Transplacental transmission of SARS-CoV-2 infection via NRP1.

Dear Editor

A novel coronavirus structurally related to the virus that causes Severe Acute Respiratory Syndrome (SARS) causes the latest outbreak of the global storm of coronavirus disease 2019 (COVID-19). Indeed, the healthcare systems in all countries around the world have faced incredible challenges with COVID-19 (SARS‐CoV‐2) since its discovery in Wuhan, Hubei Province, China in December 2019. The Center for Disease Control and Prevention (CDC) reported that the total cases of pregnant women with COVID-19 in the USA from January 22-December 28, 2020 is 51,396 including 60 deaths (https://www.cdc.gov/coronavirus/). The perinatal transmission routes of COVID-19 have been hypothesized to occur via environmental exposure or transplacental or transcervical route. In this regard, a recent study by Arash et al., (2020) reported a vertical transmission of COVID-19 in a 1-day-old neonate [1]. Moreover, Vivanti et al., (2020) demonstrated that COVID-19 could transmit from mother to fetus via the placenta during the last weeks of pregnancy to induce maternal viremia, placental inflammation, placental infection and neonatal viremia may be associated with cerebral vasculitis [2]. Subsequently, Hsu et al., (2020) showed that SARS‐CoV‐2 presents in the placenta to induce placental vasculopathy, fetal growth restriction in mild COVID-19 infection. In addition, the possibility of vertical transmission particularly for pregnant women who may be infected in the early pregnancy [3]. Several studies deduced that COVID-19 utilizes the well-known receptor Angiotensin-Converting Enzyme 2 (ACE2) and the serine protease TMPRSS2 for cell entry. Researchers have started to study the co-transcription of ACE2 and TMPRSS2 in the placenta by utilizing the data of single-cell and RNA sequencing. While there was no co-transcription of ACE2 and TMPRSS2 in the placenta, several researchers could not rule out the notion of SARS-CoV-2 transplacental transmission at any stage of pregnancy [4]. A recent neuropathological study in mice demonstrated that human COVID-19 infected Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2)-positive cells in the olfactory epithelium and bulb. However, NRP1, not NRP2 facilitates the cell entry and transport of the sized particles of the virus into the central nervous system following nasal administration to achieve anosmia and ageusia associated with infection of SARS-CoV-2 [5]. Infection-induced maternal immune activation is highlighted by clinical and preclinical data as a source of possible profound effects on neural circuit growth and as a priming mechanism for microglia in offspring [6]. We utilized the placenta gene set of Harmonizome to investigate whether ACE2, TMPRSS2, NRP1 and NRP2 are highly expressed in placenta's tissue. Interestingly, our study showed that NRP1 is only included in the proteomics datasets of the TISSUES Experimental Tissue Protein Expression Proof Scores with a high concentration of tissue placenta (Standardized Value:0.766457) (http://amp.pharm.mssm.edu/Harmonizome). Consequently, this analysis supports the hypothesis that the SARS-CoV-2 virus can transmit at any pregnancy stage through NRP1 of the placenta. Furthermore, this raises crucial alerts to (1) a later pandemic in neurodegenerative diseases decades from now and (2) future pregnancy orientations should include antenatal surveillance and routinely testing of COVID‐19 during pregnancy. Future studies will be useful in determining the impact of targeting NRP1 in pregnant women with COVID-19 infection.