{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:20:35Z","timestamp":1787062835758,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012375","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T00:00:00Z","timestamp":1735171200000}}],"reference-count":25,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T00:00:00Z","timestamp":1733961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R21-DE031888"],"award-info":[{"award-number":["R21-DE031888"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019823","name":"University of Maryland, Baltimore","doi-asserted-by":"publisher","award":["1UL-1TR00309"],"award-info":[{"award-number":["1UL-1TR00309"]}],"id":[{"id":"10.13039\/100019823","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["Z01-DE000704"],"award-info":[{"award-number":["Z01-DE000704"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["ZIA CL090070-03"],"award-info":[{"award-number":["ZIA CL090070-03"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["ZIC DC000086"],"award-info":[{"award-number":["ZIC DC000086"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Saliva contains antimicrobial peptides considered integral components of host innate immunity, and crucial for protection against colonizing microbial species. Most notable is histatin-5 which is exclusively produced in salivary glands with uniquely potent antifungal activity against the opportunistic pathogen\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    . Recently, SARS-CoV-2 was shown to replicate in salivary gland acinar cells eliciting local immune cell activation. In this study, we performed studies to investigate the implications of SARS-CoV-2 infection on salivary histatin-5 production and\n                    <jats:italic>Candida<\/jats:italic>\n                    colonization. Bulk RNA-sequencing of parotid salivary glands from COVID-19 autopsies demonstrated statistically significant decreased expression of histatin and amylase genes.\n                    <jats:italic>In situ<\/jats:italic>\n                    hybridization, coupled with immunofluorescence for co-localization of SARS-CoV-2 spike and histatin in salivary gland cells, showed that histatin was absent or minimally present in acinar cells with replicating viruses. To investigate the clinical implications of these findings, salivary histatin-5 levels and oral\n                    <jats:italic>Candida<\/jats:italic>\n                    burden in saliva samples from three independent cohorts of mild and severe COVID-19 patients and matched healthy controls were evaluated. Results revealed significantly reduced histatin-5 in SARS-CoV-2 infected subjects, concomitant with enhanced prevalence of\n                    <jats:italic>C. albicans<\/jats:italic>\n                    . Analysis of prospectively recovered samples indicated that the decrease in histatin-5 is likely reversible in mild-moderate disease as concentrations tended to increase during the post-acute phase. Importantly, salivary cytokine profiling demonstrated correlations between activation of the Th17 inflammatory pathway, changes in histatin-5 concentrations, and subsequent clearance of\n                    <jats:italic>C. albicans<\/jats:italic>\n                    in a heavily colonized subject. The importance of salivary histatin-5 in controlling the proliferation of\n                    <jats:italic>C. albicans<\/jats:italic>\n                    was demonstrated using an\n                    <jats:italic>ex vivo<\/jats:italic>\n                    assay where\n                    <jats:italic>C. albicans<\/jats:italic>\n                    was able to proliferate in COVID-19 saliva with low histatin-5, but not with high histatin-5. Taken together, the findings from this study potentially implicate SARS-CoV-2 infection of salivary glands with compromised oral innate immunity, and potential predisposition to oral candidiasis.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012375","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T13:48:50Z","timestamp":1734011330000},"page":"e1012375","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["SARS-CoV-2 infection of salivary glands compromises the production of a secreted antifungal peptide with potential implications for development of oral candidiasis"],"prefix":"10.1371","volume":"20","author":[{"given":"Areej A.","family":"Alfaifi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristan W.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed S.","family":"Sultan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy F.","family":"Meiller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Rock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Kleiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel S.","family":"Chertow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M.","family":"Hewitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Billel","family":"Gasmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Ramelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blake M.","family":"Warner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4425-3873","authenticated-orcid":true,"given":"Mary Ann","family":"Jabra-Rizk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,12]]},"reference":[{"issue":"2","key":"ppat.1012375.ref001","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1177\/0022034520957289","article-title":"Oral manifestations in patients with COVID-19: A living systematic review","volume":"100","author":"J Amorim Dos Santos","year":"2021","journal-title":"Dent Res"},{"issue":"4","key":"ppat.1012375.ref002","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s11046-020-00472-7","article-title":"Opportunistic fungal Infections in the epidemic area of COVID-19: A cinical and diagnostic perspective from Iran","volume":"185","author":"M Salehi","year":"2020","journal-title":"Mycopathologia"},{"issue":"3","key":"ppat.1012375.ref003","doi-asserted-by":"crossref","first-page":"32","DOI":"10.3390\/dj9030032","article-title":"Oral symptoms associated with COVID-19 and their pathogenic mechanisms: A literature review","volume":"9","author":"H. 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