Cross-talk between inflammation and autophagy in tuberculosis

Project Information

Inflammafish

Grant agreement ID: 655424

DOI

10.3030/655424

Project closed

EC signature date 3 March 2015

Start date 18 January 2016

End date 17 January 2018

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 177 598,80

EU contribution

€ 177 598,80

Coordinated by

UNIVERSITEIT LEIDEN
Netherlands

Periodic Reporting for period 1 - Inflammafish (Cross-talk between inflammation and autophagy in tuberculosis)

Reporting period: 2016-01-18 to 2018-01-17

Summary of the context and overall objectives of the project

The overall aim of the project “Cross-talk between inflammation and autophagy in tuberculosis” was to use the zebrafish embryo as in vivo model to gain understanding of the intercommunication between inflammation and autophagic host defence during Tuberculosis (TB).
The increasing occurrence of multidrug-resistant Mycobacterium tuberculosis strains makes TB a key priority for infectious disease research. Inflammation and autophagy are two fundamental processes critical to TB pathogenesis. Accumulating evidence shows that TB disease is worsened by deregulations of the inflammatory response. On the other hand, autophagy has recently emerged as a crucial host defence mechanism. Autophagy is also thought to control the inflammatory response. However, the interaction between inflammation and autophagy in host defence against TB remains unclear.
The specific objectives of this project included studying the effect of autophagy modulation on the inflammatory response, determining the effect that the modulation of the inflammatory response has on autophagy, but also studying genome-wide effects of autophagy modulation using RNA sequencing and proteomics during the infection and under basal condition.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The well-established zebrafish larvae model of TB was used to investigate the importance of autophagy and the inflammatory response during the infection.
The obtained results show the importance of both pathways during mycobacterial infections. The deregulation of just one of them, affects the outcome of the infection. When the autophagic host response is deficient, the bacteria are able to virulently progress inside the host. We found that under this circumstance, the manipulation of just one of the key proteins of the inflammatory pathway rescues the infection back to normal levels. We also found that the pathogen can manipulate the inflammatory response for its own benefit, increasing the spreading of the infection by inducing the pro-inflammatory death of infected cells.
The results obtained from the project were presented in several international conferences and they could open new treatment possibilities in the field of TB and other pathologies with similar characteristics.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

In this project, supported by a European Marie-Curie individual fellowship, we successfully employed the larval zebrafish model of TB to study and characterize two of the most important pathways during the infection: inflammation and autophagy.
The work carried on during this project provided new insights into the host defence mechanisms activated during the infection, showing that the inflammatory response and autophagy go together and both are necessary for an effective defence during TB.
Moreover, during the project we gained better understanding of the host-pathogen interaction occurring during TB, with possible application during the development of new anti-TB treatments. The development of new anti-mycobacterial treatment strategies is especially urgent because multi-drug resistant Mycobacterium tuberculosis strains are rapidly emerging.
Host-targeted treatments are now being considered for development of innovative therapeutic approaches that may overcome current limitations of antibiotic treatments. This underscores the importance to understand the key regulating host factors involved in mycobacterial infection and to identify potential target pathways and proteins for future drug development.
Therefore, a better understanding of the innate immune response and the mechanisms that the pathogen uses to manipulate host defence mechanisms could increase the chances of improving existing therapeutic strategies for the treatment of TB.

Infected zebrafish larvae

Project Logo

Infected zebrafish cells