Cargando…
Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease
Herpes simplex virus-associated diseases are a complex interaction between cytolytic viral replication and inflammation. Within the normally avascular and immunoprivileged cornea, HSV ocular infection can result in vision-threatening immune-mediated herpetic keratitis, the leading infectious cause o...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982329/ https://www.ncbi.nlm.nih.gov/pubmed/35391733 http://dx.doi.org/10.3389/fmicb.2022.859866 |
_version_ | 1784681786405552128 |
---|---|
author | Battaglia, Diana Marie Sanchez-Pino, Maria D. Nichols, Charles D. Foster, Timothy P. |
author_facet | Battaglia, Diana Marie Sanchez-Pino, Maria D. Nichols, Charles D. Foster, Timothy P. |
author_sort | Battaglia, Diana Marie |
collection | PubMed |
description | Herpes simplex virus-associated diseases are a complex interaction between cytolytic viral replication and inflammation. Within the normally avascular and immunoprivileged cornea, HSV ocular infection can result in vision-threatening immune-mediated herpetic keratitis, the leading infectious cause of corneal blindness in the industrialized world. Viral replicative processes are entirely dependent upon numerous cellular biosynthetic and metabolic pathways. Consistent with this premise, HSV infection was shown to profoundly alter gene expression associated with cellular amino acid biosynthetic pathways, including key tryptophan metabolism genes. The essential amino acid tryptophan is crucial for pathogen replication, the generation of host immune responses, and the synthesis of neurotransmitters, such as serotonin. Intriguingly, Tryptophan hydroxylase 2 (TPH2), the neuronal specific rate-limiting enzyme for serotonin synthesis, was the most significantly upregulated gene by HSV in an amino acid metabolism PCR array. Despite the well-defined effects of serotonin in the nervous system, the association of peripheral serotonin in disease-promoting inflammation has only recently begun to be elucidated. Likewise, the impact of serotonin on viral replication and ocular disease is also largely unknown. We therefore examined the effect of HSV-induced serotonin-associated synthesis and transport pathways on HSV-1 replication, as well as the correlation between HSV-induced ocular serotonin levels and disease severity. HSV infection induced expression of the critical serotonin synthesis enzymes TPH-1, TPH-2, and DOPA decarboxylase (DDC), as well as the serotonin transporter, SERT. Concordantly, HSV-infected cells upregulated serotonin synthesis and its intracellular uptake. Increased serotonin synthesis and uptake was shown to influence HSV replication. Exogenous addition of serotonin increased HSV-1 yield, while both TPH-1/2 and SERT pharmacological inhibition reduced viral yield. Congruent with these in vitro findings, rabbits intraocularly infected with HSV-1 exhibited significantly higher aqueous humor serotonin concentrations that positively and strongly correlated with viral load and ocular disease severity. Collectively, our findings indicate that HSV-1 promotes serotonin synthesis and cellular uptake to facilitate viral replication and consequently, serotonin’s proinflammatory effects may enhance the development of ocular disease. |
format | Online Article Text |
id | pubmed-8982329 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89823292022-04-06 Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease Battaglia, Diana Marie Sanchez-Pino, Maria D. Nichols, Charles D. Foster, Timothy P. Front Microbiol Microbiology Herpes simplex virus-associated diseases are a complex interaction between cytolytic viral replication and inflammation. Within the normally avascular and immunoprivileged cornea, HSV ocular infection can result in vision-threatening immune-mediated herpetic keratitis, the leading infectious cause of corneal blindness in the industrialized world. Viral replicative processes are entirely dependent upon numerous cellular biosynthetic and metabolic pathways. Consistent with this premise, HSV infection was shown to profoundly alter gene expression associated with cellular amino acid biosynthetic pathways, including key tryptophan metabolism genes. The essential amino acid tryptophan is crucial for pathogen replication, the generation of host immune responses, and the synthesis of neurotransmitters, such as serotonin. Intriguingly, Tryptophan hydroxylase 2 (TPH2), the neuronal specific rate-limiting enzyme for serotonin synthesis, was the most significantly upregulated gene by HSV in an amino acid metabolism PCR array. Despite the well-defined effects of serotonin in the nervous system, the association of peripheral serotonin in disease-promoting inflammation has only recently begun to be elucidated. Likewise, the impact of serotonin on viral replication and ocular disease is also largely unknown. We therefore examined the effect of HSV-induced serotonin-associated synthesis and transport pathways on HSV-1 replication, as well as the correlation between HSV-induced ocular serotonin levels and disease severity. HSV infection induced expression of the critical serotonin synthesis enzymes TPH-1, TPH-2, and DOPA decarboxylase (DDC), as well as the serotonin transporter, SERT. Concordantly, HSV-infected cells upregulated serotonin synthesis and its intracellular uptake. Increased serotonin synthesis and uptake was shown to influence HSV replication. Exogenous addition of serotonin increased HSV-1 yield, while both TPH-1/2 and SERT pharmacological inhibition reduced viral yield. Congruent with these in vitro findings, rabbits intraocularly infected with HSV-1 exhibited significantly higher aqueous humor serotonin concentrations that positively and strongly correlated with viral load and ocular disease severity. Collectively, our findings indicate that HSV-1 promotes serotonin synthesis and cellular uptake to facilitate viral replication and consequently, serotonin’s proinflammatory effects may enhance the development of ocular disease. Frontiers Media S.A. 2022-03-22 /pmc/articles/PMC8982329/ /pubmed/35391733 http://dx.doi.org/10.3389/fmicb.2022.859866 Text en Copyright © 2022 Battaglia, Sanchez-Pino, Nichols and Foster. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Battaglia, Diana Marie Sanchez-Pino, Maria D. Nichols, Charles D. Foster, Timothy P. Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease |
title | Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease |
title_full | Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease |
title_fullStr | Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease |
title_full_unstemmed | Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease |
title_short | Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease |
title_sort | herpes simplex virus-1 induced serotonin-associated metabolic pathways correlate with severity of virus- and inflammation-associated ocular disease |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982329/ https://www.ncbi.nlm.nih.gov/pubmed/35391733 http://dx.doi.org/10.3389/fmicb.2022.859866 |
work_keys_str_mv | AT battagliadianamarie herpessimplexvirus1inducedserotoninassociatedmetabolicpathwayscorrelatewithseverityofvirusandinflammationassociatedoculardisease AT sanchezpinomariad herpessimplexvirus1inducedserotoninassociatedmetabolicpathwayscorrelatewithseverityofvirusandinflammationassociatedoculardisease AT nicholscharlesd herpessimplexvirus1inducedserotoninassociatedmetabolicpathwayscorrelatewithseverityofvirusandinflammationassociatedoculardisease AT fostertimothyp herpessimplexvirus1inducedserotoninassociatedmetabolicpathwayscorrelatewithseverityofvirusandinflammationassociatedoculardisease |