{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:50:26Z","timestamp":1792018226974,"version":"4.4.0"},"reference-count":46,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011408","name":"University of South Alabama","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100011408","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01s7b5y08","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Alabama Innovation Corporation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Chikungunya virus (CHIKV) is an alphavirus that infects dermal fibroblasts as a primary target cell during natural mosquito-borne transmission. While primary human dermal fibroblasts (hDFs) have been implicated as a key source of type I interferon (IFN-I) during CHIKV infection, the dynamics of this response and its sufficiency for antiviral protection remain incompletely understood. Here, we systematically characterize in vitro CHIKV infection of primary hDFs, evaluating the effects of single-passage viral stock origin (mammalian- vs. mosquito-propagated), donor variability, and multiplicity of infection (MOI) on infection kinetics and innate immune induction. We demonstrate that hDFs support high-titered CHIKV replication at both MOI 1 and 0.01, resulting in universal cell death by 72 hpi despite robust IFN\u03b2 transcript induction\u2014reaching up to ~2800-fold over mock\u2014and secretion of pro-inflammatory cytokines, including IFN\u03b12, TNF\u03b1, IL-1\u03b2, and IL-8. Notably, IFN\u03b2 protein levels remained below 10 pg\/mL under all infection conditions, revealing a disconnect between transcriptional and translational responses, suggesting CHIKV-mediated translational suppression. Pharmacological inhibition of TBK1\/IKK\u03b5 via amlexanox did not suppress IFN\u03b2 transcript induction at any tested concentration, suggesting that canonical PRR signaling through this node\u2014including both RIG-I\/MAVS and TLR3\/TRIF pathways\u2014is not the major driver of the observed transcriptional response. In contrast, co-inoculation with exogenous IFN\u03b2 as low as 20 pg\/mL activated IFNAR signaling, robustly upregulated interferon-stimulated genes (ISGs), and fully rescued hDFs from otherwise lethal infection. Together, these findings demonstrate that CHIKV-infected hDFs mount a transcriptionally robust but translationally insufficient innate immune response and that the transcriptional response appears to operate independently of TBK1\/IKK\u03b5. These results have direct implications for understanding how the skin microenvironment may modulate early CHIKV pathogenesis and suggest that paracrine IFN\u03b2 signaling from neighboring cell types may be critical for fibroblast survival during natural infection.<\/jats:p>","DOI":"10.3390\/v18050503","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:43:51Z","timestamp":1777448631000},"page":"503","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CHIKV-Infected Human Dermal Fibroblasts Mount an IFN\u03b2 Transcriptional Response Independent of TBK1\/IKK\u03b5 Signaling That Fails to Prevent Lethal Infection"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2211-226X","authenticated-orcid":false,"given":"Meagan M.","family":"Taylor","sequence":"first","affiliation":[{"name":"Department of Microbiology & Immunology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary W.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2091-7604","authenticated-orcid":false,"given":"Jonathan O.","family":"Rayner","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Frederick P. Whiddon College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2025, September 07). Chikungunya. 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