Published on 26 November 2024

Blog Amal Fahmi – Organoids

“We showed that SARS-CoV-2 can infect the human placenta and that West Nile virus also has placental infection characteristics".

Studying the impact of viral infections on the placenta and foetal brain using ex vivo models and 3D organoids

Viral infections during pregnancy increase the risk of complications for both pregnant women and their foetuses. Examples include worse symptoms, higher miscarriage rates and potential developmental changes, especially in the brain. The placenta acts as a vital barrier during pregnancy but this protective function can sometimes be impaired when viral infections cause viraemia in pregnant women. In such cases the virus may cross the placental barrier, potentially jeopardising the well-being of the foetus and affecting its development, including that of its brain. To understand the underlying mechanisms, researchers need in vitro human models that faithfully reproduce viral infections in placental tissue and foetal brain tissue. To do this, we used sophisticated models such as human placenta explants and brain organoids to study infections caused by SARS-CoV-2, West Nile virus (WNV) and Zika virus (ZIKV). These models enabled us to study cellular tropism and viral propagation, and to characterise host responses to infection.

Interview with Dr Amal Fahmi

• What was the aim of your thesis?

  My thesis focused on two main aims. First, we set out to provide pregnancy-related information quickly during the COVID-19 pandemic. More specifically, I studied whether SARS-CoV-2 could infect and spread in human placental tissue, potentially compromising foetal development. To this end, we set up and characterised a new ex vivo model of the human placenta to assess the susceptibility of placental tissue to SARS-CoV-2.
  
  Second, I studied the potentially adverse effects of West Nile virus (WNV). We focused in particular on investigating WNV infection during brain development in comparison to a well-researched related virus, Zika virus (ZIKV). To do this, we set up and refined a 3D in vitro model of the human foetal brain based on brain organoids derived from pluripotent stem cells.

  

  Infection of placental explants (red circle) or human neural organoids (blue circle) with SARS-CoV-2 or orthoflaviviruses is monitored over time. Tissues and culture media are collected and processed for analysis.

• What are the main results of your thesis?

  We showed that SARS-CoV-2 can infect the human placenta and that the replication rate is highly dependent on the expression of ACE2, the main cell receptor that SARS-CoV-2 uses to infect cells. This means that ACE2 plays a crucial role in placental susceptibility to virus infection. We showed that ACE2 expression is different for each placenta and therefore potentially for each pregnancy.
  
  Our research also showed that WNV has placental infection characteristics and adverse effects on brain development similar to those of ZIKV. Our results demonstrate conclusively that WNV can infect the placenta and potentially disrupt the development of the human foetal brain.

• How will your results help to advance research?

  We have successfully developed an ex vivo model of the human placenta, providing a platform to deepen our understanding of how different viruses interact with this vital tissue. For example, we can study the specific mechanisms that viruses use to penetrate the placenta, such as the use of particular receptors on placental cells. We have also demonstrated the utility of brain organoids as a model for studying the mechanisms of injury caused by a viral infection such as WNV infection. These models could potentially be used to assess the efficacy of various antiviral treatments and to identify which of them could minimise the adverse effects of a viral infection on human brain development.

• What are you most proud of in this work?

  First of all, completing my thesis during the COVID-19 pandemic was difficult but also rewarding. I had to act quickly to answer fundamental questions about the biology of SARS-CoV-2 in placental tissue, given that the health of pregnant women is a key public health issue. Publishing our findings quickly was crucial to help pregnant women make informed decisions regarding the COVID-19 vaccine. Second, my work addressed fundamental questions concerning the biology of WNV in human placental and brain tissue, by using state-of-the-art in vitro models never used before in this context. Highlighting the potential impact of WNV in pregnancy posed its own challenges, exacerbated by the lack of prior research in this area. However, I saw it as a unique opportunity to contribute to an under-explored but important field of research.

• What did you especially like about undertaking your thesis?

  Throughout my thesis, I addressed the limitations of current research approaches and proposed strategies for overcoming these challenges. By stressing the importance of complex and physiologically relevant models, I have helped to advance our understanding of viral pathogenesis during pregnancy.

• What was your time at the IVI like?

  I’ve had a fantastic few years at the IVI. Everyone was always warm and friendly and I always felt safe and welcomed. I had a lot of enjoyable, productive discussions and interactions. I’d also like to thank my group, the Alves group, whose day-to-day support and positive atmosphere have contributed enormously to my career.

• What projects do you have coming up, what do you plan to do next?

  After defending my thesis, I’ll be moving on from exploring viral infections to exploring different parts of the world. This period of respite will serve as a catalyst for new prospects and inspiration, ultimately fuelling my next scientific adventure. Afterwards, I’m keen to dive into the next research challenge and contribute to discoveries in the scientific community.