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Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice
Min Yee1, E David Cohen1, Jeannie Haak1
1The Department of Pediatrics, School of Medicine and Dentistry, The University of Rochester, Rochester, NY 14642.
Insights
Early life exposure to high oxygen levels increases SARS-CoV-2 receptors in the lungs. This finding may explain why COVID-19 is more severe in the elderly and those with pre-existing conditions.
Area of Science:
- Respiratory Medicine
- Neonatal Physiology
- Virology
Background:
- COVID-19 severity is higher in the elderly and those with comorbidities.
- Preterm birth may increase COVID-19 risk due to early oxygen exposure and respiratory virus susceptibility.
- Neonatal hyperoxia (high oxygen) in mice reduces alveolar type 2 (AT2) cells, increasing influenza severity.
Approach:
- Investigated the impact of neonatal hyperoxia on SARS-CoV-2 receptor expression (ACE2, TMPRSS2) in mice.
- Examined receptor expression in airway Club cells and AT2 cells at different ages.
- Assessed the effect of mitoTEMPO, a mitochondrial superoxide scavenger, during hyperoxia in adult mice.
Key Points:
- Contrary to expectations, neonatal hyperoxia accelerates age-dependent increases in ACE2 and TMPRSS2 mRNA expression in mice.
- ACE2 is initially expressed in airway Club cells and later in AT2 cells; neonatal hyperoxia enhances this expression.
- MitoTEMPO administration during hyperoxia prevented early ACE2 receptor expression in adult mice.
Conclusions:
- Early-life insults like hyperoxia enhance SARS-CoV-2 receptor expression in the respiratory epithelium.
- This mechanism may explain the increased severity of COVID-19 lung disease in the elderly and those with comorbidities.
- Findings highlight the long-term respiratory consequences of neonatal respiratory challenges.
Abstract:
The severity of COVID-19 lung disease is higher in the elderly and people with pre-existing co-morbidities. People who were born preterm may be at greater risk for COVID-19 because their early exposure to oxygen at birth increases their risk of being hospitalized when infected with RSV and other respiratory viruses. Our prior studies in mice showed how high levels of oxygen (hyperoxia) between postnatal days 0-4 increases the severity of influenza A virus infections by reducing the number of alveolar epithelial type 2 (AT2) cells. Because AT2 cells express the SARS-CoV-2 receptors angiotensin converting enzyme (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2), we expected their expression would decline as AT2 cells were depleted by hyperoxia. Instead, we made the surprising discovery that expression of Ace2 and Tmprss2 mRNA increases as mice age and is accelerated by exposing mice to neonatal hyperoxia. ACE2 is primarily expressed at birth by airway Club cells and becomes detectable in AT2 cells by one year of life. Neonatal hyperoxia increases ACE2 expression in Club cells and makes it detectable in 2-month-old AT2 cells. This early and increased expression of SARS-CoV-2 receptors was not seen in adult mice who had been administered the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia. Our finding that early life insults such as hyperoxia enhances the age-dependent expression of SARS-CoV-2 receptors in the respiratory epithelium helps explain why COVID-19 lung disease is greater in the elderly and people with pre-existing co-morbidities.
