The dual role of host immunity in potentiating tuberculosis drug activity as well as contributing to development of drug resistance

Multi drug resistant tuberculosis (MDR TB) caused by Mycobacterium tuberculosis (Mtb) affects 500 000 patients yearly with substantial mortality and is challenging even in a low incidence country like Sweden.

Overall, this is a translational project addressing the dual role between a beneficial anti-mycobacterial effect of the host immunity in combination with TB drugs and adverse events of an overactive pro-inflammatory response leading to drug resistance mutations by oxidative stress.

Specifically, we will explore the potential synergy of free radicals such as nitric oxide produced by activated host immune cells during treatment of TB with the novel drug pretomanid and the established drug isoniazid (INH).

The major research gap of how MDR TB is developed from INH mono-resistance mediated by a deficiency in the anti-oxidative capacity of Mtb (katG mutations) will be addressed by exposure of clinical Mtb isolates to free radicals using whole genome sequencing of established resistance markers in Mtb and epigenetic analyses as readouts.

We will approach our aims using newly developed intracellular leucocyte models including from patents with TB infection along with live-cell microscopy and transcriptomics in our research BSL3 laboratory enabling work with virulent mycobacteria.

The major research output expected is to define the most efficient use of the key anti-TB drugs INH and pretomanid and how to protect them from further resistance development.