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Despite the many advances in scientific knowledge about the disease, much remains to be clarified about the molecular alterations induced by SARS-CoV-2 infection. In this work, we present a hybrid proteomics and in silico interactomics strategy to establish a COVID-19 salivary protein profile. Data are available via ProteomeXchange with identifier PXD036571. The differential proteome was narrowed down by the Partial Least-Squares Discriminant Analysis and enrichment analysis was performed with FunRich. In parallel, OralInt was used to determine interspecies Protein-Protein Interactions between humans and SARS-CoV-2. Five dysregulated biological processes were identified in the COVID-19 proteome profile: Apoptosis, Energy Pathways, Immune Response, Protein Metabolism and Transport. We identified 10 proteins (KLK 11, IMPA2, ANXA7, PLP2, IGLV2-11, IGHV3-43D, IGKV2-24, TMEM165, VSIG10 and PHB2) that had never been associated with SARS-CoV-2 infection, representing new evidence of the impact of COVID-19. Interactomics analysis showed viral influence on the host immune response, mainly through interaction with the degranulation of neutrophils. The virus alters the host\u2019s energy metabolism and interferes with apoptosis mechanisms.<\/jats:p>","DOI":"10.3390\/jcm11195571","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T21:10:05Z","timestamp":1663881005000},"page":"5571","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["COVID-19 Salivary Protein Profile: Unravelling Molecular Aspects of SARS-CoV-2 Infection"],"prefix":"10.3390","volume":"11","author":[{"given":"Eduardo","family":"Esteves","sequence":"first","affiliation":[{"name":"Universidade Cat\u00f3lica Portuguesa, Faculty of Dental Medicine (FMD), Center for Interdisciplinary Research in Health (CIIS), 3504-505 Viseu, Portugal"},{"name":"Health Sciences Research Centre (CICS-UBI), Faculty of Health Sciences, University of Beira Interior, 6201-001 Covilh\u00e3, Portugal"}]},{"given":"Vera M.","family":"Mendes","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-4042","authenticated-orcid":false,"given":"Bruno","family":"Manadas","sequence":"additional","affiliation":[{"name":"CNC\u2014Center for Neuroscience and Cell Biology, CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Rafaela","family":"Lopes","sequence":"additional","affiliation":[{"name":"Universidade Cat\u00f3lica Portuguesa, Faculty of Dental Medicine (FMD), Center for Interdisciplinary Research in Health (CIIS), 3504-505 Viseu, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3395-5973","authenticated-orcid":false,"given":"Liliana","family":"Bernardino","sequence":"additional","affiliation":[{"name":"Health Sciences Research Centre (CICS-UBI), Faculty of Health Sciences, University of Beira Interior, 6201-001 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6141-9089","authenticated-orcid":false,"given":"Maria Jos\u00e9","family":"Correia","sequence":"additional","affiliation":[{"name":"Universidade Cat\u00f3lica Portuguesa, Faculty of Dental Medicine (FMD), Center for Interdisciplinary Research in Health (CIIS), 3504-505 Viseu, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0631-4062","authenticated-orcid":false,"given":"Marlene","family":"Barros","sequence":"additional","affiliation":[{"name":"Universidade Cat\u00f3lica Portuguesa, Faculty of Dental Medicine (FMD), Center for Interdisciplinary Research in Health (CIIS), 3504-505 Viseu, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2239-2976","authenticated-orcid":false,"given":"Ana Cristina","family":"Esteves","sequence":"additional","affiliation":[{"name":"CESAM, Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4604-0780","authenticated-orcid":false,"given":"Nuno","family":"Rosa","sequence":"additional","affiliation":[{"name":"Universidade Cat\u00f3lica Portuguesa, Faculty of Dental Medicine (FMD), Center for Interdisciplinary Research in Health (CIIS), 3504-505 Viseu, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Costa, M.M., Martin, H., Estellon, B., Dup\u00e9, F.-X., Saby, F., Benoit, N., Tissot-Dupont, H., Million, M., Pradines, B., and Granjeaud, S. 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