Advancing host-directed therapy for Mycobacterium avium infection: identification of drug candidates and potential host targets

Abstract

Mycobacterium avium (Mav) infections are rising globally, and treatment is complicated by long, intensive antibiotic regimens with severe side effects, drug resistance and poor clinical outcomes. Therefore, new therapeutic strategies are urgently needed. Host-directed therapy (HDT), which targets host immune mechanisms rather than the bacteria itself, offers a promising approach to treat (intracellular) mycobacterial infections. While the development of HDT has been extensively explored for Mycobacterium tuberculosis (Mtb), a notable gap remains for Mav infection, likely reflecting limited research efforts and insufficient understanding of host–pathogen interactions during Mav infection. To address this gap, we conducted a drug repurposing screen using a well-established primary human macrophage model and identified drugs that enhance host control of Mav. Investigation into the mechanism of action revealed that these HDT candidates likely act by modulating key intracellular antibacterial pathways, including autophagy and reactive oxygen species production. Moreover, comparative transcriptomic analysis of Mav- and Mtb-infected macrophages revealed overlapping host-response pathways that enabled extrapolation of insights from Mtb to Mav, as well as previously undescribed host responses for mycobacterial infection, both representing potential targets for HDT development. Hence, this thesis presents HDT candidates and potential host targets to advance HDT for Mav infection.