Razieh Ardali - Trained immunity

Harnessing trained immunity to enhance resistance of piglets against early-life infections

Our body is equipped with two coordinated arms of defence that protect us against pathogens. Historically it was believed that only the adaptive arm of defence is capable of memorising the previous exposure to a pathogen and inducing an augmented response upon further encounter with that pathogen. However, several lines of in vitro and in vivo studies have demonstrated that the cells of innate immunity are also capable of developing memory in response to some pathogen- or damage-associated molecular patterns (PAMPs and DAMPs). Mechanistically, a transient exposure of innate cells such as macrophages, NK cells, and dendritic cells to certain PAMPs and DAMPs, induces long-term modification in the epigenetic and metabolic landscape of the cells. These modifications alter the response of innate cells to subsequent challenges with the same or different stimuli in two opposing manners: 'training' characterised by a hyper-responsive state, and 'tolerance' characterised by a hypo-responsive state.

The interesting point about innate immune memory is that it acts in a non-specific manner, thereby holding great promise for prophylaxis and combating a broader range of infectious diseases, particularly during early life when animals are at high risk and more reliant on their innate immune system.

Interview with Dr. Razieh Ardali

What was the aim of your doctoral thesis?

The main aim of my thesis was to translate the concept of trained immunity to a pig model. To meet this goal, we first tried to find candidate ligands with the potential to induce innate immune memory in porcine monocytic cells using an in vitro mode. To gain insight into the cellular and molecular mechanisms underlying the innate immune memory we used a time-course RNA sequencing and Assay for Transposase-Accessible Chromatin using sequencing (ATAC sequencing). Using these methods, we evaluated the long-lasting epigenetic and transcriptomic signature of trained cells.

infographic — General overview of the concept of trained immunity: Exposure of innate cells to some PAMPs and DAMPs alter the epigenetic and metabolic landscape of the cells. Some of these modifications stay even after removal of the stimuli and put the cells in a ready-to-go state. As a result, at the second exposure to the same or different stimuli the cells respond more vigorously.

What are the main findings of your thesis?

Using several experimental approaches, we showed that a NOD2* ligand called muramyl dipeptide (MDP) might be a potent candidate for inducing trained immunity in porcine monocytic cells. We also showed that like for human and murine monocytic cells lipopolysaccharide (LPS*), a TLR4 ligand serves as a potent inducer of tolerance, another form of innate immune memory. Furthermore, we addressed the immunomodulatory effects of all trans retinoic acid and its impact on the training effects of MDP or tolerogenic effects of LPS.

To what extent will your findings help to advance research?

The field of 'innate immune memory' is a relatively young field of research. The exact molecular mechanisms that induce trained immunity still need further systemic investigations. Studying the molecular mechanisms underlying innate immune memory can broaden our understanding of the pathogenesis of some chronic inflammatory diseases and pave the way for finding therapeutic targets. The field also has promising potential for modulating vaccines and enhancing their efficacy in combating infectious agents. This is of great importance due to the rapid progression of climate change and the emergence of microbicide-resistant microorganisms.

What did you especially like about working on your thesis?

For me, every moment of my PhD project was a rewarding life lesson. From a social perspective, moving to a completely new place with a different culture, meeting people from various backgrounds, and learning how to communicate and make new friends was a wonderful experience for me. After a while, it feels like having a second family in a different part of the world.

From a professional perspective, I learned how to logically design experiments, put the little pieces together, and derive meaningful conclusions and narratives from them. I learned that even if you are stuck at a point, you should persevere and patiently wait and try. It will pay off and, in the end, you will be surprised that the biggest lessons you have learned often come from those challenging times.

What projects do you have coming up, what are you going to do next?

There are still several questions that remain to be answered in my project. Therefore, there will be a follow-up study that Jana Mitrovic the new PhD student in Professor Artur Summerfield's group will take over. The main goal will be to test the training potential of our in vitro tested candidate ligands in vivo and see how this affects the response of piglets to vaccination or infectious agents. Furthermore, we would like to delve deeper into the cellular and molecular mechanisms of trained immunity by recruiting both porcine and mouse models.

As for myself, I will start a new project in the group of Professor Charaf Benarafa. The focus of the project will be on the interplay between the microbiome, immune system, and African swine fever virus (ASFV).

*NOD2: is a cytosolic pathogen recognition receptor (PRR) that detects the presence of certain bacterial components, MDP, a product of bacterial cell walls.

*TLR4 or Toll-Like Receptor 4: is a plasma membrane PRR that recognises and responds to PAMPs such as LPS.