased innate immune signaling and virus control in primary cells in vitro and increased mortality in mice. We also generated RIG-I ؊/؊ ؋ MDA5 ؊/؊ double-knockout mice and found that a lack of both RLRs results in a complete absence of innate immune gene induction in target cells of WNV infection and a severe pathogenesis during infection in vivo, similar to findings for animals lacking MAVS, the central adaptor molecule for RLR signaling. We also found that RNA products from WNV-infected cells but not incoming virion RNA display at least two distinct pathogen-associated molecular patterns (PAMPs) containing 5= triphosphate and double-stranded RNA that are temporally distributed and sensed by RIG-I and MDA5 during infection. Thus, RIG-I and MDA5 are essential PRRs that recognize distinct PAMPs that accumulate during WNV replication. Collectively, these experiments highlight the necessity and function of multiple related, cytoplasmic host sensors in orchestrating an effective immune response against an acute viral infection.

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“…Certain HLA types, chemokines, and interferon pathway elements are associated with a risk of more severe outcomes in humans, and multiple pathways have been investigated in murine models (7,9). In particular, the severity of WNV infection is associated with genetic polymorphisms in the interferon response pathway elements 2=-5=-oligoadenylate synthetase 1 (OAS), interferon regulatory factor 3 (IRF3), and MX-1 (7), and upregulation of type I interferons is critical for immediate antiviral defense pathways and to generate an effective adaptive T cell-and B cell-mediated sustained immune response (10,11).…”

mentioning

confidence: 99%

Systems Immunology Reveals Markers of Susceptibility to West Nile Virus Infection

Qian

Goel

Meng

et al. 2014

Clin. Vaccine Immunol.

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West Nile virus (WNV) infection is usually asymptomatic but can cause severe neurological disease and death, particularly in older patients, and how individual variations in immunity contribute to disease severity is not yet defined. Animal studies identified a role for several immunity-related genes that determine the severity of infection. We have integrated systems-level transcriptional and functional data sets from stratified cohorts of subjects with a history of WNV infection to define whether these markers can distinguish susceptibility in a human population. Transcriptional profiles combined with immunophenotyping of primary cells identified a predictive signature of susceptibility that was detectable years after acute infection (67% accuracy), with the most prominent alteration being decreased IL1B induction following ex vivo infection of macrophages with WNV. Deconvolution analysis also determined a significant role for CXCL10 expression in myeloid dendritic cells. This systems analysis identified markers of pathogenic mechanisms and offers insights into potential therapeutic strategies.

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A Systems Biology Approach Reveals that Tissue Tropism to West Nile Virus Is Regulated by Antiviral Genes and Innate Immune Cellular Processes

Cited by 83 publications

References 64 publications

Differentiation of Neurons Restricts Arbovirus Replication and Increases Expression of the Alpha Isoform of IRF-7

Differentiation of Neurons Restricts Arbovirus Replication and Increases Expression of the Alpha Isoform of IRF-7

The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection

Systems Immunology Reveals Markers of Susceptibility to West Nile Virus Infection

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