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Elife ; 112022 Jun 07.
Article in English | MEDLINE | ID: covidwho-1879632


TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), is critical for placental trophoblast syncytialization, HIV infection, and SARS-CoV2-mediated syncytialization, however, how TMEM16F is activated during cell fusion is unclear. Here, using trophoblasts as a model for cell fusion, we demonstrate that Ca2+ influx through the Ca2+ permeable transient receptor potential vanilloid channel TRPV4 is critical for TMEM16F activation and plays a role in subsequent human trophoblast fusion. GSK1016790A, a TRPV4 specific agonist, robustly activates TMEM16F in trophoblasts. We also show that TRPV4 and TMEM16F are functionally coupled within Ca2+ microdomains in a human trophoblast cell line using patch clamp electrophysiology. Pharmacological inhibition or gene silencing of TRPV4 hinders TMEM16F activation and subsequent trophoblast syncytialization. Our study uncovers the functional expression of TRPV4 and one of the physiological activation mechanisms of TMEM16F in human trophoblasts, thus providing us with novel strategies to regulate CaPLSase activity as a critical checkpoint of physiologically- and disease-relevant cell fusion events.

Sci Transl Med ; 13(617): eabm2070, 2021 Oct 27.
Article in English | MEDLINE | ID: covidwho-1476380


Pregnancy and fetal sex influence the quality of antibody responses to SARS-CoV-2 infection and immunization (Atyeo et al., Bordt et al.).

COVID-19 , SARS-CoV-2 , Female , Humans , Immunity , Pregnancy
Am J Obstet Gynecol ; 225(6): 593.e1-593.e9, 2021 12.
Article in English | MEDLINE | ID: covidwho-1439825


Pregnant individuals infected with SARS-CoV-2 have higher rates of intensive care unit admission, oxygen requirement, need for mechanical ventilation, and death than nonpregnant individuals. Increased COVID-19 disease severity may be associated with an increased risk of viremia and placental infection. Maternal SARS-CoV-2 infection is also associated with pregnancy complications such as preeclampsia and preterm birth, which can be either placentally mediated or reflected in the placenta. Maternal viremia followed by placental infection may lead to maternal-fetal transmission (vertical), which affects 1% to 3% of exposed newborns. However, there is no agreed-upon or standard definition of placental infection. The National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a group of experts to propose a working definition of placental infection to inform ongoing studies of SARS-CoV-2 during pregnancy. Experts recommended that placental infection be defined using techniques that allow virus detection and localization in placental tissue by one or more of the following methods: in situ hybridization with antisense probe (detects replication) or a sense probe (detects viral messenger RNA) or immunohistochemistry to detect viral nucleocapsid or spike proteins. If the abovementioned methods are not possible, reverse transcription polymerase chain reaction detection or quantification of viral RNA in placental homogenates, or electron microscopy are alternative approaches. A graded classification for the likelihood of placental infection as definitive, probable, possible, and unlikely was proposed. Manuscripts reporting placental infection should describe the sampling method (location and number of samples collected), method of preservation of tissue, and detection technique. Recommendations were made for the handling of the placenta, examination, and sampling and the use of validated reagents and sample protocols (included as appendices).

COVID-19 Testing/methods , COVID-19/diagnosis , Placenta Diseases/diagnosis , Placenta Diseases/virology , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/virology , SARS-CoV-2 , COVID-19 Nucleic Acid Testing , Consensus , Female , Guidelines as Topic , Humans , Immunohistochemistry , In Situ Hybridization , Microscopy, Electron , National Institute of Child Health and Human Development (U.S.) , Pregnancy , United States/epidemiology