ABSTRACT
Background: While pregnant women have been identified as a potentially at-risk group concerning COVID-19 infection, little is known regarding the susceptibility of the fetus to infection. Co-expression of ACE2 and TMPRSS2 has been identified as a pre-requisite for infection, and expression across different tissues is known to vary between children and adults. However, the expression of these proteins in the fetus is unknown. Methods: We performed a retrospective analysis of single cell data repositories. This data was then validated at both gene and protein level by performing qRT-PCR and two-colour immunohistochemistry on a library of second-trimester human fetal tissues. Findings: TMPRSS2 is present at both gene and protein level in the predominantly epithelial fetal tissues analysed. ACE2 is present at significant levels, only in the fetal intestine and kidney and is not expressed in the fetal lung. The placenta is also negative for the two proteins both during development and at term. Interpretation: This dataset indicates that the lungs are unlikely to be a viable route of SARS-CoV2 fetal infection. The fetal kidney, despite presenting both the proteins required for the infection, is anatomically protected from the exposure to the virus. However, the GI tract is likely to be susceptible to infection due to its high co-expression of both proteins, as well as its exposure to potentially infected amniotic fluid. Funding: This work was made possible by an MRC / UKRI COVID-19 Rapid response initiative grant (MR/V028480/1).
Subject(s)
COVID-19ABSTRACT
Background: While pregnant women have been identified as a potentially at-risk group concerning COVID-19 infection, little is known regarding the susceptibility of the fetus to infection. Co-expression of ACE2 and TMPRSS2 has been identified as a pre-requisite for infection, and expression across different tissues is known to vary between children and adults. However, the expression of these proteins in the fetus is unknown.Methods: We performed a retrospective analysis of single cell data repositories. This data was then validated at both gene and protein level by performing qRT-PCR and two-colour immunohistochemistry on a library of second-trimester human fetal tissues.Findings: TMPRSS2 is present at both gene and protein level in the predominantly epithelial fetal tissues analysed. ACE2 is present at significant levels, only in the fetal intestine and kidney and is not expressed in the fetal lung. The placenta is also negative for the two proteins both during development and at term.Interpretation: This dataset indicates that the lungs are unlikely to be a viable route of SARS-CoV2 fetal infection. The fetal kidney, despite presenting both the proteins required for the infection, is anatomically protected from the exposure to the virus. However, the GI tract is likely to be susceptible to infection due to its high co-expression of both proteins, as well as its exposure to potentially infected amniotic fluid.Funding Information: This work was made possible by an MRC / UKRI COVID-19 Rapid response initiative grant (MR/V028480/1).Declaration of Interests: The authors declare no conflicts of interest related to this work or its developments. DC is founder, shareholder, and consultant of Next Generation Diagnostic SRL.Ethics Approval Statement: Human fetal tissues were obtained with consent through the Human Developmental Biology Resource (HDBR; REC 18/LO/0822 – IRAS 244325; Project ID 2000478). Placental samples were obtained at delivery of an uncomplicated, full-term pregnancy (median 39 weeks PCW [Range 38+1 -39+4] for 6 patients recruited through the EVERREST Prospective Study as normal controls (National Research Ethics reference 13/LO/1254), NCT02097667 registered 31st October 2013[10].
Subject(s)
COVID-19ABSTRACT
While a substantial proportion of adults infected with SARS-CoV-2 progress to develop severe disease, children rarely manifest respiratory complications. Therefore, understanding differences in the local and systemic response to SARS-CoV-2 infection between children and adults may provide important clues about the pathogenesis of SARS-CoV-2 infection. To address this, we first generated a healthy reference multi-omics single cell data set from children (n=30) in whom we have profiled triple matched samples: nasal and tracheal brushings and PBMCs, where we track the developmental changes for 42 airway and 31 blood cell populations from infancy, through childhood to adolescence. This has revealed the presence of naive B and T lymphocytes in neonates and infants with a unique gene expression signature bearing hallmarks of innate immunity. We then contrast the healthy reference with equivalent data from severe paediatric and adult COVID-19 patients (total n=27), from the same three types of samples: upper and lower airways and blood. We found striking differences: children with COVID-19 as opposed to adults had a higher proportion of innate lymphoid and non-clonally expanded naive T cells in peripheral blood, and a limited interferon-response signature. In the airway epithelium, we found the highest viral load in goblet and ciliated cells and describe a novel inflammatory epithelial cell population. These cells represent a transitional regenerative state between secretory and ciliated cells; they were found in healthy children and were enriched in pediatric and adult COVID-19 patients. Epithelial cells display an antiviral and neutrophil-recruiting gene signature that is weaker in severe paediatric versus adult COVID-19. Our matched blood and airway samples allowed us to study the spatial dynamics of infection. Lastly, we provide a user-friendly interface for this data as a highly granular reference for the study of immune responses in airways and blood in children.