SARS-CoV-2 infection and immunity during pregnancy and fetal development

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The current 2019 coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has claimed an estimated 5.42 million deaths and more than 286 million cases confirmed. The first cases of COVID-19 were reported in Wuhan, Hubei Province, China, in December 2019, with the majority of those affected having worked in a wholesale seafood and animal market. The patients had fever, cough, chest discomfort and pneumonia, which required hospitalization and the use of ventilators for assistance, with some of them dying.

Patient samples were submitted for isolation in cell culture, followed by RT-qPCR and next-generation sequencing (NGS), indicating coronavirus (CoV) as the causative agent. Immune dysregulation, gastrointestinal illnesses, and long-term post-COVID-19 disorders have all become clinical symptoms since then. There is currently no cure or preventive treatment to prevent infection, but various vaccines have been developed and distributed around the world to minimize the rates of serious illness and death. Recently, variants of SARS-CoV-2 have emerged, raising concerns about the effectiveness of the vaccine and treatment.

There has also been a lot of interest in determining how the infection affects pregnancy and fetal development, but there is still a lot of unknowns. As a result, a review by a team of researchers from the Icahn School of Medicine at Mount Sinai, the University of Colorado and Active Motif, Incorporated is compiling information on the virology of SARS-CoV-2, transmission in utero of pregnant women infected with fetuses, new findings on possible methods of cell trafficking of SARS-CoV-2 through exosomes and the transcriptomic effects of SARS-CoV-2 infection, in order to shed light on the future studies aimed at a better understanding of COVID-19 and the development of solution therapies against SARS-CoV-2.

This review article is published in the Journal of Developmental Biology.

The study

SARS-CoV-2 was discovered to be a member of the Coronaviridae family, of the genus betacoronavirus (which includes MERS-CoV, which was the causative agent of respiratory disease outbreaks in the Middle East in 2012), and the sarbecovirus subgenus, of which SARS-CoV (associated with the 2002-2003 pandemic and first identified in Guangdong province, China) is also a member. Although SARS-CoV-2 and SARS-CoV are both sarbecoviruses, SARS-CoV-2 was found to be more closely related to other SARS-like bat beta-coronaviruses. Bats have been postulated as a reservoir for the virus due to their genetic similarity; other animals, such as pangolins, have been proposed as potential intermediate hosts due to the similarity of their genomic sequence.

Reported impacts of SARS-CoV-2 infection on fetuses by pregnant women and on children. Abbreviations: Multisystem inflammatory syndrome MISC in children. “? Indicates that the transmission mechanism is not clearly understood.

Transmission of COVID-19 from infected pregnant women to fetuses has been documented, although rarely. Cases of COVID-19 in children have been recorded, with fatal results. Long COVID, a severe infection in which symptoms last five weeks or more after an acute infection with SARS-CoV-2, has been described in children in the same way as in adults. Children have also been diagnosed with pediatric multisystem inflammatory syndrome (PIMS-TS), which has been linked to COVID-19. Compared to older children and adults, children under 5 with mild to moderate COVID-19 have more SARS-CoV-2 viral RNA in their nasopharynx, which could affect transmission.

Transmission electron microscopy (TEM) of Vero E6 cells infected with SARS-CoV-2. Exosomes and / or a SARS-CoV-2-like particle can be seen (inset) inside an MVB. Evs — extracellular vesicles, PM — plasma membrane, MVB — multivesicular bodies.

Infection with SARS-CoV-2 causes fetal discomfort as well as significant morbidity and death in infants. There is not enough evidence indicating negative impacts on future generations of people who test positive for COVID-19 during pregnancy. However, the findings of multisystem inflammatory syndrome in children (MIS-C) and other complications suggest that more research is needed to fully understand the full range of effects of COVID-19 in children, in utero development and on SARS-CoV-2 cell trafficking mediated by exosomes during in utero and perinatal developmental stages.

While it’s obvious that SARS-CoV-2 infection triggers an immune response in pregnant women, the effects on fetal immune responses are still a hot topic of discussion. A recent study looked at 205 babies born to mothers positive for COVID-19. While only 10% of newborns tested positive for COVID-19, the majority of infants infected with SARS-CoV-2 produced immunoglobulin G and M (IgG, IgM) antibodies. No viral RNA was found in the placentas of COVID-19 positive pregnant women in another study.

Additionally, there do not appear to be any verified examples of SARS-CoV-2 infection transmitted from mother to fetus during pregnancy. Although serious illness has been documented in infants less than one year of age, underlying comorbidities have been established in such cases. These data show that vertical infection is rare and that infants born to women positive for COVID-19 have innate passive immunity.

Exosomes are released by every cell type that has been studied so far. The exosomes of the mesenchymal, endothelial and trophoblastic lines have been studied in relation to the placental line and have been shown to decrease the expression of T lymphocytes. The role of exosome trafficking in utero and its importance in SARS-CoV-2 and the subsequent establishment of an immune response in newborns were examined in this study.

Exosomes are extracellular nanovesicles derived from endocytes that package cell contents. They are believed to help maintain cellular homeostasis, although the mechanism of their formation is unknown. SARS-CoV-2 infections via exosomes or the development of in utero immunity appear to be two possible ideas for exosomal contribution in utero and fetal development. While viral RNA has been identified in exosomes, there appears to be little or no viral replication during gestation. This finding refutes the first idea that exosomes could cause a viral infection in the uterus.

Implications

The effects of SARS-CoV-2 on the transcriptome provide a wealth of data that must be used effectively. Transcriptomic profiles reveal which genes are upregulated or downregulated by infection, allowing them to be therapeutically targeted to reverse the effect. These profiles can also be used as biomarkers to determine the severity of the infection, ranging from mild to severe. Finally, these profiles provide additional information on how SARS-CoV-2 infection affects cell development and programming.

To fill the gaps in the understanding of the mechanisms of maternal-fetal transmission, models of inheritance of epigenetic fingerprints can be compared between cells of mothers infected with COVID-19 and their offspring. It will be interesting to see if the epigenetic changes in the mother caused by the SARS-CoV-2 infection are passed on to her offspring. Overall, this review aims to broaden the perspective on several elements of COVID-19, which will help understand other viral infections and help us better prepare for future outbreaks.


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