Introducing MIMS-EMBL group leaders: Barbara Sixt, Cell-autonomous immunity

Over the past 12 months, MIMS has recruited five new group leaders. Here, we meet Barbara Sixt, who joined MIMS as a Group Leader in May 2018. Dr. Sixt has already started to build up her group, with plans to further expand her team. The next year will see her focus on getting her research programme going.

2019.05.29 | Annabel Darby

Photo of Barbara and her group at MIMS

Barbara Sixt (second from left) with her research group at MIMS. Photo: MIMS

Could you tell me a bit more about your background and your research?

I started my academic training in 2002 when I enrolled in the undergraduate study program “Molecular Biology” at the University of Vienna in my home country of Austria. During these studies, I developed a particular interest in microbiology and host-pathogen interaction, and learned that some bacterial disease agents are able to invade human host cells. In the interior of these host cells these so-called “intracellular bacteria” can then thrive and grow seemingly undisturbed, because they are shielded from the human immune system and its specialized immune cells. The group of intracellular bacteria includes very important bacterial pathogens. One of these is Chlamydia, which is the most frequent bacterial agent of sexually transmitted diseases and, as such, a frequent cause of infertility and adverse pregnancy outcomes.

Intracellular bacteria use very sophisticated strategies to manipulate their host cells and to turn them into a niche in which the bacteria can optimally thrive. I was very intrigued by this concept and wanted to learn more about the strategies the bacteria use to achieve this goal. Therefore, I decided to conduct my master project studies, and later my PhD studies, at the Department of Microbial Ecology in Vienna. I studied a group of intracellular bacterial species that are related to Chlamydia, but naturally infect amoebae. My most important discovery was that these bacteria were unable to grow in human and other animal-derived cells because they were not able to cope with the intrinsic defense mechanisms of animal cells. More specifically, human and animal cells have the capacity to undergo “programmed cell death”, which means that cells infected with bacteria can activate a kind of self-destruction program. By self-sacrificing themselves, infected cells can block further growth and spread of the pathogen.

While my PhD studies have highlighted the importance of bacterial pathogens for developing strategies to defend themselves against this host cell intrinsic defense, they did not uncover how bacterial pathogens can achieve this. This was then the topic of my postdoctoral studies, which I conducted between 2013 and 2018, first at Duke University in the USA, and later at the Institut Gustave Roussy in France. Using a molecular genetic approach, involving the generation and analysis of bacterial mutants, we identified a specific factor produced by Chlamydia to prevent the induction of defensive host cell death programs.

Since my first discoveries in this field, my interest in the so-called cell-autonomous immunity, that is the capacity of human cells to detect invading pathogens and to induce defense responses, has grown. It is also the central topic of my independent research program, which I initiated when I joined MIMS as a group leader in May 2018. At the moment, we are in the process of characterizing the defensive host cell death program in depth and we also aim to identify and analyze additional Chlamydia factors that block host cellular defense responses.

What is the biggest question you want to answer with your research?

There is a lot of interest in developing new means of fighting infectious diseases by exploiting the patient’s own immune system. Most of these approaches focus on specialized immune cells. In contrast, the fact that each individual cell also has an intrinsic defense response, is often neglected in this context. One of the reasons for this is that successful intracellular pathogens are so well adapted to their intracellular lifestyle that they can very effectively block the host cellular defense responses. I am very intrigued by the idea that in the future we may be able to reactivate these responses to fight infection. However, this requires us to first obtain a deep understanding of how human cells fight infection and how the bacteria can interfere with these defenses. This can then be the basis for the development of new approaches to control infectious diseases. It is my long-term goal to facilitate such developments. However, I think that getting deeper insights into the molecular mechanisms of the arms race between humans and pathogens by itself is already a very fascinating and exciting endeavor.

What will your first phase as group leader entail?

People tend to say that the first year of being a group leader is the most difficult because it is the time in which you have to build up a functional work environment from scratch and, most importantly, build your research group. I am in the fortunate situation that MIMS and the Department of Molecular Biology at Umeå University provided me with excellent starting conditions. I also obtained a Starting Grant for Medicine from the Swedish Research Council (VR) in 2018, which has given me additional financial security and which has allowed me and my team to fully focus on our research. My research team currently consists of four people. Besides myself, this includes one postdoc, one PhD student and one bachelor student. I am also in the process of recruiting a second postdoc and a second PhD student to expand the team. Recruitment is the most challenging aspect because I think the composition of the research group and their spirit will be a major determinant of success. Looking back at the last year, I think some processes developed much slower than I would have wished for, but overall I am satisfied with what we achieved and I am very optimistic about the group's future development. In the next year, we will focus on getting our projects up and running and hopefully we will be able to get some first exciting insights.

Do you currently work with any other groups in Umeå or further afield?

During my time as a postdoc I was able to establish a wide network of ongoing collaborations with researchers from both Europe and the USA. We have not yet started intensive local collaborations in practical terms. However, during my first year in Umeå, I had the chance to establish contacts and we have developed some concrete plans for collaborative projects that should be initiated within the coming year. For instance, I am very much looking forward to collaborating with researchers located at the KBC (Chemical Biology Centre) at Umeå University, for example with Mikael Elofsson and Ronnie Berntsson. In this collaboration, we will try to identify and further develop chemical inhibitors that can fight Chlamydia infection by exploiting the host cellular defense. This challenge can only be tackled by a multidisciplinary team and I am very happy that I have this opportunity. I expect that in the future we will be able to further extend our network of collaborations, hopefully also to our partners in the Nordic EMBL Partnership. But we can only go one step at a time.

What inspired you to enter into a career in research?

I have to admit that when I started to study biology, I didn't know anything about research and the life of a researcher. I just followed my interests. There were also some key moments that determined my direction. For instance, I initially aimed to become a vet, because of my love for animals. But when I worked on my final school exam thesis, I came across literature that described how bacteria were able to exchange DNA. This fascinated me so much that I wanted to learn more about the molecular mechanisms of biology and thus decided to study Molecular Biology instead. Later on, I had a similar moment in a lecture in which I first learned about the strategies of intracellular bacteria. I just knew immediately that I had to learn more about this. In terms of what a career in research actually means, I have just learned this step by step as I moved along the academic career path. I think this is also good, because the academic career path is not an easy one, and I know many people that have dropped out. There are so many big questions still to answer, which for me makes research such a fascinating and rewarding career.

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