tetano
Editor, Senior Moderator
Discov Immunol
. 2025 Aug 27;4(1):kyaf012.
doi: 10.1093/discim/kyaf012. eCollection 2025. PROS1 released by lung basal cells limits inflammation in epithelial and monocytes during SARS-CoV-2 infection
Theodoros Simakou[SUP] 1 [/SUP], Agnieszka M Szemiel[SUP] 2 [/SUP], Lucy MacDonald[SUP] 1 [/SUP], Karen Kerr[SUP] 2 [/SUP], Domenico Somma[SUP] 1 [/SUP], Katy Diallo[SUP] 1 [/SUP], Jack Frew[SUP] 1 [/SUP], Olympia M Hardy[SUP] 1 [/SUP], Marcus Doohan[SUP] 1 [/SUP], Aziza Elmesmari[SUP] 1 [/SUP], Charles McSharry[SUP] 1 [/SUP], Stefano Alivernini[SUP] 3 4 [/SUP], Thomas D Otto[SUP] 1 [/SUP], Arvind H Patel[SUP] 2 [/SUP], Mariola Kurowska-Stolarska[SUP] 1 [/SUP]
Affiliations
Introduction: Factors regulating the severity of pneumonitis during viral infections remain unresolved. We previously found higher expression of protein S (PROS1) in lung epithelium of mild compared to severe coronavirus disease 2019 (COVID-19) patients. We hypothesized that PROS1 may protect the upper airways by regulating epithelial and myeloid cell responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Methods: To test this, in vitro air-liquid interface (ALI) cultures of primary healthy human lung epithelial cells were infected with SARS-CoV-2. This model, validated through immunofluorescent staining, confocal microscopy, and single-cell RNA-sequencing, replicated pathogenic changes seen in the lungs of COVID-19. Regulation and secretion of PROS1, along with multiple soluble mediators, were quantified in control and infected cultures using ELISAs.
Results: We found that PROS1 is present in the basal cells of healthy pseudostratified epithelium and is released during SARS-CoV-2 infection through an IFN-mediated process. Transcriptome analysis revealed that PROS1 downregulated the SARS-CoV-2-induced proinflammatory phenotypes of basal cells, transforming pathogenic CXCL10/11[SUP]high[/SUP] into a regenerative S100A2[SUP]pos[/SUP]KRT[SUP]high[/SUP] basal cell phenotype. In parallel, SARS-CoV-2 increased the secretion of M-CSF from epithelial cells, which induced the expression of PROS1 receptor MERTK on monocytes interacting with the lung epithelium. PROS1, in turn, shifted SARS-CoV-2-induced pathogenic monocyte phenotypes toward a phenotype with increased MHC class II.
Conclusion: These findings highlight the crucial role of PROS1 in protecting against severe lung pathology caused by SARS-CoV-2, by reducing epithelial- and monocyte-derived inflammation, promoting pro-repair epithelial phenotypes, and enhancing antigen presentation in myeloid cells.
Keywords: PROS1; epithelial cell; inflammation; macrophage; viral.
. 2025 Aug 27;4(1):kyaf012.
doi: 10.1093/discim/kyaf012. eCollection 2025. PROS1 released by lung basal cells limits inflammation in epithelial and monocytes during SARS-CoV-2 infection
Theodoros Simakou[SUP] 1 [/SUP], Agnieszka M Szemiel[SUP] 2 [/SUP], Lucy MacDonald[SUP] 1 [/SUP], Karen Kerr[SUP] 2 [/SUP], Domenico Somma[SUP] 1 [/SUP], Katy Diallo[SUP] 1 [/SUP], Jack Frew[SUP] 1 [/SUP], Olympia M Hardy[SUP] 1 [/SUP], Marcus Doohan[SUP] 1 [/SUP], Aziza Elmesmari[SUP] 1 [/SUP], Charles McSharry[SUP] 1 [/SUP], Stefano Alivernini[SUP] 3 4 [/SUP], Thomas D Otto[SUP] 1 [/SUP], Arvind H Patel[SUP] 2 [/SUP], Mariola Kurowska-Stolarska[SUP] 1 [/SUP]
Affiliations
- PMID: 40980495
- PMCID: PMC12448451
- DOI: 10.1093/discim/kyaf012
Introduction: Factors regulating the severity of pneumonitis during viral infections remain unresolved. We previously found higher expression of protein S (PROS1) in lung epithelium of mild compared to severe coronavirus disease 2019 (COVID-19) patients. We hypothesized that PROS1 may protect the upper airways by regulating epithelial and myeloid cell responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Methods: To test this, in vitro air-liquid interface (ALI) cultures of primary healthy human lung epithelial cells were infected with SARS-CoV-2. This model, validated through immunofluorescent staining, confocal microscopy, and single-cell RNA-sequencing, replicated pathogenic changes seen in the lungs of COVID-19. Regulation and secretion of PROS1, along with multiple soluble mediators, were quantified in control and infected cultures using ELISAs.
Results: We found that PROS1 is present in the basal cells of healthy pseudostratified epithelium and is released during SARS-CoV-2 infection through an IFN-mediated process. Transcriptome analysis revealed that PROS1 downregulated the SARS-CoV-2-induced proinflammatory phenotypes of basal cells, transforming pathogenic CXCL10/11[SUP]high[/SUP] into a regenerative S100A2[SUP]pos[/SUP]KRT[SUP]high[/SUP] basal cell phenotype. In parallel, SARS-CoV-2 increased the secretion of M-CSF from epithelial cells, which induced the expression of PROS1 receptor MERTK on monocytes interacting with the lung epithelium. PROS1, in turn, shifted SARS-CoV-2-induced pathogenic monocyte phenotypes toward a phenotype with increased MHC class II.
Conclusion: These findings highlight the crucial role of PROS1 in protecting against severe lung pathology caused by SARS-CoV-2, by reducing epithelial- and monocyte-derived inflammation, promoting pro-repair epithelial phenotypes, and enhancing antigen presentation in myeloid cells.
Keywords: PROS1; epithelial cell; inflammation; macrophage; viral.