STAT1-Independent Control of a Neurotropic Measles Virus Challenge in Primary Neurons and Infected Mice

O’Donnell, Lauren A.; Conway, Stephen; Rose, R. Wesley; Nicolas, Émmanuelle; Slifker, Michael; Balachandran, Siddharth; Rall, Glenn F.

doi:10.4049/jimmunol.1101356

Cited by 29 publications

(66 citation statements)

References 53 publications

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“…Noncanonically, IRF-1, -3, and -7 can upregulate ISG expression in the absence of measurable IFN (48,(79)(80)(81)(82). Utilization of noncanonical, STAT1-independent antiviral signaling by neurons has been demonstrated in neurons during measles virus, WEEV, and St. Louis encephalitis virus infection (49,83). These studies support the importance of higher levels of Irf-7 and Irf-3 to enable differentiated neurons to orchestrate a prompt and effective antiviral response.…”

Section: Figsupporting

confidence: 54%

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: Figsupporting

confidence: 54%

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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“…Homozygous NSE-CD46 ϩ and haplotypematched homozygous immune knockout (KO) mice were intercrossed for three or more generations to obtain NSE-CD46 ϩ mice on the desired KO background. NSE-CD46 ϩ /IFN-␥ knockout and NSE-CD46 ϩ /Stat1 knockout mice have been used in our lab previously (23,30). IFNAR1-deficient mice on a 129S2/SvPas background were obtained from Luis Sigal (Fox Chase Cancer Center, Philadelphia, PA).…”

Section: Methodsmentioning

confidence: 99%

“…During the course of previous studies, we identified numerous genes that were synthesized in primary hippocampal neurons and MEFs following IFN-␥ treatment. From this list, Bst2 was among the top 5 induced genes (23). In this study, we investigated the induction and contribution of Bst2 in MV infection of CNS neurons both in vivo and ex vivo.…”

mentioning

confidence: 99%

“…To date, studies aimed at understanding Bst2's role in preventing viral infection have been limited to immune cells and rapidly dividing cell types such as fibroblasts (21). Although Bst2 has been shown to be induced in primary neurons following virus infection, whether it modulates the viral life cycle in these cells has not been explored (22,23).…”

mentioning

confidence: 99%

“…Because mice are not normally permissive to MV infection, we can use this model to restrict viral replication to CNS neurons. MV spread within primary neurons that are obtained from these mice occurs through synaptic connections in the absence of extracellular viral release, distinct from the productive and lytic infection it causes in nonneuronal cells (23,27,28). Functional clearance of MV from the CNS of NSE-CD46 ϩ mice is noncytolytic and dependent on both T cells and gamma interferon (IFN-␥) (29,30).…”

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confidence: 99%

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Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge

Holmgren

Miller

Cavanaugh

et al. 2015

J Virol

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In permissive mouse central nervous system (CNS) neurons, measles virus (MV) spreads in the absence of hallmark viral budding or neuronal death, with transmission occurring efficiently and exclusively via the synapse. MV infection also initiates a robust type I interferon (IFN) response, resulting in the synthesis of a large number of genes, including bone marrow stromal antigen 2 (Bst2)/tetherin/CD317. Bst2 restricts the release of some enveloped viruses, but to date, its role in viral infection of neurons has not been assessed. Consequently, we investigated how Bst2 was induced and what role it played in MV neuronal infection. The magnitude of induction of neuronal Bst2 RNA and protein following IFN exposure and viral infection was notably higher than in similarly treated mouse embryo fibroblasts (MEFs). Bst2 synthesis was both IFN and Stat1 dependent. Although Bst2 prevented MV release from nonneuronal cells, its deletion had no effect on viral pathogenesis in MV-challenged mice. Our findings underscore how cell-type-specific differences impact viral infection and pathogenesis. IMPORTANCE Viral infections of the central nervous system can lead to debilitating disease and death. Moreover, it is becoming increasingly clear that nonrenewable cells, including most central nervous system neurons, combat neurotropic viral infections in fundamen-tally different ways than other rapidly dividing and renewable cell populations. Here we identify type I interferon signaling as a key inducer of a known antiviral protein (Bst2) in neurons. Unexpectedly, the gene is dispensable for clearance of neurotropic viral infection despite its well-defined contribution to limiting the spread of enveloped viruses in proliferating cells. A deeper appreciation of the importance of cell type heterogeneity in antiviral immunity will aid in the identification of unique therapeutic targets for life-threatening viral infections. Many of the foundational principles in immunology have resulted from basic observations of virus-cell interactions, including the induction and antiviral function of both type I and type II interferons (IFNs) (reviewed in references 1, 2, and 3). Viral infection of a cell typically results in cellular production and secretion of type I IFNs, which can then bind to cell surface receptors in a paracrine and autocrine fashion, leading to synthesis of interferon-stimulated genes (ISGs). These ISGs, in turn, aid in clearing the viral infection by directly cleaving viral nucleic acids, triggering cellular apoptosis, inducing autophagy, upregulating major histocompatibility complex (MHC) class I expression to aid in CD8 ϩ T cell-mediated cytotoxicity, and preventing viral egress. Moreover, the induction of type I IFN contributes to the recruitment of adaptive immune effectors to infected sites, which further promotes viral clearance.One ISG that is highly induced following infection by many viruses, and in response to both type I and II IFN signaling, is the gene for bone marrow stromal antigen 2 (Bst2; also known a...

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Type II interferon signaling in the brain during a viral infection with age‐dependent pathogenesis

Creisher

Chandwani

Kamte

et al. 2020

Developmental Neurobiology

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Viral infections of the central nervous system (CNS) often cause disease in an agedependent manner, with greater neuropathology during the fetal and neonatal periods. Transgenic CD46+ mice model these age-dependent outcomes through a measles virus infection of CNS neurons. Adult CD46+ mice control viral spread and survive the infection in an interferon gamma (IFNγ)-dependent manner, whereas neonatal CD46+ mice succumb despite similar IFNγ expression in the brain. Thus, we hypothesized that IFNγ signaling in the adult brain may be more robust, potentially due to greater basal expression of IFNγ signaling proteins. To test this hypothesis, we evaluated the expression of canonical IFNγ signaling proteins in the neonatal and adult brain, including the IFNγ receptor, Janus kinase (JAK) 1/2, and signal transducer and activator of transcription-1 (STAT1) in the absence of infection. We also analyzed the expression and activation of STAT1 and IFNγ-stimulated genes during MV infection. We found that neonatal brains have equivalent or greater JAK/STAT1 expression in the hippocampus and the cerebellum than adults. IFNγ receptor expression varied by cell type in the brain but was widely expressed on neuronal and glial cells. During MV infection, increased STAT1 expression and activation correlated with viral load in the hippocampus regardless of age, but not in the cerebellum where viral load was consistently undetectable in adults. These results suggest the neonatal brain is capable of initiating IFNγ signaling during a viral infection, but that downstream STAT1 activation is insufficient to limit viral spread.

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STAT1-Independent Control of a Neurotropic Measles Virus Challenge in Primary Neurons and Infected Mice

Cited by 29 publications

References 53 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

Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge

Type II interferon signaling in the brain during a viral infection with age‐dependent pathogenesis

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