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.

Keywords: ACE2; Rhesus monkey; SARS-CoV-2; TMPRSS2; development.

FIGURE 1

Spatiotemporal expression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mediators in Rhesus monkey development. The heatmap represents gene expression value [log2(RPKM + 1)] of tissues from four organs at different developmental stages, including early (F45d–F70d), middle (F100d), and antenatal (F157d) stages of fetuses, neonates (post born 5–7 days), and adults (post born 5–7 years).

FIGURE 2

Dynamic expression of eight genes during lung and colon development. Gene expression value of receptors (A) and proteases (B) along with developmental times are presented for the lungs (red) or colon (cyan). The trend curves were fitted by using LOESS method, with standard errors, as shown by shadows.

FIGURE 3

Correlation analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mediators in monkey development. Correlation map represents the Pearson correlation coefficient between each pair of genes. The bottom bars indicate the color legends of the Pearson correlation coefficient r. Results are shown in the lungs (A), colon (B), brain (C), and liver (D).

FIGURE 4

Immune features of four organs in monkey development. (A) Gene expression scores of immune cell populations in developmental tissues. (B) Five immune cells are elevated in adult lungs. (C) Expression profiles of 15 cytokines. (D) IL-1β and TNF-α are elevated in adult lungs. P-value was calculated by unpaired Student’s t-test and adjusted by using the Benjamini and Hochberg method for multiple tests. Note: *, adjusted p < 0.05.