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How HDAC6 modulates the immune response in macrophages?

IMMUNOACETYL - Marie-Curie Individual Fellowship 894690 - Horizon 2020

On the Left: Acetyl-tubulin (green) is one of the target of HDAC6 

Final Report 2023 (download here)

 

Explanation of the work carried out by the beneficiaries and overview of the progress 

The innate immune system is the first line of defence against invading pathogens. It involves soluble and cellular mediators, such as macrophages, which detect microbial products (e.g. lipopolysaccharide - LPS) via Toll-like Receptors (TLRs). TLR stimulation of macrophages triggers a rapid change in gene expression, leading to the production of cytokines/chemokines and antimicrobial proteins. The histone deactetylase (HDAC) family of enzymes, which deacetylate lysine residues on target proteins, are important regulators of macrophage functions through their capacity to control signalling and gene expression. 

HDAC6 is predominantly cytoplasmic and interacts with several proteins, among which alpha tubulin, HSP90 and others, demonstrating a role beyond histone modifications. One recently identified substrate is mitofusin (MFN) 1 that regulates mitochondrial dynamics. Mitochondria constantly shift between a fragmented state and a more tubular state, modulating several physiological aspects in the cell, but the actual functions of this cellular process in immune contexts are still unclear, as are the roles of HDAC6. Furthermore, since mitochondria is one of the main drivers of metabolism and that HDAC6 has been shown to target some enzyme of the TCA cycle, I hypothesised that HDAC6 could play an important, yet still unknown, role in immunometabolism. 

To answer these questions, I joined the group of Prof. Patrick Matthias– world expert on HDACs, in particular HDAC6 – at the Friedrich Miescher Institute for Biomedical Research (FMI) in Basel, Switzerland.

 

Projects Aims: The 3 aims of the proposed project address distinct aspects of Hdac6 and innate immunity. I will characterise the role of Hdac6 in mitochondrial dynamics (Aim1) and immunometabolism (Aim2) and will also perform a screen to find unknown substrates that modulate the immune response (Aim3).

1 Objectives 

This MSCA-IF project had three major goals: a) to investigate the role of HDAC6 in macrophages, the importance of its catalytic domains and how it can modulate mitochondria and immunometabolism; b) to extend my knowledge in new area (such as proteomic) and develop my leadership skills and; c) to allow me to reintegrate the European research environment and to open my own research group in the field of innate immunity and antimicrobial response.

In this project, the objectives have been addressed via seven specific work packages: (1) creation of CRISPR cell line; (2) understanding the role of HDAC6 in mitochondrial dynamics; (3) understanding the role of HDAC6 in bacterial infection; (4/5) understanding the role of HDAC6 in immunometabolism; (6) training in scientific knowledge, leadership skills, industry network; and (7) dissemination of the research. In summary, the project has achieved its objectives and its milestones for the period, with relatively minor deviations.  

 

2 Explanation of the work carried out per WP (Work Package)  

2.1 Results 

WKP 1: CRISPR HDAC6ko in the macrophagic cell line RAW264.7. We have hold up the creation of the CRISPR cell line from the start until the mid/end part of the project for different reasons. First, there has been a delayed start in the lab (due to COVID-19 lockdown) and in hindsight, we believed the use of an acetylome assay on primary macrophages, rather than a SILAC on cell lines, would provide a clearer result for microscopy and proteomics. As stated in the proposal, these cells were planned to be used at a later stage of the project (mainly proteomics). Nevertheless, the generation of the CRISPR lines are under way for other purposes and should be finished by the time I leave the group (Deliverable 1-2).

 

WKP 2: HDAC6 and mitochondrial dynamics. I have used two approaches that show that the mitochondrial dynamics is mainly driven by the deacetylase activity of HDAC6 rather than the zinc-finger domain. First, I have performed a microscopy analysis of the mitochondrial dynamics in cells of all different genotypes and observed an effect only in HDAC6-/- and catalytic site CD2 mutant. Then, using retroviral transfection of MFN1 harbouring mutation mimicking acetylation on their lysine (K22Q), I showed that MFN1-dependent mitochondrial dynamics was only modulated by the acetylation state of the lysine K22 (Milestone 1). From that point, I focussed my research more on the role of the deacetylase activity of HDAC6.

Main scientific and/or technological achievements: A major discovery was that HDAC6 counters mitochondrial fission and that mitochondrial fission triggers a whole transcriptional program via the translocation of the Activating Transcription Factor (ATF) 5. We investigated this pathway using state-of-the-art Cut-&-Run method; this technique allowed us to identify the promotor regions where ATF5 binds in the macrophage chromatin. The sequencing data from this experiment have been uploaded in a public database (GEO GSE225734). One manuscript and one book chapter have been published on mitochondrial dynamics. A large part of these data has been used in a third manuscript that has been submitted for publication (Deliverable 3).

We also found that the lack of HDAC6 or the mutation of the zinc-binding domain had only a minor effect on inflammasome-dependent cytokine production, notably for interleukin (Il)-1beta. In collaboration with a colleague (Dr Longlong Wang), we used several state-of-the-art systems (PROTAC, DARPIN as well as KO mice, inhibitors) and cell types (macrophages, monocytes, epithelial cells) to confirm our results. This is an important finding as it puts in perspective recent work from another lab on immortalised bone-marrow macrophages showing a role of HDAC6 in inflammasome activation. These data are compiled in a manuscript in preparation (New Deliverable).

 

WKP 3: HDAC6 and bacterial infection. Since HDAC6 controls mitochondrial fusion and that mitochondrial dynamic is involved in the immune response, I investigated if HDAC6 could be modulated and pharmaceutically targeted to enhance macrophages anti-bacterial response. 

Main scientific and/or technological achievements: We discovered that the pathogenic bacterium Salmonella modulates the mitochondrial fission for its own survival: by inhibiting the fragmentation of the mitochondrial network (fission), Salmonellablocks the host antimicrobial response. Pharmacological inhibition or absence of HDAC6 enhance the fission of mitochondrial network, hence, promoting bacterial clearance. More precisely, the deacetylase activity is important and we did not find a clear role of the zinc-finger binding domain on the antibacterial activity of macrophages (Milestone 2). These data have been compiled with WKP2 into a manuscript that has been submitted for publication (Deliverable 3). 

 

WKP 4: HDAC6 and metabolic screen. While characterising HDAC6 function in macrophages, I found that HDAC6 activity is modulated by inflammatory signals (such as LPS) by investigating HDAC6 deacetylation on known targets as Tubulin. My preliminary data also showed that the concentration of some metabolites (e.g Lactate or Itaconate) were altered by the addition of HDAC6 inhibitors. Thus, I investigated the role of HDAC6 in modulating cell metabolism during inflammatory responses. 

Main scientific and/or technological achievements: I have first examined the role of HDAC6 on global gene expression using RNA-sequencing. I found that only very few genes were differentially regulated in the absence of HDAC6, as expected, thus confirming that HDAC6 is playing a role mostly at the post-transcriptional level.  To identify differences in immunometabolism, I have used mass spectrophotometry to produce a large dataset of metabolites modulated by HDAC6 during inflammatory response (Deliverable 4). These data will be correlated with the acetylome (WKP5) to confirm which metabolic pathways are controlled by HDAC6.

 

WKP 5: HDAC6 and acetylome. After consulting the proteomic platform experts, we have decided to use BMM from the CRISPR mice and compare their acetylome by TMT labelling rather than a SILAC approach. We have performed the experiment on WT and HDAC6-/- macrophages, and are running the analysis of the data at the moment (Deliverable 5). I will cross-reference the data with the immunoprecipitation of HDAC6 targets during inflammatory response in WT mice. The metabolite analysis and acetylome, both using state-of-the-art technologies, will be combined in a second manuscript in preparation (Deliverable 6). Furthermore, I am further validating key findings by selecting a few candidates for more detailed analyses (Milestone 3-4).

 

WKP 6: Training – Leadership - Industry. As described below in point 2.2, I have followed two workshops on leadership, helped two students in the host lab and continued supervising three PhD students from my former lab in Australia. I have also met with group leaders and directors of NOVARTIS to talk about my project, possible collaborations and careers in industry.

 

WKP 7: Dissemination – Networking – Conference. I have published two manuscripts and have participated in nine meetings during the course of the project where I presented results from this project while always acknowledging the EU funding. 

Progress of the Activities 

 

  • main research / innovation 

This project main focus was to identify the role of HDAC6 in the mitochondrial dynamics and more broadly in the immunometabolism. One strength of this project was the combination of a specific question (role of HDAC6 in the mitochondrial dynamics - Aim1 – manuscript submitted) with a large screen that will provide us with a list of metabolites regulated by HDAC6 (Metabolome, Aim2 – manuscript in preparation) as well as potentially new HDAC6 substrates. 

This project highlights innovative pathways that could control mitochondria function, and thus, many inflammatory disorders and infectious diseases. Here, we explore the concept that, given the bacterial ancestry of mitochondria, mitochondrial fragmentation can be considered as analogous to intracellular bacterial replication, alerting the host of an impending infection. 

  • researcher's training: 

During the project, I have extended my scientific knowledge and technical skills in genomics, proteomics, as well as in the area of ubiquitination and aggresome formation, which are the main strengths of the host group and the host institute. I have also participated in several workshops in order to develop my skills (WKP 6):

- “Module 1 Certificate for animal experimentation” after attending the course from the University of Zürich Institute of Laboratory Animal Science (LTK) - accredited by the Federation of European Laboratory Animal Science Associations (FELASA). Aug 2021

- "Starting a Professional Career in Industry" – Basel University, June 2022

- “Genetic Approaches in Biomedical Research” – Basel University, Lecture series 1st semester 2022.

- "Project Management for Researchers" – Basel University, Sept 2022

- "Learning How to Lead and to Build a Successful Work Environment" – Basel University, Sept 2022

- I have also improved my command of the German language, by following German courses in collaboration with the University of Basel (1h/week). I have now reached the «intermediate» level B2 (WKP 7).

Being in Basel, a giant hub for pharmaceutical companies, allowed me to develop links with the world of industry, in particular with the parent company NOVARTIS. 

- I have met several times my mentor Dr Pius Loetcher (Director, Autoimmunity Transplantation and Inflammatory Diseases -ATI-) and my collaborator Dr. Joerg Betschinger (Group leader, ATI) to discuss about my project and career in industry. 

- I have participated in the NOVARTIS PostDoc Research Day in June 2022. 

- I have been invited to present my work at a monthly NOVARTIS ATI Research Meeting in December 2022. I received excellent feedback at both events.

  • transfer of knowledge: 

I shared my knowledge on macrophages and technical skills with the group of Patrick Matthias. These include methods of molecular biology, cell biology, immunology. The group is now working with macrophages to study ubiquitination. I have also maintained a strong international academic network (e.g Australia, Spain) that allowed me to achieve the first aim of the project.

  • difficulties or problems encountered; how they were solved (please report any deviations from the DoA in section 5) 

No major difficulties were encountered. There were minor deviations from the work plan proposed in my MSCA application, mainly concerning the switch from a SILAC approach to an acetylome assay and, thus, negating the need for a CRISPR cell line. These changes did not alter the intent of the work and we believe that they are an improvement on the previous plan.

I also have to mention that I started my MSCA project in February 2021, right in the middle of the COVID-19 pandemic in Switzerland. In 2021, in two separate occasions, the local and federal government decided to enforce a lockdown. The first one (mid-January to end-May) slowed down the start of the project, the second one (mid-December to end-January) put a halt to some experiments. In addition to not being able to work physically in the laboratory, another consequence of the lockdown was that we had to minimise the breeding of mice colonies, which slowed down the number of experiments the first 3 months post-lockdown (3 months is the average time needed to breed and obtain 7-8 weeks old mice). Some of my WKP needed the four different genotypes in parallel, this has limited the number of experiments I could perform at that time.

Nevertheless, this has not prevented me to publish two manuscripts, finish one of the aims (manuscript submitted) and having two other manuscripts in preparation. During the lockdown time, I worked on reviews and applications for tenure-track group leader positions

Details on the (non-scientific) management activities of the project
 

  • was the researcher involved in all management aspects of the fellowship? 

During the project, I was in constant contact with the group leader (budget), lab manager (orders, mice colonies) and state-of-the-art core facilities managers for microscopy, genomics and structural biology.

  • did the researcher manage the financial part of the project?

To facilitate finance and ordering, a separate internal order for my MSCA was created in the FMI accounting system and costs incurred for the project were assigned to this internal order. Nevertheless, I kept track of the budget linked to my personal project. Any material that was shared between me and other lab member were ordered on the group core-budget. 

  • did the researcher receive support from the administrative staff at the host institution?

One research manager and one research assistant from the host group provided great help when I required it. The FMI showed exceptional administrative support with respect to research communication, laboratory safety, IT, finance and human resources. The FMI (in particular Dr. Piera Cicchetti, FMI guidance counsellor) also supported postdoc career development. I have participated in a mock chalk-talk in December 2021 to prepare myself for future group leader interview. 

  • how was the integration of the researcher within the host/department? 
    The beginning of the project was a bit challenging as I arrived during COVID-19 lockdown and was required to work from home as much as possible. Thus, it took a bit more time than expected to getting to know the colleagues within the institute, but nevertheless, I was well integrated to the host institute. Prof Patrick Matthias presented me to several other group leader and core facilities manager. During the length of the fellowship, I presented my project to the divisional meeting (Multicellular System department), getting feedback from others group leaders. In September 2022, I was selected to give a presentation at the Annual Meeting of the Host Institute, allowing me to reach out and present my results to all colleagues within the institute. This presentation was very well received and was the basis for setting up a collaboration with Dr. Jörg Betschinger, a colleague from Novartis who was present at our Annual Meeting.

  • did the researcher supervise Master/PhD students?

Unfortunately, it was nearly impossible to get a student within the first year due to the two COVID-19 lockdowns. On the second year, due to the limited time left on the project, I have looked for a Master student but no candidate contacted me. Basel, due to its flourishing number of biotech companies, and very large number of labs, presents many more job opportunities than Master students available. 

Although not officially considered as a supervisor, I have helped and guided one Master (Mrunali Wairkar) and one PhD student (Sucheta Ghosh) in the group. Both students had started their projects just before my arrival and the start of the pandemic.

I have also continued looking after three PhD students that I was supervising in Australia via email and videocalls. Two of them (Dr. James Curson and Dr. Seyda Farhana Afroz) have now graduated and the third student (Jessica von Pein) has submitted her thesis.

  • were there weekly meetings with the supervisor?

The host group had weekly meeting where I presented my data approximately every 3 months to receive feedback. I had also one-to-one meeting with the group leader every two weeks to discuss many topics including the project, conferences attendances, group-leader position applications. 

  • was the researcher involved in setting up external collaboration (if any), and in the publication of the results?

I expanded my academic network and met new collaborators. First, I have set up a collaboration within the host institute (Dr. Koen Oost) working on intestinal organoids to explore the role of HDAC6 in that context. With the help of the group leader, I have also initiated collaborations with two groups from the pharmaceutical industry NOVARTIS (Basel, Switzerland); one working on metabolites screening (Dr. Juan Zhang) and the other one on mitochondrial dynamics (Dr. Joerg Betschinger). The results of these research projects are not yet published. 

Within Switzerland, I have also participated to the Research Seminar in Infection Biology at the Biozentrum (University of Basel) where I have been invited to present my research. I have met with Prof. Dr. Christoph Dehio, expert on uropathogenic E. colipathogenicity, and plan for future collaboration. I have also been in contact with Prof. Adriano Aguzzi (in Zurich) for a potential collaboration using his state-of-the-art CRISPR libraries. Both collaborations could help identify which host pathways intracellular bacteria such as Salmonella or UPEC are highjacking for their own survival.

Impact

  1. Impact on the researcher's career:

One important aim of this fellowship was to allow me to reintegrate the European research environment and to establish my own research group in a near future in the field of innate immunity and antimicrobial response. This goal has been clearly reached as I have obtained a tenured position at the INRAE - Unité mixte de recherche Infectiologie et santé publique (UMR ISP) of Nouzilly in France, starting on the 01st September 2023. I will join a large microbiology/cell biology team as Directeur de Recherche DR2 (i.e group leader of the cell biology sub-group) and lead my own research group in the field of host-pathogen interaction, metal ions and Salmonella.

Several other points of my career development plan have also been successful:

  • Network Impact:  As stated in point 16, I expanded my academic network and met new collaborators at the local, national and the international level. Testifying of my peer recognition, I have been invited to be a review editor for Frontiers and the Journal of Leukocyte Biology (JLB) as well as guest editor for a Special Issue on Mitochondrial Dynamics in Seminars in Cell and Development Biology (SCDB)

  • Leadership Impact: I have participated in workshops on leadership skills, supported students from the host group and I have continued supervising three PhD student from my former position in Australia. Two of these have now passed, the third one has submitted her thesis. I have also been authorised to pass my habilitation (HDR) in France – the important step in securing a tenured position. 

  • Scientific Impact: Since my arrival in the host institute (February 2021), I have co-authored 8 articles, reaching a number of 40 publications and have maintained an outstanding research productivity, as evidenced by citation record (>4000, Google Scholar, H-index 25). Two of these publications derived from my MCIF fellowship (EU funding has been acknowledged), the others six were projects I contributed before 2021 and therefore did not fall within the scope of this project. 

    1. Does the work carried out enhance innovation capacity, create new market opportunities, strengthen competitiveness and growth of companies, address issues related to climate change or the environment, address industrial and/or societal needs at regional level or bring other important benefits for society?

This project addresses two health societal needs: it identifies new ways to control mitochondrial function via the manipulation of its dynamics. Indeed, mitochondria are involved in many inflammatory disorders, in particular neuroinflammation. My research also shows that modulating mitochondrial dynamics via HDAC6 inhibition enhances antimicrobial activity. Thus, my results could contribute to the development of novel antimicrobial treatment strategies as alternatives to antibiotics. Indeed, a UK review on Antimicrobial Resistance estimated that by 2050, if nothing is done, up to 10 million people could die annually from AMR. During the course of the project, I have made several contacts within the industry world and, in the future, will strive for translational opportunities in the healthcare and livestock industries

  1. Give information on the relevant innovation activities carried out (prototypes, testing activities, standards, clinical trials) and/or new products, services, reference materials, processes or methods (to be) launched to the market, if any. 

No prototype, testing or clinical trial have been performed. This project was more fundamental rather than applied research.

  1. Does the work carried out contribute towards European policy objectives and strategies and/or have an impact on policy making? 

This project stayed in line with the Horizon 2020 Programme objectives. The EU 2020 funding was focused on three main priorities:   1) carry excellent science, 2) improve Europe industry competitiveness, research and innovation and 3) convert research results to market which will deliver direct benefits to citizens. During the course of this MSCA project, I have produced quality research data (published and submitted work in peer-reviewed journals), I have closely worked with industries research groups within NOVARTIS who are interested in the project, and finally my results could pave the way towards future non-antibiotics antimicrobial treatments. 

Another objective of the Individual Fellowships is to support the mobility of researchers as well as helping to attract the researchers who have emigrated outside of EU to come back working in the Europe. This objective was a success as, after my two postdoc positions in Australia and Switzerland, I have now secured a tenured position back in France as a group leader.

  1. Please identify potential users of the project results. Has there been suitable communication with interested parties?] 

In recent years, there has been great interest in the molecular and cellular mechanisms of mitochondrial dynamics in many biological systems, but no clear picture has emerged as to the relevance of this process to host defense. We characterised an antimicrobial pathway linked to mitochondrial fission and have dissected the steps from bacteria-induced fission to inducible gene expression to lipid droplet production to elimination of intracellular bacteria. Hence, we revealed a novel connection between HDAC6, mitochondrial fission and lipid droplet production in the process that could be of high interest to the international scientific community. 

The beneficial role of HDAC6 inhibition during bacterial infection could also lead to potential development of novel antimicrobial treatment strategies as alternatives to antibiotics with translational opportunities in the healthcare and livestock industries. Collaboration with pharmacological and veterinary industries will be initiated in the future.

Finally, we ensured open access to the peer-reviewed publications relating to this project as well as free access to sequencing data, allowing us to reach more potential users. This research project should lead to 7 publications (two already published, one submitted, four in preparation).

2.5 Access Provisions to Research Infrastructures 

Not applicable for MSCA-Individual Fellowships. 

2.6 Resources used to provide access to Research Infrastructures 

Not applicable for MSCA-Individual Fellowships. 

3. Update of the plan for exploitation and dissemination of results (if applicable) 

3.1 List the conferences attended (at least the most important ones), and any other activities undertaken to disseminate the results of the project. 

In order to disseminate my research and maximize academic network, I have presented my work at 9 national and international (I), national (N) and local (L) conferences. EU fundings have always been acknowledged in all presentations.

Invited for oral presentation:

- (I) “OutZincing” antibiotic-resistant bacteria: Defining zinc-mediated innate immune antimicrobial responses and pathogen evasion strategies”, Seminar at the UMR1282 ISP – Infectious Diseases and Public Health, INRAE, Nouzilly, France. 23-24 May 2022.

- (I) “A chink in the armour. Zinc poisoning and bacterial membrane targeting as a promising two-pronged antimicrobial strategy”, International Conference of Trace Elements and Minerals 2022 (ICTEM), Aachen, Germany. 5-10 June 2022.

 

Selected for oral presentation:

- (I) “More than the powerhouse of the cell: mitochondrial dynamics modulate a new antibacterial pathway in macrophages“, 34th conference of the European Macrophage and Dendritic cell Society (EMDS), 24-25 June 2021, online

- (L) “More than the powerhouse of the cell: mitochondrial dynamics modulate a new antibacterial pathway in macrophages“, 10th Anniversary Basel Postdoc Network Meeting, Kandersteg, Switzerland, 13-15 October 2021

- (L) “More than the powerhouse of the cell: mitochondria control the immune response“, FMI Annual Meeting, 21-22 September 2022, Grindelwald, Switzerland

- (L) “A particular HDAC: cytoplasmic Histone Deacetylase 6 regulates antimicrobial functions and immunometabolism in macrophages”, Upper Rhine Immunology Group, Karlsruhe, Germany. 21 October 2022.

- (L) “OutZinking” uropathogenic E. coli - Defining zinc-mediated innate immune antimicrobial responses and pathogen evasion strategies”, Research Seminar in Infection Biology, Biozentrum, Basel, Switzerland. 21 December 2022

- (N - Cancelled) “OutZincking” Bacteria - Deciphering the role of metal ions in the host-pathogen interactions”, Life Science Switzerland (LS2) Annual Meeting. 16-17 February 2023. I have been selected as one of the four finalists for the “PI of Tomorrow (PIoT)” competition. Unfortunately, I had to cancel my talk due to sickness.

- (N - Cancelled) “Targeting HDACs and mitochondria to fight bacterial infections in human and livestock”, Life Science Switzerland (LS2) Annual Meeting. 16-17 February 2023. (Declined due to selection as a finalist for PioT).

Poster presentation:

- (L) “More than the powerhouse of the cell: mitochondria & bacterial pathogens”, Virtual IGBMC-FMI Graduate Student Symposium, 26-29 April 2021

- (I) “Divide and conquer - Mitochondrial fission regulates a new antibacterial pathway in macrophages”, Annual Meeting of the French Society for Immunology (SFI), Paris, France. 7-9 Decembre 2021

- (L) “More than the powerhouse of the cell. Mitochondrial dynamics modulate a new antibacterial pathway in macrophages“. PostDoc Research Day NOVARTIS, Basel. 28 June 2022

  1. Provide details on the protection of the acquired intellectual property (patents applications, etc.), if applicable: 

For the Aim 1 of my project (mitochondrial dynamics), no patent application was deemed necessary. This will be reassessed before the publication of my Aim 2 (immunometabolism).

  1. Did you disseminate project results in scientific publications as planned in – or in addition to – the DoA (including the deposition of publications in open access repositories)? Do they include a reference to EU funding? 

The project led to 1 published article, 1 published chapter book (both on mitochondrial dynamics), and one submitted manuscript on the role of HDAC6/mitochondrial dynamics on the antimicrobial response. There are also two other manuscripts in preparation: one on the role of HDAC6 and the inflammasome, the other on the role of HDAC6 on the immunometabolism. Finally, I have established a collaborative work to explore the role of HDAC6 on the intestinal stem cell regeneration. This will also lead to a co-authored publication in the near future.

The two first publications were published as open access and included references to the EU funding:

- (Published) Mitochondrial dynamics in macrophages: divide to conquer or unite to survive? Afroz SF, Raven KD, Lawrence GMEP, Kapetanovic R, Schroder K, Sweet MJ. Biochem Soc Trans. 2023 Feb 27;51(1):41-56. doi: 10.1042/BST20220014.PMID: 36815717

- (Published) Quantifying Regulated Mitochondrial Fission in Macrophages. Afroz SF, Condon ND, Sweet MJ, Kapetanovic R. Methods Mol Biol. 2022;2523:281-301. doi: 10.1007/978-1-0716-2449-4_18.PMID: 35759204

- (Submitted) Mitochondrial fission mediates an evolutionarily conserved innate defense. response against bacterial infection. Ronan kapetanovic; Syeda Farhana Afroz; Ina Kirmes; Divya Ramnath; Stephan Nothjunge; Karoline D. Raven; Bernhard Keller; Grace M.E.P. Lawrence; Kaustav Das Gupta; Melanie R. Shakespear; Charles Ferguson; Claudia J. Stocks; Nilesh J. Bokil; James E.B. Curson; Gabriele Matthias; Tam T. K. Nguyen; Zeinab G. Khalil; Robert C. Reid; Karl A. Hansford; Philip M. Hansbro; Matthew A. Cooper; Mark A. Schembri; Marta Bosch; Albert Pol; Antje Blumenthal; Kate Schroder; David P. Fairlie; Patrick Matthias; Robert G. Parton; Steven Zuryn; Matthew J. Sweet

  1. List all the outreach activities undertaken (visit to schools, Researchers' Night, etc.). 

I arrived in Basel early 2021 in the mist of COVID-19 epidemic (two separate lockdowns). During this year, most outreach activities were cancelled due to local laws. Furthermore, no Researcher’s Night were organised in Switzerland in 2022, possibly due to the disagreement between Switzerland and EU, which led to the withdrawal of the 2021-27 Horizon Europe research and innovation programme.

  1. Did you disseminate and communicate project activities and results by other means than scientific publications (social media, press-release, the project web site, video/film, etc.) as planned in – or in addition to – the DoA? Do they include a reference to EU funding?] 

During the course of the project, I have used my Twitter account (@Ronan_KP, 679 followers) to disseminate activities and results. In the last 3 months, I had an average of a 4.2% engagement rate on my tweets, reaching 6-7% for my scientific tweets (an engagement between 1-5% is considered as good). I have also created a Mastodon account (@ronan_KP@mastodon.online). I have displayed in both bio profile that my funding comes from EU_MCIF.

When my submitted paper will be accepted, I will use the communication team of the host institute to promote the work and the EU funding.

Finally, the project’s website has been created and will be used as my platform for my future research

3. Update of the Data Management Plan (if applicable) 

I followed the Friedrich Miescher Institute for Biomedical Research and EU data management guidelines. The projects involved were identified as “low risk” with no ethical issues. Data were managed based on the current GDPR standards (lawfulness, fairness and transparency; purpose limitation; data minimisation; accuracy; storage limitation; integrity and confidentiality (security); and accountability). 

4. Follow-up of recommendations and comments from previous review(s) 

Not applicable for European Fellowships and the first phase of Global Fellowships. 

5. Deviations from Annex 1 and Annex 2 (if applicable) 

No deviations were noted.

5.1 Tasks 

All important objectives proposed in the MSCA application have been fully achieved, with no major deviations. A minor deviation from the work plan involved using primary cells rather than cell lines for our acetylome, as explained in 2.2.4. The deliverables are meeting expectations, with two manuscripts published, one submitted (Aim1) and a second one close to submission (Aim2-3). Furthermore, many additional manuscripts, resulting from this project and from collaborations, are currently under development.  These will greatly improve the impact of this project. The personal website and the project EU website will be updated in the future.

5.2 Use of resources 

Not applicable for MSCA-Individual Fellowships. 

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