Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, U.S. National Institutes of Health, Bethesda, MD 20892, USA.
Cell Rep. 2020 Sep 29;32(13):108199. doi: 10.1016/j.celrep.2020.108199. Epub 2020 Sep 6.
ACE2 binds the coronavirus SARS-CoV-2 and facilitates its cellular entry. Interferons activate ACE2 expression in pneumocytes, suggesting a critical role of cytokines in SARS-CoV-2 target cells. Viral RNA was detected in breast milk in at least seven studies, raising the possibility that ACE2 is expressed in mammary tissue during lactation. Here, we show that Ace2 expression in mouse mammary tissue is induced during pregnancy and lactation, which coincides with the activation of intronic enhancers. These enhancers are occupied by the prolactin-activated transcription factor STAT5 and additional regulatory factors, including RNA polymerase II. Deletion of Stat5a results in decommissioning of the enhancers and an 83% reduction of Ace2 mRNA. We also demonstrate that Ace2 expression increases during lactation in lung, but not in kidney and intestine. JAK/STAT components are present in a range of SARS-CoV-2 target cells, opening the possibility that cytokines contribute to the viral load and extrapulmonary pathophysiology.
ACE2 结合冠状病毒 SARS-CoV-2 并促进其细胞进入。干扰素在肺细胞中激活 ACE2 的表达，表明细胞因子在 SARS-CoV-2 靶细胞中起关键作用。至少有七项研究在母乳中检测到病毒 RNA，这增加了 ACE2 在哺乳期乳腺组织中表达的可能性。在这里，我们表明，在怀孕和哺乳期，小鼠乳腺组织中的 Ace2 表达被诱导，这与内含子增强子的激活相吻合。这些增强子被催乳素激活的转录因子 STAT5 和其他调节因子占据，包括 RNA 聚合酶 II。Stat5a 的缺失导致增强子失活，Ace2 mRNA 减少 83%。我们还证明，在哺乳期肺中 Ace2 的表达增加，但在肾和肠中则没有。JAK/STAT 成分存在于一系列 SARS-CoV-2 靶细胞中，这使得细胞因子有可能导致病毒载量和肺外病理生理学的变化。
