African swine fever (ASF) is harmless to humans but causes a fatal haemorrhagic disease in domestic pigs and boars. In 2007 a highly virulent strain was accidently introduced in Georgia and has since spread to Europe and South-east Asia where millions of animals have died. In spite of numerous scientific efforts, no therapy is known to date, nor is a safe vaccination against ASF known to be available. Fundamental research on the factors of the host which influence the severity of the disease and immune responses has long been neglected, thereby hindering the development of a safe and effective vaccine. Thanks to its high security laboratory, the IVI carries out research on the immune system of pigs and on its interaction with various pathogens. The techniques of phenotyping and sequencing enable a detailed investigation of the biology of immune cells. Moreover, the IVI employs genetic engineering to study the structure, the molecular composition and the mechanisms of replication of the ASF virus, and in particular the mechanisms of interference used by the virus on the immune response of the host.
To study their immune response, the IVI has bred pigs for many years under exceptional experimental sanitary conditions characterised by the absence of swine pathogens. This special sanitary statute is associated with a particularly naïve immune system with a response to ASF virus infection that has enabled fundamental advances described in this project.
Interview with Dr Emilia Radulovic
What was the objective of your thesis?
The aim of my thesis was to better understand factors of the host which impact the pathogenesis of the ASF during an in vivo infection, and those that are crucial for the entry of the virus at the cellular level. Several questions that had not been explored up to then were studied:
- Which factors of the host determine the evolution of the severity of the disease?
- Do the factors of the host modulate the adaptive immunity and the long-term protection?
- At the cellular level, which are the host factors, induced during the differentiation of the monocytes, are associated with the infection of the cell?
Which are the most important findings of your thesis?
I was able to demonstrate that the immunological and sanitary statute of the host has a real influence on the pathology of the disease. Practically, our research group, including Kemal Mehinagic, Nicolas Ruggli, Artur Summerfield, Charaf Benarafa and myself, first characterised the basic immune status of domestic pigs of the IVI, which are free from specific pig pathogens (SPF-IVI) with a naïve immunity system and of domestic pigs reared in a conventional farm. The SPF-IVI pigs showed a weaker inherent immune activity than the farm pigs with significant differences in the composition of the intestinal microbiome. After inoculation of a highly virulent strain of genotype II of the ASF virus (Armenia 2008), the two groups presented severe clinical signs leading to 100 % mortality within 7 days. In contrast, when infected with an attenuated strain (Estonia 2014), the SPF-IVI pigs presented a more moderate clinical disease and recovered completely, whereas the farm pigs presented a serious and prolonged disease with a lethality of 50%. We then investigated whether the SPF-IVI pigs and the farm pigs which survived the first infection with Estonia 2014 had acquired an adaptive protective immunity subsequent to a reinfection with the highly virulent strain Armenia 2008. Strikingly, we have shown that the SPF-IVI pigs are clinically totally protected when infected with the virulent strain Armenia 2008, whereas the farm pigs present a high viraemia, severe clinical signs and a fatality of 40%. These results underline the importance of the baseline immune status on the innate and adaptive responses following infection by the ASF virus and provide an experimental framework to identify key markers and mechanisms associated with protection.
To what extent will your findings help to advance research?
The results that we have observed in the frame of my thesis project bring new insights in the overall understanding of immune-pathogenesis of ASF and suggest interesting questions for fundamental research. The SPF-IVI pigs that we have described are an excellent model for the study of the resilience factors to ASF. These findings are also of major importance for the future development of live attenuated vaccines.
What are you most proud of in this work?
As a PhD student, one is reliant on one’s own drive and must overcome one’s own hurdles in order to be able to reach the objectives. There were periods of frustration in the laboratory which I had to face and which had a strong impact on my overall motivation. By persevering, the experiments began to work; finally, I am proud to have found in myself the means for this.
What did you particularly appreciate when working on your thesis?
I had extensive freedom with regard to the direction that my project was taking. Consequently, the project was really multidisciplinary; I learnt various methods of immunology and virology, as well as planning animal experimentation, coding and analysing RNA data sequencing, microbiota etc. I really appreciated the fact that my days were as dynamic as they were and were never the same. That also enabled me to expand my skills.
How were your years in the IVI?
At first, each time I entered the IVI high security laboratory I had the impression of entering a submarine. One is totally disconnected from the rest of the world and one then creates very strong links to colleagues in the same situation. I enjoyed great years during my PhD - with a lot of work compensated by a lot of pleasure.
What are your next projects and what are you going to do?
My head is full of projects. After having spent some years in the academy, one quickly forgets that another world exists outside.
Last modification 28.03.2023