While infants and young children are far less susceptible to the ravages of COVID-19, the reason why has been puzzling. The strength of a young immune system alone doesn’t explain the low rates of infectious symptoms.
A new study offers a compelling case that TMPRSS2, a serine protease gene in epithelial cells, may be a key age-related determinant.
“TMPRSS2 is unlikely to be the sole factor, but this work indicates that age-related changes in expression may significantly affect susceptibility to SARS-CoV-2,” said Bryce Schuler, M.D., a resident in pediatrics and medical genetics at Vanderbilt University Medical Center who worked with investigators Jennifer Sucre, M.D., an assistant professor of pediatrics, and Jonathan Kropski, M.D., on the study.
“TMPRSS2 is unlikely to be the sole factor, but this work indicates that age-related changes in expression may significantly affect susceptibility to SARS-CoV-2.”
Genetics of Lung Development
When the COVID-19 pandemic hit, Kropski, Sucre and Schuler were completing a genetic data set on lung development from early life through adulthood.
“With SARS-CoV-2, infants and children are largely spared from severe disease,” Sucre said. “We wondered if there was something about the early developing lung that made it resistant to infection.”
Comparing the lungs of young mice and young people to adults revealed two- to six-fold lower concentrations of TMPRSS2, a gene which encodes a protease that “uncorks” spikes on the virus and enables entry. “It is well-known that TMPRSS2 is a coreceptor for the coronavirus. What is special about our study is that we were able to show an age-related trajectory,” Schuler said.
Coronaviruses depend on activation of host cell glycoproteins to enter. The Vanderbilt research team explored the developmental trajectories of ACE2 receptors, where the first step in the binding process occurs. They also studied TMPRSS2 and endosomal cysteine proteases furin and cathepsin B, coreceptors that populate the cell surface.
The new study describes an age-dependent, progressive increase in the proportion of TMPRSS2 among specific epithelial cell types in the respiratory tract. Of the genes tested, it had the most significant age-related trajectories.
In both mouse and human tissue, the researchers found a greater concentration of TMPRSS2 expression in ciliated and type 1 alveolar cells, specifically. As they examined lung tissue from a patient who died of COVID-19, they found a high concentration of SARS-CoV-2 RNA in the same lung epithelial cell subtypes and co-localized with TMPRSS2.
Said Schuler, “This further supports the hypothesis that TMPRSS2 is a key player in mediating cellular infection by SARS-CoV-2.”
Implications for COVID-19 Therapy
“This study provides a potential biologic rationale for what we are observing clinically,” Sucre said. It may also explain why infants born to infected mothers tend to be spared. “Vertical transmission is incredibly rare, even when the placentas have lots of virus in them,” she added. “It really suggests that these babies are lacking key cellular machinery to let the virus in.”
“It really suggests that these babies are lacking key cellular machinery to let the virus in.”
Sucre points out that, fortunately, TMPRSS2 is a known agonist for prostate cancer. The antagonist camostat has been used to treat cancer patients for years. “So far, we have observed that these drugs effectively inhibit the virus in cultures. They could constitute a strategy to either prevent severe infection or serve a prophylactic role for people at high risk.”