Background SARS-CoV-2 infection appears to increase the risk of adverse pregnancy outcomes such as preeclampsia in pregnant women. The mechanism(s) by which this occurs remains unclear. Methods We investigated the pathophysiology of SARS-CoV-2 at maternal-fetal interface in pregnant women who tested positive for the virus using RNA in situ hybridization (viral RNA), immunohistochemistry, and hematoxylin and eosin staining. To investigate whether viral infection alters the renin angiotensin system (RAS) in placenta which controls blood pressure, we treated human trophoblasts with recombinant Spike protein or a live modified virus with a vesicular stomatitis viral backbone expressing Spike protein (VSV-S). Findings Viral colonization was highest in maternal decidua, fetal trophoblasts, Hofbauer cells, and in placentas delivered prematurely. We localized SARS-CoV-2 to cells expressing Angiotensin-converting enzyme 2 (ACE2), and demonstrate that infected placentas had significantly reduced ACE2. In response to both Spike protein and VSV-S, cellular ACE2 decreased while Angiotensin II receptor type 1 (AT 1 R) increased with concomitant increase in soluble fms-like tyrosine kinase-1(sFlt1). Viral infection decreased pro-angiogenic factors, AT 2 R and Placental growth factor, which competitively binds to sFlt1. Sera from infected pregnant women had elevated levels of sFlt1 and Angiotensin II type 1-Receptor Autoantibodies prior to delivery, both signatory markers of preeclampsia. Conclusions SARS-CoV-2 colonizes ACE2-expressing maternal and fetal cells in the placenta. Infection in pregnant women correlates with alteration of placental RAS. As RAS regulates blood pressure, SARS-CoV-2 infection may thus increase adverse hemodynamic outcomes such as preeclampsia in pregnant women. Funding NIH/NICHD grants R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement)
Highlights d Urothelial cells produce reactive oxygen species upon uropathogenic E. coli infection d Infection results in dissociation of NRF2-KEAP1 complex and NRF2 nuclear translocation d NRF2 transcriptionally activates RAB27B and facilitates UPEC expulsion d Dimethyl fumarate, a NRF2 activator, promotes UPEC clearance and dampens inflammation
A differential proteomics approach led to the identification of several novel epididymal sperm proteins. One of the novel proteins was methylmalonate-semialdehyde dehydrogenase (MMSDH). In the present study, we carried out an in-depth characterization to study its regulation by androgen, its appearance during ontogeny, and the mechanism of its interaction with and acquisition by the sperm. Western blotting and immunohistochemical studies suggest that the protein is present in both tissue and sperm from all regions of the epididymis, indicating synthesis as well as acquisition of the protein in these regions. Androgen depletion resulted in reduction of the MMSDH protein level in the epididymis, which completely disappeared 1 week after castration. The protein reappeared after testosterone propionate injection, indicating that the protein is regulated by androgens. Ontogeny studies indicated that the protein appeared from day 10 postnatal with a gradual increase at day 30, which maximized at day 50, indicating that the protein is developmentally regulated and is probably involved in epididymal development. Sequential extraction of sperm proteins indicated that MMSDH exists both as a peripheral and integral form on the plasma membrane. We also found that the protein can be transferred from the epididymosomes to testicular sperm in vitro. The study provides evidence regarding the acquisition of this multidomain androgen and developmentally regulated protein in the epididymis via the epididymosomes. The molecule has generated enough interest and deserves to be investigated further for its physiological relevance.
Background Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. Methods and Results We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose‐response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double‐outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3‐exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor‐β1, and extracellular matrix proteins were the most highly enriched in CVB3‐infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. Conclusions We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes.
Liprin α3 was reported for the first time using sperm proteomics. Present study reports its localization on sperm and immunochemical characterization. Liprin α3 is identified as a 133 kDa protein in testis and epididymal protein extracts. In testis, immunohistochemical localization was seen in pachytenes, diplotenes, round spermatids whereas it was localized in the epithelial cells and luminal sperm in all the three regions of epididymis. Protein was localized in acrosome of rat sperm, which was further confirmed by sequential treatment of sperm with hypertonic solution. In the spermatogenic cells the protein was found to be located in developing acrosome as evident by its co-localization with Golgi marker. Protein was found to be developmentally regulated. In silico analysis of Liprin α3 revealed presence of the estrogen responsive elements upstream to initiation site and its regulation by estrogen was experimentally validated using a tamoxifen treated rat model. Western blot analysis of epididymosomes showed the presence of Liprin α3, indicating its involvement in trafficking of vesicle. The protein expression was seen in both mouse and human sperm indicating conserved nature and a probable role in acrosome reaction.
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