Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem Cells
Within the family Herpesviridae, sub-family β-herpesvirinae, and genus Roseolovirus, there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic...
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.847106/full |
| _version_ | 1828760284005662720 |
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| author | Elham Bahramian Elham Bahramian Mercede Furr Jerry T. Wu Ruben Michael Ceballos Ruben Michael Ceballos Ruben Michael Ceballos Ruben Michael Ceballos |
| author_facet | Elham Bahramian Elham Bahramian Mercede Furr Jerry T. Wu Ruben Michael Ceballos Ruben Michael Ceballos Ruben Michael Ceballos Ruben Michael Ceballos |
| author_sort | Elham Bahramian |
| collection | DOAJ |
| description | Within the family Herpesviridae, sub-family β-herpesvirinae, and genus Roseolovirus, there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses. Sequence divergence (e.g., >30%) in key coding regions and significant differences in physiological and biochemical profiles (e.g., use of different receptors for viral entry) underscore the conclusion that HHV-6A and HHV-6B are distinct viruses of the β-herpesvirinae. Despite these viruses being implicated as causative agents in several nervous system disorders (e.g., multiple sclerosis, epilepsy, and chronic fatigue syndrome), the mechanisms of action and relative contributions of each virus to neurological dysfunction are unclear. Unresolved questions regarding differences in cell tropism, receptor use and binding affinity (i.e., CD46 versus CD134), host neuro-immunological responses, and relative virulence between HHV-6A versus HHV-6B prevent a complete characterization. Although it has been shown that both HHV-6A and HHV-6B can infect glia (and, recently, cerebellar Purkinje cells), cell tropism of HHV-6A versus HHV-6B for different nerve cell types remains vague. In this study, we show that both viruses can infect different nerve cell types (i.e., glia versus neurons) and different neurotransmitter phenotypes derived from differentiated human neural stem cells. As demonstrated by immunofluorescence, HHV-6A and HHV-6B productively infect VGluT1-containing cells (i.e., glutamatergic neurons) and dopamine-containing cells (i.e., dopaminergic neurons). However, neither virus appears to infect GAD67-containing cells (i.e., GABAergic neurons). As determined by qPCR, expression of immunological factors (e.g., cytokines) in cells infected with HHV-6A versus HHV6-B also differs. These data along with morphometric and image analyses of infected differentiated neural stem cell cultures indicate that while HHV-6B may have greater opportunity for transmission, HHV-6A induces more severe cytopathic effects (e.g., syncytia) at the same post-infection end points. Cumulatively, results suggest that HHV-6A is more virulent than HHV-6B in susceptible cells, while neither virus productively infects GABAergic cells. Consistency between these in vitro data and in vivo experiments would provide new insights into potential mechanisms for HHV6-induced epileptogenesis. |
| first_indexed | 2024-12-11T01:11:27Z |
| format | Article |
| id | doaj.art-101372b2609c4702af5c16f48ab08709 |
| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-12-11T01:11:27Z |
| publishDate | 2022-07-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-101372b2609c4702af5c16f48ab087092022-12-22T01:26:02ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-07-011310.3389/fimmu.2022.847106847106Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem CellsElham Bahramian0Elham Bahramian1Mercede Furr2Jerry T. Wu3Ruben Michael Ceballos4Ruben Michael Ceballos5Ruben Michael Ceballos6Ruben Michael Ceballos7Department of Biological Sciences, University of Arkansas, Fayetteville, AR, United StatesCell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, United StatesDepartment of Biological Sciences, University of Arkansas, Fayetteville, AR, United StatesDepartment of Biology, Johns Hopkins University, Baltimore, MD, United StatesDepartment of Biological Sciences, University of Arkansas, Fayetteville, AR, United StatesCell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, United StatesEcology, Evolution, and Organismal Biology Group, University of Arkansas, Fayetteville, AR, United StatesArkansas Center for Space and Planetary Sciences, University of Arkansas, Fayetteville, AR, United StatesWithin the family Herpesviridae, sub-family β-herpesvirinae, and genus Roseolovirus, there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses. Sequence divergence (e.g., >30%) in key coding regions and significant differences in physiological and biochemical profiles (e.g., use of different receptors for viral entry) underscore the conclusion that HHV-6A and HHV-6B are distinct viruses of the β-herpesvirinae. Despite these viruses being implicated as causative agents in several nervous system disorders (e.g., multiple sclerosis, epilepsy, and chronic fatigue syndrome), the mechanisms of action and relative contributions of each virus to neurological dysfunction are unclear. Unresolved questions regarding differences in cell tropism, receptor use and binding affinity (i.e., CD46 versus CD134), host neuro-immunological responses, and relative virulence between HHV-6A versus HHV-6B prevent a complete characterization. Although it has been shown that both HHV-6A and HHV-6B can infect glia (and, recently, cerebellar Purkinje cells), cell tropism of HHV-6A versus HHV-6B for different nerve cell types remains vague. In this study, we show that both viruses can infect different nerve cell types (i.e., glia versus neurons) and different neurotransmitter phenotypes derived from differentiated human neural stem cells. As demonstrated by immunofluorescence, HHV-6A and HHV-6B productively infect VGluT1-containing cells (i.e., glutamatergic neurons) and dopamine-containing cells (i.e., dopaminergic neurons). However, neither virus appears to infect GAD67-containing cells (i.e., GABAergic neurons). As determined by qPCR, expression of immunological factors (e.g., cytokines) in cells infected with HHV-6A versus HHV6-B also differs. These data along with morphometric and image analyses of infected differentiated neural stem cell cultures indicate that while HHV-6B may have greater opportunity for transmission, HHV-6A induces more severe cytopathic effects (e.g., syncytia) at the same post-infection end points. Cumulatively, results suggest that HHV-6A is more virulent than HHV-6B in susceptible cells, while neither virus productively infects GABAergic cells. Consistency between these in vitro data and in vivo experiments would provide new insights into potential mechanisms for HHV6-induced epileptogenesis.https://www.frontiersin.org/articles/10.3389/fimmu.2022.847106/fullhuman herpesvirus 6cell tropismimmunological responseneural stem cellsepilepsyroseolovirus |
| spellingShingle | Elham Bahramian Elham Bahramian Mercede Furr Jerry T. Wu Ruben Michael Ceballos Ruben Michael Ceballos Ruben Michael Ceballos Ruben Michael Ceballos Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem Cells Frontiers in Immunology human herpesvirus 6 cell tropism immunological response neural stem cells epilepsy roseolovirus |
| title | Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem Cells |
| title_full | Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem Cells |
| title_fullStr | Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem Cells |
| title_full_unstemmed | Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem Cells |
| title_short | Differential Impacts of HHV-6A versus HHV-6B Infection in Differentiated Human Neural Stem Cells |
| title_sort | differential impacts of hhv 6a versus hhv 6b infection in differentiated human neural stem cells |
| topic | human herpesvirus 6 cell tropism immunological response neural stem cells epilepsy roseolovirus |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.847106/full |
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