9 results on '"Bertke, Andrea S."'
Search Results
2. Stress Hormones Epinephrine and Corticosterone Selectively Reactivate HSV-1 and HSV-2 in Sympathetic and Sensory Neurons.
- Author
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Goswami, Poorna, Ives, Angela M., Abbott, Amber R. N., and Bertke, Andrea S.
- Subjects
ADRENALINE ,CORTICOSTERONE ,GLUCOCORTICOID receptors ,HERPES simplex virus ,MINERALOCORTICOID receptors - Abstract
Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) establish latency in sensory and autonomic neurons, from which they can reactivate to cause recurrent disease throughout the life of the host. Stress is strongly associated with HSV recurrences in humans and animal models. However, the mechanisms through which stress hormones act on the latent virus to cause reactivation are unknown. We show that the stress hormones epinephrine (EPI) and corticosterone (CORT) induce HSV-1 reactivation selectively in sympathetic neurons, but not sensory or parasympathetic neurons. Activation of multiple adrenergic receptors is necessary for EPI-induced HSV-1 reactivation, while CORT requires the glucocorticoid receptor. In contrast, CORT, but not EPI, induces HSV-2 reactivation in both sensory and sympathetic neurons through either glucocorticoid or mineralocorticoid receptors. Reactivation is dependent on different transcription factors for EPI and CORT, and coincides with rapid changes in viral gene expression, although genes differ for HSV-1 and HSV-2, and temporal kinetics differ for EPI and CORT. Thus, stress-induced reactivation mechanisms are neuron-specific, stimulus-specific and virus-specific. These findings have implications for differences in HSV-1 and HSV-2 recurrent disease patterns and frequencies, as well as development of targeted, more effective antivirals that may act on different responses in different types of neurons. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
3. A VP26-mNeonGreen Capsid Fusion HSV-2 Mutant Reactivates from Viral Latency in the Guinea Pig Genital Model with Normal Kinetics
- Author
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Pieknik, J. R., Bertke, Andrea S., Tang, S., and Krause, P. R.
- Subjects
ENVELOPE ,reactivation ,viruses ,vaginal infection model ,HERPES-SIMPLEX-VIRUS ,LOCALIZATION ,HSV-2 ,GANGLIA ,TRANSPORT ,Virology ,REPLICATION ,INFECTION ,fluorescent HSV-2 ,GREEN FLUORESCENT PROTEIN ,TEGUMENT ,guinea pig ,mNeonGreen ,IN-VIVO - Abstract
Fluorescent herpes simplex viruses (HSV) are invaluable tools for localizing virus in cells, permitting visualization of capsid trafficking and enhancing neuroanatomical research. Fluorescent viruses can also be used to study virus kinetics and reactivation in vivo. Such studies would be facilitated by fluorescent herpes simplex virus recombinants that exhibit wild-type kinetics of replication and reactivation and that are genetically stable. We engineered an HSV-2 strain expressing the fluorescent mNeonGreen protein as a fusion with the VP26 capsid protein. This virus has normal replication and in vivo recurrence phenotypes, providing an essential improved tool for further study of HSV-2 infection. Published version
- Published
- 2018
4. Neurotrophic Factors NGF, GDNF and NTN Selectively Modulate HSV1 and HSV2 Lytic Infection and Reactivation in Primary Adult Sensory and Autonomic Neurons
- Author
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Yanez, Andy A., Harrell, Telvin, Sriranganathan, Heather J., Ives, Angela M., Bertke, Andrea S., Biological Sciences, Biomedical Sciences and Pathobiology, and Population Health Sciences
- Subjects
reactivation ,nervous system ,HSV2 ,neurotrophic factors ,primary neurons ,HSV1 ,herpes simplex virus ,latency - Abstract
Herpes simplex viruses (HSV1 and HSV2) establish latency in peripheral ganglia after ocular or genital infection, and can reactivate to produce different patterns and frequencies of recurrent disease. Previous studies showed that nerve growth factor (NGF) maintains HSV1 latency in embryonic sympathetic and sensory neurons. However, adult sensory neurons are no longer dependent on NGF for survival, some populations cease expression of NGF receptors postnatally, and the viruses preferentially establish latency in different populations of sensory neurons responsive to other neurotrophic factors (NTFs). Thus, NGF may not maintain latency in adult sensory neurons. To identify NTFs important for maintaining HSV1 and HSV2 latency in adult neurons, we investigated acute and latently-infected primary adult sensory trigeminal (TG) and sympathetic superior cervical ganglia (SCG) after NTF removal. NGF and glial cell line-derived neurotrophic factor (GDNF) deprivation induced HSV1 reactivation in adult sympathetic neurons. In adult sensory neurons, however, neurturin (NTN) and GDNF deprivation induced HSV1 and HSV2 reactivation, respectively, while NGF deprivation had no effects. Furthermore, HSV1 and HSV2 preferentially reactivated from neurons expressing GFRα2 and GFRα1, the high affinity receptors for NTN and GDNF, respectively. Thus, NTN and GDNF play a critical role in selective maintenance of HSV1 and HSV2 latency in primary adult sensory neurons. Published version
- Published
- 2017
5. Stress Hormones Epinephrine and Corticosterone Selectively Modulate Herpes Simplex Virus 1 (HSV-1) and HSV-2 Productive Infections in Adult Sympathetic, but Not Sensory, Neurons.
- Author
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Ives, Angela M. and Bertke, Andrea S.
- Subjects
- *
HERPES simplex virus , *ADRENALINE , *CORTICOSTERONE , *NEURONS , *SYMPATHETIC nervous system , *CERVICAL ganglia - Abstract
Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) infect and establish latency in peripheral neurons, from which they can reactivate to cause recurrent disease throughout the life of the host. Stress is associated with the exacerbation of clinical symptoms and the induction of recurrences in humans and animal models. The viruses preferentially replicate and establish latency in different subtypes of sensory neurons, as well as in neurons of the autonomic nervous system that are highly responsive to stress hormones. To determine if stress-related hormones modulate productive HSV-1 and HSV-2 infections within sensory and autonomic neurons, we analyzed viral DNA and the production of viral progeny after treatment of primary adult murine neuronal cultures with the stress hormones epinephrine and corticosterone. Both sensory trigeminal ganglion (TG) and sympathetic superior cervical ganglion (SCG) neurons expressed adrenergic receptors (activated by epinephrine) and the glucocorticoid receptor (activated by corticosterone). Productive HSV infection colocalized with these receptors in SCG but not in TG neurons. In productively infected neuronal cultures, epinephrine treatment significantly increased the levels of HSV-1 DNA replication and production of viral progeny in SCG neurons, but no significant differences were found in TG neurons. In contrast, corticosterone significantly decreased the levels of HSV-2 DNA replication and production of viral progeny in SCG neurons but not in TG neurons. Thus, the stress-related hormones epinephrine and corticosterone selectively modulate acute HSV-1 and HSV-2 infections in autonomic, but not sensory, neurons. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
6. An acutely and latently expressed herpes simplex virus 2 viral microRNA inhibits expression of ICP34.5, a viral neurovirulence factor.
- Author
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Shuang Tang, Bertke, Andrea S., Patel, Amita, Wang, Kening, Cohen, Jeffrey I., and Krause, Philip R.
- Subjects
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HERPES simplex virus , *DISEASE risk factors , *GENOMES , *PHENOTYPES , *RNA , *SENSORY ganglia , *GENETIC code - Abstract
Latency-associated transcript (LAT) sequences regulate herpes simplex virus (HSV) latency and reactivation from sensory neurons. We found a HSV-2 LAT-related microRNA (miRNA) designated miR-I in transfected and infected cells in vitro and in acutely and latently infected ganglia of guinea pigs in vivo. miR-I is also expressed in human sacral dorsal root ganglia latently infected with HSV-2. miR-l is expressed under the LAT promoter in vivo in infected sensory ganglia. We also predicted and identified a HSV-1 LAT exon-2 viral miRNA in a location similar to miR-l, implying a conserved mechanism in these closely related viruses. In transfected and infected cells, miR-l reduces expression of ICP34.5, a key viral neurovirulence factor. We hypothesize that miR-l may modulate the outcome of viral infection in the peripheral nervous system by functioning as a molecular switch for ICP34.5 expression. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
7. A VP26-mNeonGreen Capsid Fusion HSV-2 Mutant Reactivates from Viral Latency in the Guinea Pig Genital Model with Normal Kinetics.
- Author
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Pieknik, Julianna R., Bertke, Andrea S., Tang, Shuang, and Krause, Philip R.
- Subjects
- *
GUINEA pigs , *HERPES simplex virus , *CAPSIDS , *CIRCOVIRUS diseases , *FLUORESCENT proteins , *HERPES genitalis , *CHIMERIC proteins - Abstract
Fluorescent herpes simplex viruses (HSV) are invaluable tools for localizing virus in cells, permitting visualization of capsid trafficking and enhancing neuroanatomical research. Fluorescent viruses can also be used to study virus kinetics and reactivation in vivo. Such studies would be facilitated by fluorescent herpes simplex virus recombinants that exhibit wild-type kinetics of replication and reactivation and that are genetically stable. We engineered an HSV-2 strain expressing the fluorescent mNeonGreen protein as a fusion with the VP26 capsid protein. This virus has normal replication and in vivo recurrence phenotypes, providing an essential improved tool for further study of HSV-2 infection. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
8. Stress hormones epinephrine and corticosterone modulate herpes simplex virus 1 and 2 productive infection and reactivation primarily in sympathetic, not sensory, neurons
- Author
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Ives, Angela M., Biomedical and Veterinary Sciences, Bertke, Andrea S., Meng, Xiang-Jin, Moore, Ignacio T., Theus, Michelle H., and Klein, Bradley J.
- Subjects
stress ,reactivation ,viruses ,herpes simplex virus - Abstract
Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) infect and establish latency in peripheral neurons, from which they can reactivate to cause recurrent disease throughout the life of the host. Stress is associated with exacerbation of clinical symptoms and induction of recurrences in humans and animal models. The viruses preferentially replicate and establish latency in different subtypes of sensory neurons, as well as in neurons of the autonomic nervous system that are highly responsive to stress hormones. To determine if stress-related hormones modulate productive and latent HSV-1 and HSV-2 infection within sensory and autonomic neurons, we analyzed viral DNA after treatment of primary adult murine neuronal cultures with the stress hormones epinephrine and corticosterone. Both sensory trigeminal (TG) and sympathetic superior cervical ganglia (SCG) neurons expressed adrenergic receptors and glucocorticoid receptor. In productively infected neuronal cultures, epinephrine treatment significantly increased HSV-1 DNA replication and production of viral progeny in SCG neurons, but no significant differences were found in TG neurons. In contrast, corticosterone significantly decreased HSV-2 DNA replication and production of viral progeny in SCG neurons, but not in TG neurons. In quiescently infected neuronal cultures, epinephrine and corticosterone significantly increased HSV-1 reactivation from sympathetic SCG neurons, but not sensory TG neurons. In contrast, corticosterone increased HSV-2 reactivation from both SCG and TG neurons, but epinephrine had no effect. Adrenergic or epinephrine-induced reactivation of HSV-1 in SCG neurons involved activation of several adrenergic receptors, the cyclic AMP response element binding protein (CREB), the transcription factor β-catenin, and the c-Jun N-terminal kinase (JNK). Corticosterone-induced reactivation of HSV-1 in SCG neurons required activation of glucocorticoid receptor (GCR) and transcription factors CREB and JNK. In contrast, corticosterone-induced reactivation of HSV-2 in TG and SCG neurons could utilize either the GCR or mineralocorticoid receptor (MCR) and most likely involves the chromatin remodeling properties of those receptors. Thus, stress-related hormones, epinephrine and corticosterone, selectively modulate productive and quiescent HSV-1 and HSV-2 infections primarily in sympathetic, but not sensory, neurons through different mechanisms. These results have implications for describing a mechanism by which stress-induced reactivation may occur in humans. Ph. D. Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) are major human pathogens, which establish latency in neurons of the peripheral nervous system and reactivate to cause recurrent disease in humans. Physiological stress, which includes the secretion of the stress hormones epinephrine and cortisol, has been associated with increases in severity of clinical signs and increased recurrent disease in humans and animal models of herpetic disease. The mechanism by which physiological stress induces HSV reactivation has been assumed to be through suppression of the immune system. In addition, it has been assumed that sensory neurons harboring latent HSV are the primary source of reactivating virus for recurrent HSV disease. However, my dissertation provides evidence that the stress hormones epinephrine and corticosterone (the rodent equivalent of cortisol) can act on peripheral neurons in which the virus is latent, rather than through immune system suppression. In addition, my dissertation provides evidence that the autonomic nervous system, which modulates the physiological stress response, is an important source of reactivating virus to cause recurrent disease. The molecular pathway by which epinephrine and corticosterone induce HSV reactivation in primary adult murine neurons involves specific receptors, transcription factors, and protein kinases that could potentially be targeted in humans for inhibition of HSV reactivation and prevention of herpetic recurrent disease.
- Published
- 2017
9. The role of autonomic neurons in the pathegenesis of herpes simplex virus infection
- Author
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Lee, Sung Seok, Veterinary Medicine, Bertke, Andrea S., Meng, Xiang-Jin, Valdez, Gregorio, and LeRoith, Tanya
- Subjects
Autonomic neurons ,viruses ,Herpes Simplex virus infection ,Latency ,Reactivation - Abstract
Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are major human pathogens. HSV establishes latency in the nervous system and reactivates to cause recurrent disease, resulting in transmission of progeny virions to naïve individuals. Though HSV-1 and HSV-2 share similar structure and genes, they have distinctive recurrence profiles. Generally, HSV-1 reactivation is associated with disease 'above the waist' and HSV-2 reactivation is associated with disease 'below the waist'. This phenomenon was described decades ago but still remains unexplained. The mechanism of HSV latent infection in the peripheral nervous system (PNS) has been extensively investigated, especially with in sensory neurons. Another component of the peripheral nervous system (PNS), autonomic neurons, were also known to be infected with HSV productively and latently, but largely ignored because of the assumption that there is no difference in the pathogenesis of HSV in the neurons and that both HSV-1 and HSV-2 behave in the same way in different types of neurons. However, autonomic neurons differ in physiological function compared to sensory neurons. Activation factors of autonomic neurons, such as emotional stress, trauma and hormonal fluctuation, are also known HSV reactivation triggering factors. Therefore, I hypothesized that autonomic neurons innervating the site of HSV infection are responsible the different reactivation frequencies of HSV-1 and HSV-2 after peripheral invasion. In this report, the role of autonomic neurons in HSV pathogenesis were examined using the female guinea pig reactivation model. Major findings of this report are that 1) parasympathetic ganglia innervating the ocular region support latent infection of HSV-1 selectively, thus contributing the more frequent HSV-1 reactivation, 2) mixed autonomic ganglia in the genital area support HSV-2 latent infection selectively, and 3) sympathetic neurons in the genital region supported productive and latent infection of HSV-1 and HSV-2 differently. All of the results in this report indicate that autonomic neurons play a distinctive role in HSV pathogenesis compared to the sensory neurons and are responsible for the different reactivation frequencies of HSV-1 and HSV-2. This report raises the importance of autonomic neurons in HSV pathogenesis and challenges the paradigm of HSV pathogenesis. Ph. D.
- Published
- 2016
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