Activation of the innate immune response against DENV in normal non-transformed human fibroblasts.

<h4>Background</h4>When mosquitoes infected with DENV are feeding, the proboscis must traverse the epidermis several times ("probing") before reaching a blood vessel in the dermis. During this process, the salivary glands release the virus, which is likely to interact first wit...

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Autores principales:	José Bustos-Arriaga, Jazmín García-Machorro, Moisés León-Juárez, Julio García-Cordero, Leopoldo Santos-Argumedo, Leopoldo Flores-Romo, A René Méndez-Cruz, Francisco J Juárez-Delgado, Leticia Cedillo-Barrón
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/4142457882d14b39a89d7d434cd1fa85
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spelling	oai:doaj.org-article:4142457882d14b39a89d7d434cd1fa852021-11-18T09:14:37ZActivation of the innate immune response against DENV in normal non-transformed human fibroblasts.1935-27271935-273510.1371/journal.pntd.0001420https://doaj.org/article/4142457882d14b39a89d7d434cd1fa852011-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22206025/?tool=EBIhttps://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735<h4>Background</h4>When mosquitoes infected with DENV are feeding, the proboscis must traverse the epidermis several times ("probing") before reaching a blood vessel in the dermis. During this process, the salivary glands release the virus, which is likely to interact first with cells of the various epidermal and dermal layers, cells which could be physiologically relevant to DENV infection and replication in humans. However, important questions are whether more abundant non-hematopoietic cells such as fibroblasts become infected, and whether they play any role in antiviral innate immunity in the very early stages of infection, or even if they might be used by DENV as primary replication cells.<h4>Methodology/principal findings</h4>Fibroblasts freshly released from healthy skin and infected 12 hours after their isolation show a positive signal for DENV. In addition, when primary skin fibroblast cultures were established and subsequently infected, we showed DENV-2 antigen-positive intracellular signal at 24 hours and 48 hours post-infection. Moreover, the fibroblasts showed productive infection in a conventional plaque assay. The skin fibroblasts infected with DENV-2 underwent potent signaling through both TLR3 and RIG- 1, but not Mda5, triggering up-regulation of IFNβ, TNFα, defensin 5 (HB5) and β defensin 2 (HβD2). In addition, DENV infected fibroblasts showed increased nuclear translocation of interferon (IFN) regulatory factor 3 (IRF3), but not interferon regulatory factor 7 (IRF7), when compared with mock-infected fibroblasts.<h4>Conclusions/significance</h4>In this work, we demonstrated the high susceptibility to DENV infection by primary fibroblasts from normal human skin, both in situ and in vitro. Our results suggest that these cells may contribute to the pro-inflammatory and anti-viral microenvironment in the early stages of interaction with DENV-2. Furthermore, the data suggest that fibroblast may also be used as a primary site of DENV replication and provide viral particles that may contribute to subsequent viral dissemination.José Bustos-ArriagaJazmín García-MachorroMoisés León-JuárezJulio García-CorderoLeopoldo Santos-ArgumedoLeopoldo Flores-RomoA René Méndez-CruzFrancisco J Juárez-DelgadoLeticia Cedillo-BarrónPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 5, Iss 12, p e1420 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
spellingShingle	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 José Bustos-Arriaga Jazmín García-Machorro Moisés León-Juárez Julio García-Cordero Leopoldo Santos-Argumedo Leopoldo Flores-Romo A René Méndez-Cruz Francisco J Juárez-Delgado Leticia Cedillo-Barrón Activation of the innate immune response against DENV in normal non-transformed human fibroblasts.
description	<h4>Background</h4>When mosquitoes infected with DENV are feeding, the proboscis must traverse the epidermis several times ("probing") before reaching a blood vessel in the dermis. During this process, the salivary glands release the virus, which is likely to interact first with cells of the various epidermal and dermal layers, cells which could be physiologically relevant to DENV infection and replication in humans. However, important questions are whether more abundant non-hematopoietic cells such as fibroblasts become infected, and whether they play any role in antiviral innate immunity in the very early stages of infection, or even if they might be used by DENV as primary replication cells.<h4>Methodology/principal findings</h4>Fibroblasts freshly released from healthy skin and infected 12 hours after their isolation show a positive signal for DENV. In addition, when primary skin fibroblast cultures were established and subsequently infected, we showed DENV-2 antigen-positive intracellular signal at 24 hours and 48 hours post-infection. Moreover, the fibroblasts showed productive infection in a conventional plaque assay. The skin fibroblasts infected with DENV-2 underwent potent signaling through both TLR3 and RIG- 1, but not Mda5, triggering up-regulation of IFNβ, TNFα, defensin 5 (HB5) and β defensin 2 (HβD2). In addition, DENV infected fibroblasts showed increased nuclear translocation of interferon (IFN) regulatory factor 3 (IRF3), but not interferon regulatory factor 7 (IRF7), when compared with mock-infected fibroblasts.<h4>Conclusions/significance</h4>In this work, we demonstrated the high susceptibility to DENV infection by primary fibroblasts from normal human skin, both in situ and in vitro. Our results suggest that these cells may contribute to the pro-inflammatory and anti-viral microenvironment in the early stages of interaction with DENV-2. Furthermore, the data suggest that fibroblast may also be used as a primary site of DENV replication and provide viral particles that may contribute to subsequent viral dissemination.
format	article
author	José Bustos-Arriaga Jazmín García-Machorro Moisés León-Juárez Julio García-Cordero Leopoldo Santos-Argumedo Leopoldo Flores-Romo A René Méndez-Cruz Francisco J Juárez-Delgado Leticia Cedillo-Barrón
author_facet	José Bustos-Arriaga Jazmín García-Machorro Moisés León-Juárez Julio García-Cordero Leopoldo Santos-Argumedo Leopoldo Flores-Romo A René Méndez-Cruz Francisco J Juárez-Delgado Leticia Cedillo-Barrón
author_sort	José Bustos-Arriaga
title	Activation of the innate immune response against DENV in normal non-transformed human fibroblasts.
title_short	Activation of the innate immune response against DENV in normal non-transformed human fibroblasts.
title_full	Activation of the innate immune response against DENV in normal non-transformed human fibroblasts.
title_fullStr	Activation of the innate immune response against DENV in normal non-transformed human fibroblasts.
title_full_unstemmed	Activation of the innate immune response against DENV in normal non-transformed human fibroblasts.
title_sort	activation of the innate immune response against denv in normal non-transformed human fibroblasts.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/4142457882d14b39a89d7d434cd1fa85
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Activation of the innate immune response against DENV in normal non-transformed human fibroblasts.

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