Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mode of action of the vaccine adjuvant flagellin in fusion proteins has been clarified

05.09.2017

Fusion proteins consisting of antigens and the bacterial adjuvant flagellin are promising vaccine candidates. They have the potential to induce immune responses in a targeted and reliable manner, thus conveying protection against infectious diseases. In addition, they can favourably influence misdirected immune reactions, for example as part of a treatment against allergies. Researchers from the Paul-Ehrlich-Institut have now clarified the mode of action of such a candidate for the treatment of birch pollen allergies. In its edition of 05 September 2017, the Journal of Allergy and Clinical Immunology reports on the results of this research.

To induce sufficiently strong immune responses during vaccination, either the antigen itself against which the immune response is directed at (for example pathogens or parts of such agents) must induce a sufficiently strong immune response or the additional administration of adjuvants, which increase the immunogenicity of the co-applied antigen, is required.


The fusion protein rFlaA:Betv1 suppresses allergic reactions via an mTOR-mediated activation of the cell metabolism, which leads to the production of the anti-inflammatory cytokine IL-10.

Source: PEI

Such adjuvants are viral, bacterial, or chemical components which are recognised as foreign by our immune system, thus also inducing immune responses against the co-administrated antigens.

The protein flagellin is a promising adjuvant. Flagellin is a major component of spiral-shaped protein filaments on the surface of certain bacteria – so-called flagella. They serve the mobility of freely floating bacteria. Flagellin is recognised by the toll-like receptor 5 (TLR5). TLR5 belongs to a group of “pattern recognition receptors”, which, among other things, can be found on cells of the innate immune system. They recognise pathogens on the basis of their unique molecular patterns, which helps them induce immune responses reliably.

The benefit of flagellin is that the gene sequence encoding for flagellin can be merged with gene sequences of various different antigens using genetic engineering technologies. This produces so-called fusion proteins, in which the antigen against which an immune response is to be induced and flagellin are closely connected with each other in a single molecule.

Although multiple animal models and clinical studies have shown before that the administration of such fusion proteins efficiently induces immune responses against the fused antigen, it has up to now largely been unknown how such fusion proteins exactly induce these immune responses.

Researchers from the Paul-Ehrlich-Institut under the supervision of Dr Stefan Schülke, Research Group Molecular Allergology of the Vice President of the Paul-Ehrlich-Institut, Professor Stefan Vieths, jointly with researchers from Mainz, Essen, and Vienna, have now succeeded in describing the mechanism of action of such a fusion protein in more detail for the first time. For this purpose, Dr Schülke and colleagues examined a fusion protein developed by them consisting of flagellin A (from listeria) and the major allergen of birch pollen (Bet v 1).

Contrary to the protection from infectious diseases, the aim of a “vaccination” with allergens, which for instance cause hay fever, is to stimulate the immune system to bring about tolerance against the allergen. After the researchers were in a position to show that their fusion protein – however, not the mixture of both single proteins – was able to prevent the development of allergic reactions in the mouse model efficiently, they examined the mechanism of action of their fusion protein.

Preliminary research work had already suggested that the observed suppression of allergic reactions after immunisation with the fusion protein is caused by the release of the immune messenger interleukin-10 (IL-10). IL-10 is an autologous cytokine. Its function is to reduce overreaching immune responses.

Based on complex immunological tests, the researchers established that dendritic cells incorporated the fusion protein, which was present as aggregates, much better than the non-fused mixture of the two single proteins. Dendritic cells are important immune cells for the induction of immune responses. In these cells, stimulation with the fusion protein led to a very strong activation of these cells, which subsequently released both pro-inflammatory and anti-inflammatory cytokines.

In additional experiments, the research team was able to show that an enhanced activation of the cell metabolism occurred in dendritic cells which were stimulated with the fusion protein. This condition of an increased metabolic activity, the so-called Warburg effect, was caused by the activation of the mTOR1-complex. The mTOR1-complex is a central regulator of metabolic activity in all body cells and is also important for the induction of immune responses.

To examine the role for the mTOR1-complex in the cytokine release induced by the fusion protein, the researchers treated dendritic cells with rapamycin, a specific inhibitor of mTOR1 activation. While the release of the anti-inflammatory cytokine IL-10 could be inhibited by rapamycin, the production of pro-inflammatory cytokines remained unaffected by this treatment. Taken together, these results show that the production of IL-10 conveyed by the fusion protein was caused by the activation of the cell metabolism in the dendritic cells.

“This result, which is surprising for us, for the first time shows that the immune modulating activity of a flagellin-containing vaccine candidate can be mediated by an activation of the cell metabolism. This knowledge can contribute to a better understanding of the complex immunological processes that occur during the use of such vaccine candidates and can support the development of new vaccine candidates”, as Dr Schülke explained the relevance of the results.

Original publication: Schülke S, Fiedler AH, Junker C, Flaczyk A, Wolfheimer S, Heinz A, Beckert H, Nagl B, Bohle B, Vieths S, Toda M, Scheurer S(2017): Critical role of mTOR for IL-10 DC induction by a flagellin FlaA-conjugate preventing allergic sensitization. J Allergy Clin Immunol
(DOI:http://dx.doi.org/10.1016/j.jaci.2017.07.002) 2017; [epub ahead of print]


The Paul-Ehrlich-Institut, the Federal Institute for Vaccines and Biomedicines, in Langen near Frankfurt/Main is a senior federal authority reporting to the Federal Ministry of Health (Bundesministerium für Gesundheit, BMG). It is responsible for the research, assessment, and marketing authorisation of biomedicines for human use and immunological veterinary medicinal products. Its remit also includes the authorisation of clinical trials and pharmacovigilance, i.e. recording and evaluation of potential adverse effects. Other duties of the institute include official batch control, scientific advice and inspections. In-house experimental research in the field of biomedicines and life science form an indispensable basis for the manifold tasks performed at the institute. The Paul-Ehrlich-Institut, with its roughly 800 members of staff, also has advisory functions nationally (federal government, federal states (Länder)), and internationally (World Health Organisation, European Medicines Agency, European Commission, Council of Europe etc.).

Please contact the Press Office if you have any questions
Phone +49/6103 / 77 1030 or fax +49/6103 / 77 1262
Email presse@pei.de

Weitere Informationen:

http://www.jacionline.org/article/S0091-6749(17)31170-3/abstract - Link to the Abstract of the Publication
http://www.pei.de/EN/information/journalists-press/press-releases/2017/12-mode-o... -This press release on the PEI-Website

Dr. Susanne Stöcker | idw - Informationsdienst Wissenschaft

More articles from Life Sciences:

nachricht Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View
22.06.2018 | University of Sussex

nachricht New cellular pathway helps explain how inflammation leads to artery disease
22.06.2018 | Cedars-Sinai Medical Center

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Graphene assembled film shows higher thermal conductivity than graphite film

22.06.2018 | Materials Sciences

Fast rising bedrock below West Antarctica reveals an extremely fluid Earth mantle

22.06.2018 | Earth Sciences

Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View

22.06.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>