Activation of the innate immune response against DENV in normal non-transformed human fibroblasts
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 epiderma...
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| creator | Bustos-Arriaga, José García-Machorro, Jazmín León-Juárez, Moisés García-Cordero, Julio Santos-Argumedo, Leopoldo Flores-Romo, Leopoldo Méndez-Cruz, A René Juárez-Delgado, Francisco J Cedillo-Barrón, Leticia |
| description | 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.
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.
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. |
| doi_str_mv | 10.1371/journal.pntd.0001420 |
| format | Article |
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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.
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.</description><identifier>ISSN: 1935-2735</identifier><identifier>ISSN: 1935-2727</identifier><identifier>EISSN: 1935-2735</identifier><identifier>DOI: 10.1371/journal.pntd.0001420</identifier><identifier>PMID: 22206025</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>beta-Defensins - immunology ; beta-Defensins - metabolism ; Biology ; Cells, Cultured ; Dengue ; Dengue Virus - immunology ; Epidermis ; Fibroblasts ; Fibroblasts - immunology ; Fibroblasts - virology ; Flow Cytometry ; Gene Expression Profiling ; Genetic aspects ; Health aspects ; Humans ; Immune response ; Immune system ; Immunity, Innate ; Infections ; Interferons - immunology ; Interferons - metabolism ; Medicine ; Microscopy, Fluorescence ; Physiological aspects ; Prevention ; Proteins ; Receptors, Immunologic - immunology ; Receptors, Immunologic - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Risk factors ; Signal Transduction ; Skin - cytology ; Studies ; Translocation ; Tropical diseases ; Tumor Necrosis Factor-alpha - immunology ; Tumor Necrosis Factor-alpha - metabolism ; Viral Plaque Assay ; Virus Replication</subject><ispartof>PLoS neglected tropical diseases, 2011-12, Vol.5 (12), p.e1420-e1420</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Bustos-Arriaga et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Bustos-Arriaga J, García-Machorro J, León-Juárez M, García-Cordero J, Santos-Argumedo L, et al. (2011) Activation of the Innate Immune Response against DENV in Normal Non-Transformed Human Fibroblasts. PLoS Negl Trop Dis 5(12): e1420. doi:10.1371/journal.pntd.0001420</rights><rights>Bustos-Arriaga et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c689t-f506b41a0b8186dc9b66090fa2158f7e289c4ca786c10eedd9404b5c8cd0ffc23</citedby><cites>FETCH-LOGICAL-c689t-f506b41a0b8186dc9b66090fa2158f7e289c4ca786c10eedd9404b5c8cd0ffc23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243703/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243703/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53770,53772,79347,79348</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22206025$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Lopes da Fonseca, Benedito A.</contributor><creatorcontrib>Bustos-Arriaga, José</creatorcontrib><creatorcontrib>García-Machorro, Jazmín</creatorcontrib><creatorcontrib>León-Juárez, Moisés</creatorcontrib><creatorcontrib>García-Cordero, Julio</creatorcontrib><creatorcontrib>Santos-Argumedo, Leopoldo</creatorcontrib><creatorcontrib>Flores-Romo, Leopoldo</creatorcontrib><creatorcontrib>Méndez-Cruz, A René</creatorcontrib><creatorcontrib>Juárez-Delgado, Francisco J</creatorcontrib><creatorcontrib>Cedillo-Barrón, Leticia</creatorcontrib><title>Activation of the innate immune response against DENV in normal non-transformed human fibroblasts</title><title>PLoS neglected tropical diseases</title><addtitle>PLoS Negl Trop Dis</addtitle><description>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.
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.
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.</description><subject>beta-Defensins - immunology</subject><subject>beta-Defensins - metabolism</subject><subject>Biology</subject><subject>Cells, Cultured</subject><subject>Dengue</subject><subject>Dengue Virus - immunology</subject><subject>Epidermis</subject><subject>Fibroblasts</subject><subject>Fibroblasts - immunology</subject><subject>Fibroblasts - virology</subject><subject>Flow Cytometry</subject><subject>Gene Expression Profiling</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunity, Innate</subject><subject>Infections</subject><subject>Interferons - immunology</subject><subject>Interferons - metabolism</subject><subject>Medicine</subject><subject>Microscopy, Fluorescence</subject><subject>Physiological aspects</subject><subject>Prevention</subject><subject>Proteins</subject><subject>Receptors, Immunologic - immunology</subject><subject>Receptors, Immunologic - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Risk factors</subject><subject>Signal Transduction</subject><subject>Skin - cytology</subject><subject>Studies</subject><subject>Translocation</subject><subject>Tropical diseases</subject><subject>Tumor Necrosis Factor-alpha - immunology</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Viral Plaque Assay</subject><subject>Virus Replication</subject><issn>1935-2735</issn><issn>1935-2727</issn><issn>1935-2735</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNptkl1v0zAUhiMEYmPwDxBEQoKrFn8mzs2kagyYNMENcGud-KN1ldjFdibx73FpNrVoysWJ7ee8tl-_VfUaoyWmLf64DVP0MCx3PuslQggzgp5U57ijfEFayp8e_Z9VL1LaIsQ7LvDz6owQghpE-HkFK5XdHWQXfB1snTemdt5DLmUcJ2_qaNIu-GRqWIPzKdefrr_9KkztQxxhKMUvcgSfbBkbXW-mEXxtXR9DP0DK6WX1zMKQzKu5XlQ_P1__uPq6uP3-5eZqdbtQjejywnLU9AwD6gUWjVZd3zSoQxYI5sK2hohOMQWtaBRGxmjdMcR6roTSyFpF6EX19qC7G0KSsztJYiIExqxhrBA3B0IH2MpddCPEPzKAk_8mQlxLiNmpwUhW3GS8FYJozHrageh0qxllSmMLghety3m3qS_XVsYXE4YT0dMV7zZyHe4kJYy2iBaBD7NADL8nk7IcXVJmGMCbMCXZYUpxW16wkO_-Ix-_3EytoZzfeRvKtmqvKVekbTgWqG0KtXyEKp82o1PBG-vK_EnD-6OGjYEhb1IYpn1g0inIDqCKIaVo7IMXGMl9YO9PLfeBlXNgS9ubYx8fmu4TSv8C-Lvncw</recordid><startdate>20111201</startdate><enddate>20111201</enddate><creator>Bustos-Arriaga, José</creator><creator>García-Machorro, Jazmín</creator><creator>León-Juárez, Moisés</creator><creator>García-Cordero, Julio</creator><creator>Santos-Argumedo, Leopoldo</creator><creator>Flores-Romo, Leopoldo</creator><creator>Méndez-Cruz, A René</creator><creator>Juárez-Delgado, Francisco J</creator><creator>Cedillo-Barrón, Leticia</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7SS</scope><scope>7T2</scope><scope>7T7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8C1</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>F1W</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>H95</scope><scope>H97</scope><scope>K9.</scope><scope>L.G</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20111201</creationdate><title>Activation of the innate immune response against DENV in normal non-transformed human fibroblasts</title><author>Bustos-Arriaga, José ; García-Machorro, Jazmín ; León-Juárez, Moisés ; García-Cordero, Julio ; Santos-Argumedo, Leopoldo ; Flores-Romo, Leopoldo ; Méndez-Cruz, A René ; Juárez-Delgado, Francisco J ; Cedillo-Barrón, Leticia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c689t-f506b41a0b8186dc9b66090fa2158f7e289c4ca786c10eedd9404b5c8cd0ffc23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>beta-Defensins - 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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.
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.
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22206025</pmid><doi>10.1371/journal.pntd.0001420</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1935-2735 |
| ispartof | PLoS neglected tropical diseases, 2011-12, Vol.5 (12), p.e1420-e1420 |
| issn | 1935-2735 1935-2727 1935-2735 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central Open Access; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | beta-Defensins - immunology beta-Defensins - metabolism Biology Cells, Cultured Dengue Dengue Virus - immunology Epidermis Fibroblasts Fibroblasts - immunology Fibroblasts - virology Flow Cytometry Gene Expression Profiling Genetic aspects Health aspects Humans Immune response Immune system Immunity, Innate Infections Interferons - immunology Interferons - metabolism Medicine Microscopy, Fluorescence Physiological aspects Prevention Proteins Receptors, Immunologic - immunology Receptors, Immunologic - metabolism Reverse Transcriptase Polymerase Chain Reaction Risk factors Signal Transduction Skin - cytology Studies Translocation Tropical diseases Tumor Necrosis Factor-alpha - immunology Tumor Necrosis Factor-alpha - metabolism Viral Plaque Assay Virus Replication |
| title | Activation of the innate immune response against DENV in normal non-transformed human fibroblasts |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T02%3A14%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Activation%20of%20the%20innate%20immune%20response%20against%20DENV%20in%20normal%20non-transformed%20human%20fibroblasts&rft.jtitle=PLoS%20neglected%20tropical%20diseases&rft.au=Bustos-Arriaga,%20Jos%C3%A9&rft.date=2011-12-01&rft.volume=5&rft.issue=12&rft.spage=e1420&rft.epage=e1420&rft.pages=e1420-e1420&rft.issn=1935-2735&rft.eissn=1935-2735&rft_id=info:doi/10.1371/journal.pntd.0001420&rft_dat=%3Cgale_plos_%3EA276518076%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1288114644&rft_id=info:pmid/22206025&rft_galeid=A276518076&rft_doaj_id=oai_doaj_org_article_4142457882d14b39a89d7d434cd1fa85&rfr_iscdi=true |