Target TB: The Role of Mycobacterial Virulence Factors during Infection.

In Norway, most people know tuberculosis (TB) from media, school and/or vaccination programs. Some have a parent, grandparent or great grandparent who suffered this deadly, infectious disease. TB is caused by infection of the bacterium Mycobacterium tuberculosis. Luckily, the occurrence of TB in Norway is relatively low (350-400 reported cases/year), and most of these cases are actually non-active, non-contagious so-called latent TB. However, globally TB is still a great public health problem. In fact, only beaten by HIV/AIDS, TB is the deadliest infectious disease in the world. World Health Organization reports that 1.4 million people died from TB in 2019. That is almost every third Norwegian. The increase of antibiotic-resistant bacteria is at the same time a major emerging threat to human health, and TB resistant to our current drugs is on a rise. New drugs for TB treatment are urgently needed. The history of TB therapeutics tells us that it is unlikely to find one single drug that alone can efficiently combat this disease. The current treatment of TB consists of a cocktail of at least four different antibiotics given for 6 months or more. While it is evident that we need to tackle this pathogen from various angles, it has been proposed that to target virulence factors (the bacteria's weapons to establish infection) for TB treatment will generate less resistance than traditional antibiotics affecting basic bacterial growth. Therefore, to contribute to TB drug development by the discovery of new drug targets, this project aims to discover and unravel the role of mycobacterial virulence factors during infection. To identify new mycobacterial virulence factors, we have turned to animal models like mouse and fruit fly. The common fruit fly (Drosophila melanogaster) is a well-established animal model to study innate immunity, and highly relevant to mammalian biology as major aspects of Drosophila and human immunity are evolutionary conserved. The use of the common fruit fly to study mycobacterial virulence, with its inexpensive and easy handling, short infection and host life span, reduced ethical and safety issues and access to a vast variety of mutants, might have a major impact on future research questions. Thus, we have optimized protocols for mycobacterial infections of Drosophila, using M. marinum (a commonly used, less pathogenic model of M. tuberculosis) as infectious agent. We have found that major, previously known mycobacterial virulence factors also are required for M. marinum infection of Drosophila, indicating that this animal infection model is attractive to study mycobacterial virulence. We found that >90% of the M. marinum virulence genes required for Drosophila infection where also founf in M. tuberculosis. These genes could therefore also be required for M. tuberculosis virulence. Now we are validating a few of the genes we identified for their importance in mycobacterial infections. With this, we are laying the ground work for future development of new drugs to disarm the tuberculosis bacteria during infection.

Virkningen på prosjektets deltagere: For prosjektleder har prosjektet vært viktig for å videre fremme selvstendighet og internasjonal nettverksbygging, i tillegg til å bygge ny forskningskompetanse. Til sammen har prosjektet dermed formet et solid grunnlag for den videre akademiske karrieren til prosjektleder. Virkningen på prosjektets omgivelser: For omgivelsene har prosjektet vært viktig for økt kompetanse på mykobakterielle virulensfaktorer som kan danne grunnlaget for framtidig utvikling av nye anti-TB legemidler. Prosjektet har vært et samarbeid mellom NTNU og IGTP i Spania, og har med dette etablert et internasjonalt samarbeid mellom disse to institusjonene. Effekter av prosjektet: Resultatene fra prosjektet bidrar til å utvide forståelsen for hvordan patogene mykobakterier forårsaker sykdom, noe som på lengre sikt kan føre til bedre helse på globalt nivå ved forbedret terapi, vaksiner og diagnostiske verktøy til å bekjempe TB og andre sykdommer forårsaket av mykobakterier.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the world's second deadliest infectious disease. The standard vaccine treatment is not particularly effective against lung TB in adults. TB is curable by a strictly followed, six-month regimen with multiple drugs, but drug resistance is increasing due to incorrect use and premature treatment interruption. The threat of resistant TB adds significant burden to an already existing world health problem. We urgently need new and improved drugs to combat TB. The history of TB therapeutics tells us that it is unlikely to find one single drug that alone can efficiently combat TB, and it is evident that we need to tackle this pathogen from various angles. To target virulence factors have been suggested to generate less resistance than the current TB antibiotics affecting basic bacterial proliferation. Thus, the primary research goal of this proposal is to identify new mycobacterial virulence factors and determine their role during infection. The most critical R&D challenge to this project might be to conduct experiments in the host-pathogen intersection. To succeed, we need not only good models to study mycobacterial infections, but also expertize and tools within the fields of mycobacterial virulence and host defense mechanisms. Strengthening the collaboration between VU University (Wilbert Bitter lab, Amsterdam), Germans Trias i Pujol Research Institute (Pere Joan Cardona lab, Barcelona) and NTNU (Trude Flo lab, Trondheim), through the mobility of postdoctoral fellow Marte Dragset, will complement knowledge in the fields of virulence and host defense in a way that will benefit the proposed project, the national institution and the career of the postdoctoral candidate. Results from this project can reveal novel drug targets for future TB drug development.