667fa4cfa3e75af6fd19b875f994b422 pmc_34578296.pdf fe49224815e0dfc72fa3091d962359fb9f17eb2e pmc_34578296.pdf a34788a045997785718af69976438f2982d65e60629645dd11ea2cc272fd1e0d pmc_34578296.pdf Title: SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients Subject: Angiotensin converting enzyme 2 (ACE2) is a host ectopeptidase and the receptor for the SARS-CoV-2 virus, albeit virus-ACE2 interaction goes far beyond viral entry into target cells. Controversial data exists linking viral infection to changes in ACE2 expression and function, which might influence the subsequent induction of an inflammatory response. Here, we tested the significance of soluble ACE2 enzymatic activity longitudinally in nasopharyngeal swabs and plasma samples of SARS-CoV-2 infected patients, along with the induction of inflammatory cytokines. Release of soluble functional ACE2 increases upon SARS-CoV-2 infection in swabs and plasma of infected patients, albeit rapidly decreasing during infection course in parallel with ACE2 gene expression. Similarly, SARS-CoV-2 infection also induced the expression of inflammatory cytokines. These changes positively correlated with the viral load. Overall, our results demonstrate the existence of mechanisms by which SARS-CoV-2 modulates ACE2 expression and function, intracellular viral sensing and subsequent inflammatory response, offering new insights into ACE2 dynamics in the human upper respiratory tract and pointing towards soluble ACE2 levels as a putative early biomarker of infection severity. Keywords: SARS-CoV-2-ACE2; inflammation; biomarker Author: Lucía Gutiérrez-Chamorro, Eva Riveira-Muñoz, Clara Barrios, Vanesa Palau, Maria Nevot, Sònia Pedreño-López, Jordi Senserrich, Marta Massanella, Bonaventura Clotet, Cecilia Cabrera, Oriol Mitjà, Marta Crespo, Julio Pascual, Marta Riera and Ester Ballana Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Fri Sep 3 13:57:52 2021 CEST ModDate: Sat Sep 4 03:11:36 2021 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 11 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 602514 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- HBLXEW+VnURWPalladioL Type 1 Custom yes yes no 10 0 KGKEMO+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 WLZOTN+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 HKLEWI+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 SGWBNM+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 HOWKDX+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 36 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 58 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 62 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 66 0 HHBSSZ+CMSY10 Type 1 Builtin yes yes no 78 0 REGJRM+EURM10 Type 1 Builtin yes yes no 85 0 URYLRZ+URWPalladioL-BoldItal Type 1 Custom yes yes no 92 0 Arial TrueType WinAnsi no no no 104 0 BCDEEE+Calibri TrueType WinAnsi yes yes no 107 0 BCDFEE+Calibri-Italic TrueType WinAnsi yes yes no 111 0 Symbol CID TrueType Identity-H yes no yes 118 0 ArialMT TrueType WinAnsi no no no 127 0 Arial TrueType WinAnsi no no no 144 0 BCDEEE+Calibri TrueType WinAnsi yes yes no 147 0 BCDFEE+Calibri-Italic TrueType WinAnsi yes yes no 151 0 ArialMT TrueType WinAnsi no no no 156 0 Arial,Italic TrueType WinAnsi no no no 164 0 Arial TrueType WinAnsi no no no 179 0 BCDEEE+Calibri TrueType WinAnsi yes yes no 182 0 BCDFEE+Calibri-Italic TrueType WinAnsi yes yes no 186 0 Symbol CID TrueType Identity-H yes no yes 193 0 ArialMT TrueType WinAnsi no no no 203 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:39:19 CEST RepresentationInformation: pmc_34578296.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:05:47 CEST Size: 602514 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 387 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Patients and Samples Destination: subsection.2.1 Item: Title: ACE2 Enzymatic Assay Destination: subsection.2.2 Item: Title: SARS-CoV-2 PCR Detection and Viral Load Quantification Destination: subsection.2.3 Item: Title: Quantitative RT-Polymerase Chain Reaction (qRT-PCR) Destination: subsection.2.4 Item: Title: IL6 Plasma Levels Destination: subsection.2.5 Item: Title: Statistical Analysis Destination: subsection.2.6 Item: Title: Results Destination: section.3 Children: Item: Title: SARS-CoV-2 Infection Modulates ACE2 Function and Expression in Upper Respiratory Tract Destination: subsection.3.1 Item: Title: SARS-CoV-2 Infection Modulates Inflammatory Cytokine Expression in Upper Respiratory Track Destination: subsection.3.2 Item: Title: Soluble ACE2 Is Transiently Elevated in Plasma of SARS-CoV-2 Infected Patients and Correlates with Inflammation Markers Destination: subsection.3.3 Item: Title: Discussion Destination: section.4 Item: Title: References Destination: section.4 Info: Title: SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients Author: Lucía Gutiérrez-Chamorro, Eva Riveira-Muñoz, Clara Barrios, Vanesa Palau, Maria Nevot, Sònia Pedreño-López, Jordi Senserrich, Marta Massanella, Bonaventura Clotet, Cecilia Cabrera, Oriol Mitjà, Marta Crespo, Julio Pascual, Marta Riera and Ester Ballana Subject: Angiotensin converting enzyme 2 (ACE2) is a host ectopeptidase and the receptor for the SARS-CoV-2 virus, albeit virus-ACE2 interaction goes far beyond viral entry into target cells. Controversial data exists linking viral infection to changes in ACE2 expression and function, which might influence the subsequent induction of an inflammatory response. Here, we tested the significance of soluble ACE2 enzymatic activity longitudinally in nasopharyngeal swabs and plasma samples of SARS-CoV-2 infected patients, along with the induction of inflammatory cytokines. Release of soluble functional ACE2 increases upon SARS-CoV-2 infection in swabs and plasma of infected patients, albeit rapidly decreasing during infection course in parallel with ACE2 gene expression. Similarly, SARS-CoV-2 infection also induced the expression of inflammatory cytokines. These changes positively correlated with the viral load. Overall, our results demonstrate the existence of mechanisms by which SARS-CoV-2 modulates ACE2 expression and function, intracellular viral sensing and subsequent inflammatory response, offering new insights into ACE2 dynamics in the human upper respiratory tract and pointing towards soluble ACE2 levels as a putative early biomarker of infection severity. 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