The Dynamic Expression of Potential Mediators of Severe Acute Respiratory Syndrome Coronavirus 2 Cellular Entry in Fetal, Neonatal, and Adult Rhesus Monkeys

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, induced by the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly all over the world. There is considerable variability among neonates, children, and adults in the incidence of infection and severe disease following exposure to SARS-CoV-2. In our study, we analyzed the transcriptome data of primate animal model of Rhesus monkeys to evaluate the expression levels of possible SARS-CoV-2 receptors and proteases and immunologic features in the lungs, colons, livers, and brains at different developmental stages. Our results revealed that ACE2 and TMPRSS2 were highly expressed in neonates compared with other populations, which imply the high incidence of infection. Other potential receptors and Type II transmembrane serine proteases (TTSPs) and cathepsin of endosomal proteases also exhibited dynamic and differential expression patterns. The expression of receptors (ACE2, BSG, and DPP4) and proteases (TMPRSS2, TMPRSS9, CTSL, and CTSB) were highly correlated during lung development, suggesting the high susceptibility of the lungs. TMPRSS9 was specifically highly expressed in the lungs and reached the highest level in neonates, similar to TMPRSS2. Moreover, the immune cell infiltration analysis revealed immunity immaturity in neonates, implying the association with the mild or moderate type of COVID-19. The results might help researchers design protective and therapeutic strategies for COVID-19 in populations at different ages.

Differential effects of age, sex and dexamethasone therapy on ACE2/TMPRSS2 expression and susceptibility to SARS-CoV-2 infection

“…However, ACE2 is highly expressed at the gene and protein levels in the very young and it is not developmentally regulated in mice. Our results are consistent with an earlier study showing greater expression of ACE2 in the lung of young Rhesus monkeys and mice ( 21 , 34 ). However, our findings contradict another report showing continued expression of ACE2 in the lung as mice age ( 35 ).…”

A genome-wide CRISPR screen identifies interactors of the autophagy pathway as conserved coronavirus targets

“…Interestingly, we did find that TMPRSS9 and cathepsin H were significantly enriched in our HCoV-229E and MERS-CoV screens, respectively. TMPRSS9 is highly expressed in lungs [25], and a possible role of TMPRSS9 in biological pathways leading to respiratory symptoms has been suggested [26]. Its role in HCoV infection needs to be further elucidated.…”

The lung employs an intrinsic surfactant-mediated inflammatory response for viral defense

“…Interestingly, ECM, alveolar-like cells, and the infected cluster showed the highest expression of the viral genes but the lowest expression of ACE2 and TMPRSS2 . We interrogated other viral entry genes ( 73 ) including FURIN ( 74, 75 ) , HAVCR1 ( 76 ) , AXL ( 77 ) , NRP1 ( 78, 79 ) , SLC6A19 ( 69, 80 ) , CTSB ( 81 ) , CTSL ( 82 ) , CTSS ( 83 ), and BSG (CD147) ( 84, 85 ) [Fig. 2f] .…”

“…We found BSG expressed in 16 of the 18 clusters and CTSB was expressed in 11 of the 18 clusters. CTSB and CTSL code for proteins important in endocytic viral entry (81)(82)(83). Serous and mucous-like cells expressed both the canonical and non-canonical viral entry genes (ACE2, TMPRSS2, CTSB, CTSL), while primordial lung progenitor, pre-goblet, club, and ionocyte expressed BSG only.…”