{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:30:39Z","timestamp":1792801839818,"version":"4.5.0"},"reference-count":49,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"crossref","award":["2019\/25119-7"],"award-info":[{"award-number":["2019\/25119-7"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"crossref","award":["2016\/24680-9"],"award-info":[{"award-number":["2016\/24680-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2019\/25119-7"],"award-info":[{"award-number":["2019\/25119-7"]}],"id":[{"id":"https:\/\/ror.org\/02ddkpn78","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2016\/24680-9"],"award-info":[{"award-number":["2016\/24680-9"]}],"id":[{"id":"https:\/\/ror.org\/02ddkpn78","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Zika virus (ZIKV) infection during pregnancy is a critical driver of Congenital Zika Syndrome (CZS), yet the mechanisms of pathogenesis at the placental barrier remain incompletely understood. This article is a translational, observational, and experimental study combining clinical placental analyses, placental explants cultures and in vivo murine model to investigate the mechanisms involved in ZIKV infection. We evaluate the histopathological analyses to verify presence of inflammation in ZIKV-infected human placentas from newborns with CZS and without CZS (N-CZS), identifying more intense Hofbauer cell hyperplasia, villitis and decidual inflammation in CZS group. Moreover, placental immunohistochemistry analyses identified decreased TLR4 expression in the villi and reduced TNF and IL-10 levels across placental layers of CZS group. Next, we investigated the effects of inflammation on viral replication and explored whether the flavonoid Naringenin (NGN) could modulate this inflammation. Using a placental villous explant model, we verified that inflammation induced by LPS exacerbates viral replication and pathological markers. Notably, treatment with the NGN rescued the inflammatory and virological outcomes. These findings were further validated in a murine model of congenital infection, where NGN administration alleviated microcephaly-related structural alterations in ZIKV-exposed neonates. Our results indicate that placental inflammation is a key provocateur of ZIKV replication and subsequent fetal brain malformation. Furthermore, we identify NGN as a promising bifunctional antiviral and anti-inflammatory candidate for mitigating the developmental impacts of ZIKV infection.<\/jats:p>","DOI":"10.3390\/v18060615","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T09:57:43Z","timestamp":1779962263000},"page":"615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inflammation Exacerbates Congenital Zika Virus Infection and Naringenin Provides Protective Effects"],"prefix":"10.3390","volume":"18","author":[{"given":"Anna Cl\u00e1udia Calvielli Castelo","family":"Branco","sequence":"first","affiliation":[{"name":"Laboratory of Medical Investigation in Dermatology and Immunodeficiencies (LIM-56), Department of Dermatology, Faculdade de Medicina, Instiuto de Medicina Tropical de SP, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmim \u00c1lefe Leuzzi","family":"Ramos","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Investigation in Dermatology and Immunodeficiencies (LIM-56), Department of Dermatology, Faculdade de Medicina, Instiuto de Medicina Tropical de SP, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina Manganeli","family":"Polonio","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagela Ghabdan","family":"Zanluqui","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian Gomes de","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean Pierre Schatzmann","family":"Peron","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"},{"name":"UMass Chan Medical School, Department of Neurology, Worcester, MA 3050, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6112-7107","authenticated-orcid":false,"given":"F\u00e1bio Seiti","family":"Yamada Yoshikawa","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Investigation in Dermatology and Immunodeficiencies (LIM-56), Department of 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Immunodeficiencies (LIM-56), Department of Dermatology, Faculdade de Medicina, Instiuto de Medicina Tropical de SP, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8861-635X","authenticated-orcid":false,"given":"Emanuella Sarmento Alho de","family":"Sousa","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Investigation in Dermatology and Immunodeficiencies (LIM-56), Department of Dermatology, Faculdade de Medicina, Instiuto de Medicina Tropical de SP, Universidade de S\u00e3o Paulo, S\u00e3o Paulo 05403-000, Brazil"},{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamiris","family":"Azamor da Costa Barros","sequence":"additional","affiliation":[{"name":"Instituto Fernandes Figueira, Funda\u00e7\u00e3o Oswaldo Cruz FIOCRUZ, Rio de Janeiro 22250-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elyzabeth","family":"Avvad-Portari","sequence":"additional","affiliation":[{"name":"Instituto Fernandes Figueira, Funda\u00e7\u00e3o Oswaldo Cruz FIOCRUZ, Rio de Janeiro 22250-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2193-2224","authenticated-orcid":false,"given":"Zilton Farias Meira De","family":"Vasconcelos","sequence":"additional","affiliation":[{"name":"Instituto Fernandes Figueira, Funda\u00e7\u00e3o Oswaldo Cruz FIOCRUZ, Rio de Janeiro 22250-020, 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