MYCONEUTROPHILS · Elucidating the involvement of neutrophils in the pathogenesis of tuberculosis using a zebrafish model
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-03-01 → 2019-02-28
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Elucidating the involvement of neutrophils in the pathogenesis of tuberculosis using a zebrafish model
After centuries of research, tuberculosis, caused by Mycobacterium tuberculosis, remains one of the greatest scourges to human health. The limited effectiveness of existing vaccines and treatments and the increase of drug-resistant M. tuberculosis are leading to the rise of the disease. The World Health Organization reported 10 million cases and 1.6 million deaths in 2017. Thus, a better understanding of the mechanisms of disease pathogenesis is essential to stop this epidemy. Macrophages and neutrophils are the two main phagocytic immune cells that rapidly engulf and destroy the microorganisms that invade our organism. The role of macrophages in the response against tuberculosis is well known because they form the typical and intensively studied granuloma, but little is known about the role of neutrophils despite their presence in tuberculous tissues of humans. Neutrophils present a surprising unconventional behaviour in response to mycobacterial infections. While they are the first responders to most infections, they do not migrate at all to the mycobacterial initial infection sites, suggesting that mycobacteria might be somehow inhibiting neutrophil recruitment and function. Therefore, the main objective of this project is to uncover the mechanism used by mycobacteria to avoid neutrophil response, as well as to determine whether that mechanism can be counteracted so that neutrophils can migrate to the infection site and kill the mycobacteria. Moreover, we propose to study in detail how neutrophils might be fighting the infection if we are able to abrogate the inhibition that mycobacteria exert on them, focusing on the possibilities that they could release neutrophil extracellular traps, and/or that there may be different neutrophil subpopulations that behave different as previously observed in the context of the early granuloma. Shedding light on all this will be crucial for the development of new therapies for the treatment of tuberculosis. Summarizing the final conclusions of this project, we have been able to describe the mechanism that mycobacteria use to avoid neutrophil response, and have demonstrated that abrogating it results in the attenuation of the infection through a novel neutrophil-macrophage-mediated mechanism never described before in the context of mycobacterial infections.
Data: CORDIS, © European Union
Project objective
Tuberculosis has afflicted humans for about 70,000 years and continues to take a huge toll on human health. The increase of drug-resistant Mycobacterium tuberculosis and the limited effectiveness of the existing treatments make urgent a deeper understanding of its immunopathogenesis. The role of macrophages in the disease has been intensively studied, but little is known about the involvement of neutrophils. Recent findings indicate that neutrophils play crucial roles in the pathogenesis of tuberculosis that are unknown until the present. Thus, in this project I will use the recognized zebrafish-Mycobacterium marinum infection model, available in the host lab, to study the role played by neutrophils in mycobacterial infection. I propose to use this infection model combined with in vivo imaging of the interactions host-pathogen, gain and loss of gene function strategies, the use of zebrafish transgenic and mutant lines, gene expression analysis, and multitude of other techniques available in the host lab to study (1) how mycobacteria can evade neutrophil recruitment and phagocytosis, (2) what is the origin of the two functionally different neutrophil populations observed in mycobacterial infection, (3) how neutrophils can kill mycobacteria in the absence of macrophages and without any physical interaction, and (4) why neutrophils act as macrophage scavengers. The elucidation of all these questions never studied before will allow me to shed light on the involvement of neutrophils in the pathogenesis of tuberculosis, and will represent a relevant improvement in the field with biomedical implications. Moreover, it will be a crucial step in my scientific career thinking of becoming a group leader in the field of immunology and infectious diseases, since I will have the opportunity to work in a relevant biomedical question, with the support of the main experts in the field, in an unsurpassable scientific environment, and with the best facilities.
Original text from CORDIS.
Participants
- THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGECoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union