Vulnerability of Young Children with COVID-19: Impacts of ACE2 Expression Patterns and Lung Progenitor Cells on Infants

Background: An increasing number of children with severe coronavirus disease 2019 (COVID-19) is being reported, yet the spectrum of disease severity and expression patterns of angiotensin- converting enzyme 2 (ACE2) in children at different developmental stages are largely unknow.  Methods: We analysed clinical features in a cohort of 173 children with COVID-19 (0-15 yrs.-old) between January 22, 2020 and March 25, 2020. We systematically examined the expression and distribution of ACE2 in different developmental stages of children by using a combination of children’s lung biopsies, pluripotent stem cell-derived lung cells, RNA-sequencing profiles, and ex vivo SARS-CoV-2 pseudoviral infections.  Findings: It revealed that infants ( 1 yrs.-old) are more resistant to lung injury. The expression levels of ACE2 however do not vary by age in children’s lung. ACE2 is notably expressed not only in Alveolar Type II (AT II) cells, but also in SOX9 positive lung progenitor cells detected in both pluripotent stem cell derivatives and infants’ lungs. The ACE2+ SOX9+ cells are readily infected by SARS-CoV-2 pseudovirus and the numbers of the double positive cells are significantly decreased in older children.  Interpretation: Infants (<1 yrs.-old) with COVID-19 infection are more vulnerable to lung injuries. ACE2 expression in multiple types of lung cells including SOX9 positive progenitor cells, in cooperation with an unestablished immune system, could be risk factors contributing to vulnerability of infants with COVID-19. There is a need to continue monitoring lung development in young children who have recovered from COVID-19 infection.  Funding: National Natural Science Grant of China (No 31571407; 31970910); Hong Kong Health and Medical Research Fund (HMRF) (No:06172956), and Stem Cell and Regenerative Medicine Fund (Guangzhou Women and Children's Medical Centre, Grant No:5001-4001010) Declaration of Interests: The authors declare no competing interest. Ethics Approval Statement: This study was approved by the respective Institutional Review Board. Written informed consent was obtained from patients and/or guardians before data collected.