Increased expression of a cellular enzyme called TMPRSS2, well known for its role in prostate cancer was observed to play a role in older individuals coming in contact with the virion.
The recent findings, published in the Journal of Clinical Investigation, by a group of researchers at Vanderbilt University Medical Center (VUMC) and their colleagues have determined a key factor as to why COVID-19 appears to infect and sicken adults and older people preferentially while seeming to spare younger children.
The study observes that children have lower levels of an enzyme/co-receptor that SARS-CoV-2, the RNA virus, needs to invade airway epithelial cells in the lung. The study supports efforts to block the enzyme to potentially treat or prevent COVID-19 in older people.
Jennifer Sucre, MD, assistant professor of Pediatrics (Neonatology), who led the research with Jonathan Kropski, MD, assistant professor of Medicine, reports that their study provides a biologic rationale for why particularly infants and very young children seem to be less likely to either get infected or to have severe disease symptoms. The study team infers that there is still so much to learn about SARS-CoV-2. But this much is known: that after a viral particle is inhaled into the lungs, protein “spikes” that stick out like nail studs in a soccer ball attach to ACE2, a receptor on the surfaces of certain lung cells.
A cellular enzyme called TMPRSS2 chops up the spike protein, enabling the virus to fuse into the cell membrane and “break into” the cell. Once inside, the virus hijacks the cell’s genetic machinery to make copies of its RNA genome. Dr. Sucre and Dr. Kropski, have collaborated since 2016 and studied lung diseases in premature infants and adults, the epidemiological patterns observed in the ongoing outbreak made them wonder if TMPRSS2 had something to do with the greater severity of COVID-19 symptoms observed in older people compared to children, specially if children expressed lesser levels of TMPRSS2 and ACE2.
Using single-cell RNA-sequencing, which can detect the expression of genes in individual cells of tissues such as the lung, the researchers were able to track the expression of genes known to be involved in the body’s response to COVID-19 over time. Their study indicated that while the gene for ACE2 was expressed at low levels in the mouse lung, “TMPRSS2 stood out as having a really striking trajectory of increased expression during development, later using RNA in situ hybridization, using fluorescent probes, they were able to visualize expression of the TMPRSS2 gene , which increased over time in specific types of epithelial cells that line the lungs. Analyzing human lung specimen obtained across different ages of patients confirmed a similar trajectory in TMPRSS2 expression to what they’d found in mice.
These findings allowed the researchers to conclusively underscore the opportunity to consider TMPRSS2 inhibition as a potential therapeutic target for SARS-CoV-2.
The research was supported by several grants from National Institutes of Health and the background work for this paper was built upon the collaborative efforts of the Human Cell Atlas (HCA) Lung Biological Network, The Vanderbilt COVID-19 Consortium Cohort, a multi-disciplinary effort to understand more fully why some people are at greater risk of COVID-19 infection and illness.
Bryce A. Schuler, A. Christian Habermann, Erin J. Plosa, Chase J. Taylor, Christopher Jetter, Nicholas M. Negretti, Meghan E. Kapp, John T. Benjamin, Peter Gulleman, David S. Nichols, Lior Z. Braunstein, Alice Hackett, Michael Koval, Susan H. Guttentag, Timothy S. Blackwell, Steven A. Webber, Nicholas E. Banovich, Jonathan A. Kropski, Jennifer M. S. Sucre. Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium. Journal of Clinical Investigation, 2020; DOI: 10.1172/JCI140766
P.S. Content edited for style and length
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