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Several mosquito-borne flaviviruses that can cause human illness, including West Nile, Usutu, and St. Louis encephalitis, have associations with birds. However, the susceptibility of chickens to ZIKV and their role in viral epidemiology is not currently known. We investigated the susceptibility of chickens to experimental ZIKV infection using chickens ranging from 1-day-old chicks to 6-week-old birds. ZIKV caused no clinical signs in chickens of all age groups tested. Viral RNA was detected in the blood and tissues during the first 5 days post-inoculation in 1-day and 4-day-old chicks inoculated with a high viral dose, but ZIKV was undetectable in 6-week-old birds at all timepoints. Minimal antibody responses were observed in 6-week-old birds, and while present in younger chicks, they waned by 28 days post-infection. Innate immune responses varied significantly between age groups. Robust type I interferon and inflammasome responses were measured in older chickens, while limited innate immune activation was observed in younger chicks. Signal transducer and activator of transcription 2 (STAT2) is a major driver of host restriction to ZIKV, and chicken STAT2 is distinct from human STAT2, potentially contributing to the observed resistance to ZIKV infection. The rapid clearance of the virus in older chickens coincided with an effective innate immune response, highlighting age-dependent susceptibility. Our study indicates that chickens are not susceptible to productive ZIKV infection and are unlikely to play a role in the ZIKV epidemiology.<\/jats:p>","DOI":"10.3390\/v16040569","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T10:11:55Z","timestamp":1712571115000},"page":"569","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Susceptibility of Chickens to Zika Virus: A Comprehensive Study on Age-Dependent Infection Dynamics and Host Responses"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3102-7447","authenticated-orcid":false,"given":"Ruth H.","family":"Nissly","sequence":"first","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6661-6997","authenticated-orcid":false,"given":"Levina","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA"},{"name":"DermBiont, Inc., 451 D Street, Suite 908, Boston, MA 02210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margo R.","family":"Keller","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian M.","family":"Bird","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA"},{"name":"Applied Biological Sciences Group, The Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gitanjali","family":"Bhushan","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA"},{"name":"College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sougat","family":"Misra","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7109-7810","authenticated-orcid":false,"given":"Shubhada K.","family":"Chothe","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miranda C.","family":"Sill","sequence":"additional","affiliation":[{"name":"Department of Biology, Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nagaram Vinod","family":"Kumar","sequence":"additional","affiliation":[{"name":"College of Veterinary Science, Sri Venkateswara Veterinary University, Tirupati 517 602, Andhra Pradesh, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. V. N.","family":"Sivakumar","sequence":"additional","affiliation":[{"name":"College of Veterinary Science, Sri Venkateswara Veterinary University, Tirupati 517 602, Andhra Pradesh, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B. Rambabu","family":"Naik","sequence":"additional","affiliation":[{"name":"College of Veterinary Science, Sri Venkateswara Veterinary University, Tirupati 517 602, Andhra Pradesh, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhushan M.","family":"Jayarao","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8640-254X","authenticated-orcid":false,"given":"Suresh V.","family":"Kuchipudi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1007\/s00705-023-05835-1","article-title":"Renaming of the genus Flavivirus to Orthoflavivirus and extension of binomial species names within the family Flaviviridae","volume":"168","author":"Postler","year":"2023","journal-title":"Arch. 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