ARQ_2021 - Kinase Inhibitors for Adjunct Antibiotic Treatment of Tuberculosis
Project Abstract
Tuberculosis (TB) encompasses pulmonary and extra-pulmonary infections by the deadly obligate human pathogen Mycobacterium tuberculosis (MTB). Upon exposure to infectious aerosols, host immune responses build up multi-cellular structures called granulomas that aim to encapsulate the bacteria at the infection foci. The mechanisms allowing granulomas to sterilize or control the infection, pushing MTB to enter a slow or non-replicating dormant state, are likely multi-factorial and not well understood.
This research project will take advantage of our established in vitro granuloma model to further our understanding of protective immune responses against MTB and to evaluate the efficacy of kinase inhibitors as host-directed therapy (HDT) agents, which could synergize with antibiotics, to improve TB treatment. We will build on our established capacities to: i) pursue mechanistic investigations to disentangle the on- and/or off-target effects of kinase inhibitors; ii) evaluate the differential impact of the tested compounds to boost immune control of MTB replication by granulomatous responses and iii) profile the compounds’ safety by assessing their impact on immune cell functions and survival. We intend to demonstrate that in vitro granulomas constitute a relevant tool to study drug-targetable host immune pathways. These results will have an impact on the selection of adjunct HDT agents against TB.
