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HHV-6A Infection and Systemic Sclerosis: Clues of a Possible Association.

ABSTRACT: Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, excessive extracellular matrix deposition, and fibrosis of the skin and internal organs. Several infectious agents, including human herpesvirus-6 (HHV-6), have been suggested as possible triggering factors, but a direct association is still missing. We characterized 26 SSc patients for the presence of HHV-6 in tissues and blood, the anti-HHV-6 response, HLA-G plasma levels, and KIR typing. Given the prominent role of endothelial cells (EC) in SSc pathogenesis, along with HHV-6 tropism for EC, we also investigated the expression of pro-fibrosis factors in HHV-6 infected EC. Results showed the presence of HHV-6A in skin biopsies, and an increased virus load was associated with disease severity and poor natural killer (NK) response against the virus, particularly in subjects exhibiting a KIR2 phenotype. HLA-G plasma levels were significantly higher in HHV-6A/B-KIR2 positive SSc patients and in vitro HHV-6A infection-induced pro-fibrosis factors expression in EC, supporting its role in the development of the fibrosing process. Our data suggest an association between virus infection/reactivation and disease, opening the way to future studies to understand the mechanisms by which HHV-6A might contribute to the multifactorial pathogenesis of SSc.

SUBMITTER: Caselli E

PROVIDER: S-EPMC7022325 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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HHV-6A Infection and Systemic Sclerosis: Clues of a Possible Association.

Caselli Elisabetta E Soffritti Irene I D'Accolti Maria M Bortolotti Daria D Rizzo Roberta R Sighinolfi Gianluca G Giuggioli Dilia D Ferri Clodoveo C

Microorganisms 20191224 1

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, excessive extracellular matrix deposition, and fibrosis of the skin and internal organs. Several infectious agents, including human herpesvirus-6 (HHV-6), have been suggested as possible triggering factors, but a direct association is still missing. We characterized 26 SSc patients for the presence of HHV-6 in tissues and blood, the anti-HHV-6 response, HLA-G plasma levels, and KIR typing. Given the prominent role o ...[more]

PMID: 31878218

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Project 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.

Project description:Human betaherpesviruses 6A and 6B (HHV-6A and HHV-6B) are highly prevalent in human populations. The genomes of these viruses can be stably integrated at the telomeres of human chromosomes and be vertically transmitted (inherited chromosomally integrated HHV-6A/HHV-6B, iciHHV-6A/iciHHV-6B). We reconstructed the population structures of HHV-6A and HHV-6B, showing that HHV-6A diverged less than HHV-6B genomes from the projected common ancestral population. Thus, HHV-6B genomes experienced stronger drift, as also supported by calculation of nucleotide diversity and Tajima's D. Analysis of ancestry proportions indicated that HHV-6A exogenous viruses and iciHHV-6A derived most of their genomes from distinct ancestral sources. Conversely, ancestry proportions were similar in exogenous HHV-6B viruses and iciHHV-6B. In line with previous indications, this suggests the distinct exogenous viral populations that originated iciHHV-6B in subjects with European and Asian ancestry are still causing infections in the corresponding geographic areas. Notably, for both iciHHV-6A and iciHHV-6B, we found that European and American sequences tend to have high proportions of ancestry from viral populations that experienced considerable drift, suggesting that they underwent one or more bottlenecks followed by population expansion. Finally, analysis of HHV-6B exogenous viruses sampled in Japan indicated that proportions of ancestry components of most of these viruses are different from the majority of those sampled in the USA. More generally, we show that, in both viral species, both integrated and exogenous viral genomes have different ancestry components, partially depending on geographic location. It would be extremely important to determine whether such differences account for the diversity of HHV-6A/HHV-6B-associated clinical symptoms and epidemiology. Also, the sequencing of additional exogenous and integrated viral genomes will be instrumental to confirm and expand our conclusions, which are based on a relatively small number of genomes, sequenced with variable quality, and with unequal sampling in terms of geographic origin.

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Dataset Information

HHV-6A Infection and Systemic Sclerosis: Clues of a Possible Association.

Publications

HHV-6A Infection and Systemic Sclerosis: Clues of a Possible Association.

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