Introduction
While the COVID-19 pandemic continues to have a significant global health impact, rates of maternal to infant vertical transmission remain low (<5%). Parenchymal changes of placentas from COVID-19 infected mothers have been reported by several groups, but the localization and relative abundance of SARS-CoV-2 viral proteins and cellular entry machinery has not been fully characterized within larger placental tissue cohorts.
Methods
An extended placental tissue cohort including samples from 15 COVID-19 positive maternal-fetal dyads (with n = 5 cases with evidence of fetal transmission) in comparison with 10 contemporary COVID-19 negative controls. Using comparative immunofluorescence, we examined the localization and relative tissue abundance of SARS-CoV2 spike glycoprotein (CoV2 SP) along with the co-localization of two SARS-CoV2 viral entry proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2).
Results/conclusions
CoV2 SP was present within the villous placenta in COVID-19 positive pregnancies with and without evidence of fetal transmission. We further identified the predominance of ACE2 expression in comparison with TMPRSS2. Importantly, both CoV2 SP and ACE2 expression consistently localized primarily within the outer syncytiotrophoblast layer placental villi, a key physiologic interface between mother and fetus. Overall this study provides an important basis for the ongoing evaluation of SARS-CoV-2 physiology in pregnancy and highlights the importance of the placenta as a key source of primary human tissue for ongoing diagnostic and therapeutic research efforts to reduce the global burden of COVID-19.
Head and neck cancer is one of the deadliest malignant diseases and chemotherapy is a common treatment option. Despite the development of chemotherapies for several decades, how these drugs affect the dynamics of gene regulation is still largely unknown. In our previous study, miR-375 was shown to be underexpressed in oral cancers and thus unable to serve as a tumor suppressor microRNA to regulate certain putative oncogenes. In this study, we found that common anti-cancer drugs reactivated miR-375 in tongue cancer cells. Incubation of tongue cancer cells CAL 27 and SCC-25 in medium containing doxorubicin, 5-fluorouracil, trichostatin A, or etoposide significantly increased the expression of miR-375 and its primary transcript pri-miR-375. The dose- and time-dependent effects of doxorubicin in CAL 27 were demonstrated by miR-375 increases in response to the drug. Significant suppression of pri-miR-375 expression was observed in human tongue cancer specimens and this decrease was more prominent in advanced stage tumors. Bioinformatics from four publicly available mRNA microarray data sets suggested that these candidate miR-375 targets are mainly involved in cancer biology, indicating that these targets are likely to be suppressed via miR-375 due to the treatment with these drugs. Together, our data suggest that the four anti-cancer drugs examined in this study induce the expression of tumor suppressor miR-375 in tongue cancer.
While COVID-19 infection during pregnancy is common, fetal transmission is rare, suggesting that intrauterine mechanisms form an effective blockade against SARS-CoV-2. Key among these is the decidual immune environment of the placenta. We hypothesized that decidual leukocytes are altered by maternal SARS-CoV-2 infection in pregnancy and that this decidual immune resonse is shaped by the timing of infection during gestation. To address this hypothesis, we collected decidua basalis tissues at delivery from women with symptomatic COVID-19 during second (2nd Tri COVID, n=8) or third trimester (3rd Tri COVID, n=8) and SARS-CoV-2-negative controls (Control, n=8). Decidual natural killer (NK) cells, macrophages and T cells were evaluated using quantitative microscopy, and pro- and anti-inflammatory cytokine mRNA expression was evaluated using quantitative reverse transcriptase PCR (qRT-PCR). When compared with the Control group, decidual tissues from 3rd Tri COVID exhibited significantly increased macrophages, NK cells and T cells, whereas 2nd Tri COVID only had significantly increased T cells. In evaluating decidual cytokine expression, we noted that IL-6, IL-8, IL-10 and TNF-α were significantly correlated with macrophage cell abundance. However, in 2nd Tri COVID tissues, there was significant downregulation of IL-6, IL-8, IL-10, and TNF-α. Taken together, these results suggest innate and adaptive immune responses are present at the maternal-fetal interface in maternal SARS-CoV-2 infections late in pregnancy, and that infections earlier in pregnancy show evidence of a resolving immune response. Further studies are warranted to characterize the full scope of intrauterine immune responses in pregnancies affected by maternal COVID-19.
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