COVID-19: Assessing the vulnerability of the fetus to SARS-CoV2 infection across development
Lead Research Organisation:
University College London
Department Name: Institute of Child Health
Abstract
Numerous studies have shown, that pandemic coronavirus strains such as SARS enter the patient body through ACE2, a specific protein expressed in the airways. ACE2 is important for controlling blood pressure and it is increased in patients with hypertension and kidney conditions. Both of these groups are known to be more susceptible to severe SARS-CoV-2 infection. During the current COVID-19 pandemic, it has been observed that infants and children are less susceptible to severe infection, with extremely low numbers reported across the world requiring intensive care. Strikingly, newborns seems to be unaffected by this condition, even when the mother tested positive for COVID-19. While the data available are still limited, this has led the UK Governement to define pregnant women as a 'high-risk' group. Therefore, it is important to understand the mechanisms behind the low incidence of complications in fetuses and newborns. Our hypothesis is that the fetus is not susceptible to SARS-CoV-2 infection because it lacks the ACE2, in tissues that may be exposed to the virus during development and early postnatal care. Our study will provide the health service and advisory boards with new data, that will help inform updated guidance to pregnant mothers during the current pandemic.
Technical Summary
While the SARS-CoV-2 (CoVID-19) virus has generated a pandemic, little is known about its impact on pregnant women and their fetuses. With this study, we plan to analyse fetal, placental and postnatal tissues for the expression of gene and proteins associated with SARS-CoV-2 infection and entry into the human cells. Our study will not only focus on the ACE2 receptor, but will also include proteins such as the transmembrane protease TMPRSS2 - felt to be required for viral entry into the cell. We plan to analyse a broad library of fetal tissues already obtained at the UCL Great Ormond Street Institute of Child Health, through the Human Developmental Biology Resource. In addition, we will study placenta and amniotic membrane at various gestational stages as well as cells isolated from the amniotic fluid, obtained through the UCLH Fetal Medicine Unit / UCL EGA Institute for Women's Health. We will then compare our results with postnatal tissues acquired through the UCLH and Great Ormond Steet Hospital pathology biobanks. This research will involve the use of RT-qPCR to assess gene expression, immunostaining and western blot for protein expression and localisation. Finally, RNA sequencing, will be used to analyse the expression profiles in a high troughput manner. This will not only allow us to investigate ACE2, and other SARS-CoV-2 related genes, but will also provide insights into the mechanisms of fetal protection against COVID-19.
People |
ORCID iD |
| Mattia Gerli (Principal Investigator) |
Publications
Beesley MA
(2022)
COVID-19 and vertical transmission: assessing the expression of ACE2/TMPRSS2 in the human fetus and placenta to assess the risk of SARS-CoV-2 infection.
in BJOG : an international journal of obstetrics and gynaecology
| Description | This work looked at the susceptibility of pregnant women and fetuses to SARS-CoV-2, the virus which caused the COVID-19 global pandemic. To do this, we assessed the presence of the two proteins required for viral infection (ACE2 and TMPRSS2) in multiple fetal tissues and the placenta. Initially we assessed the expression of the genes in reference datasets and then confirmed this ourselves using fresh fetal tissues. Finally, we carried out imaging to confirm the protein localisation matched the gene expression. Our findings demonstrated that the placenta had an innate low susceptibility due to low expression of the two genes, which was far below the expression in the adult lung which acted as our positive control. However, the fetal intestine showed high expression of both genes. The reference data allowed us to assess if the genes were co-expressed in the same cells, which was true for the fetal intestine. The intestinal epithelia had high expression of both ACE2 and TMPRSS2 genes. The protein localisation was shown to follow the gene expression patterns detected and the presence of both proteins was confirmed in the intestine. While neither were present at high levels in the placenta (neither the chorionic villi or the amniotic membrane). |
| Exploitation Route | We carried out this research in the height of the global COVID-19 pandemic, when scientists globally were pushing to understand the virus better and be able to more accurately direct doctors. Our work formed part of a series of publications which led to the reversal of clinical practise away from inducing pregnancies in infected mothers to protect their child, and instead delaying pregnancies till the mother had at least partially recovered. Our research helped to confirm that in the majority of cases, the fetus would be safe from infection while still in the womb. However, infection could occur during the birth itself. This new approach was shown to increase the survival of both mother and child. Since its publication on 4th November 2021, the article has been cited 18 times and had significant news interest. Overall, it has the 2nd highest Altmetric 'Attention Score' of all 92 articles published by the British Journal of Obstetrics & Gynaecology around that time. |
| Sectors | Healthcare |
| Description | After publication, along with 19 citations in various scientific works; this study has been reported by a number of news outlets - both general (Evening Standard, MSN (Poland, Greece and Italy) and Times of India) as well as scientific (MedicineNet.com and HolaDoctor.com). These stories will have reached thousands if not millions of viewers. By reporting our results in our press release in a measured and understandable way that emphasises the known clinical facts, we hope that we will have been able to provide sensible information to this large readership and allow for informed decision making by the general public around the world. |
| First Year Of Impact | 2021 |
| Sector | Healthcare |
| Impact Types | Societal |
| Description | Collaboration with the bioinformatics team of Professor Davide Cacchiarelli at the Telethon Institute for Genomics and Medicine, Italy |
| Organisation | Telethon Foundation |
| Department | Telethon Institute of Genetics and Medicine (TIGEM) |
| Country | Italy |
| Sector | Charity/Non Profit |
| PI Contribution | Our team produced primary data using qRT-PCR and immunohistochemical techniques. We are now aiming at validating our results with a bioinformatic analysis on available datasets from public repositories. |
| Collaborator Contribution | Professor Cacchiarelli's bioinformatics team is contributing to the analyses on RNAseq entries identified from the literature. This novel collaboration is helping with the validation of our outcomes and will help strengthening our future publications. |
| Impact | No outcomes published yet. The collaboration is multidisciplinary as it combines biology, bioinformatics, data mining and data science. |
| Start Year | 2020 |
| Description | GIFT-SURG Patients and Public Engagement group meeting |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | The activity main aim was to interact with the PPI engagement group, present the data related to our project "COVID-19: Assessing the vulnerability of the fetus to SARS-CoV2 infection across development". We reported that the project was COVID-19-focused. There are recognised age-related differences between adults and kids, pregnant women: risk category since the beginning based on data from previous coronavirus pandemics, but limited evidence if the fetus is actually at risk. In the case of severe maternal illness: possible risk of stillbirth (but this is based on previous evidence from other coronavirus pandemics). There is a higher risk of delivering earlier. Our methodology used a library of fetal tissue; evaluate tissue-level gene expression, assess protein. Fetal lung shows much lower expression of the COVID-related genes than adult lung and no co-expression. Kidney has high expression of both the proteins. We then investigated if there is a pattern whether the fetus becomes more susceptible to infection as gestation progresses: this is difficult with the techniques used to account for variability. One value was very high, the remaining showed a gentle increase. Importantly, we looked at the fetal intestine where there was co-localisation of TMPRSS2 and ACE2, these proteins would facilitate viral entry into the intestinal cells. We concluded that 2nd trimester fetus may be infected COVID-19 infection through the intestine (by swallowing amniotic fluid), but the virus is unlikely to be present in amniotic fluid - in case of severe maternal illness only (also risk of preterm labour). The infection of the fetus unlikely to be clinically significant - very few severe cases of newborn COVID-19 infection. Deaths numbering fewer than 10 worldwide. The presentation was followed by a panel discussion, where the panel recommended to be clear that if there isn't evidence to suggest that COVID-19 can affect the babies, it's important to not meddle with that. Be very open and honest about what the research says. We need more data we say for sure. Great that there's finally research coming out of this. Overall we have been recommended to underline that the suggestion would be to don't let pregnant women get really sick - importance of vaccine. The panel recognised that the advice given to pregnant women is not always clear. If there is a clear recommendation (e.g. pregnant women should get vaccinated), communicating it is very important. |
| Year(s) Of Engagement Activity | 2021 |