The host-directed therapeutic imatinib mesylate accelerates immune responses to Mycobacterium marinum infection and limits pathology associated with granulomas

Infections caused by members of the mycobacterium tuberculosis complex [MTC] and nontuberculous mycobacteria [NTM] can induce widespread morbidity and mortality in people. Mycobacterial infections cause both a delayed immune response, which limits rate of bacterial clearance, and formation of granulomas, which contain bacterial spread, but also contribute to lung damage, fibrosis, and morbidity. Granulomas also limit access of antibiotics to bacteria, which may facilitate development of resistance. Bacteria resistant to some or all antibiotics cause significant morbidity and mortality, and newly developed antibiotics readily engender resistance, highlighting the need for new therapeutic approaches. Imatinib mesylate, a cancer drug used to treat chronic myelogenous leukemia [CML] that targets Abl and related tyrosine kinases, is a possible host-directed therapeutic [HDT] for mycobacterial infections, including those causing TB. Here, we use the murine Mycobacterium marinum [Mm] infection model, which induces granulomatous tail lesions. Based on histological measurements, imatinib reduces both lesion size and inflammation of surrounding tissue. Transcriptomic analysis of tail lesions indicates that imatinib induces gene signatures indicative of immune activation and regulation at early time points post infection that resemble those seen at later ones, suggesting that imatinib accelerates but does not substantially alter anti-mycobacterial immune responses. Imatinib likewise induces signatures associated with cell death and promotes survival of bone marrow-derived macrophages [BMDMs] in culture following infection with Mm. Notably, the capacity of imatinib to limit formation and growth of granulomas in vivo and to promote survival of BMDMs in vitro depends upon caspase 8, a key regulator of cell survival and death. These data provide evidence for the utility of imatinib as an HDT for mycobacterial infections in accelerating and regulating immune responses, and limiting pathology associated with granulomas, which may mitigate post-treatment morbidity. Author summary Mycobacterial infections remain an important cause of morbidity and mortality in humans; for example, Mycobacterium tuberculosis [Mtb], the cause of tuberculosis [TB], kills similar to 1.5 million and newly infects similar to 10 million each year. Although most people effectively combat mycobacterial infections, treatment is compromised in at-risk individuals by an indolent immune response and chronic inflammation, which results in granulomas that encase the bacteria and limit spread. Granulomas also contribute to tissue damage and limit access of antibiotics to bacteria, which engenders resistance. We proposed using imatinib mesylate, a host directed therapeutic [HDT], against mycobacterial infections. Imatinib, a cancer therapeutic that inhibits Abl and related tyrosine kinases, alters intracellular transit of bacteria during infection. Using systems biology approaches in conjunction with murine infections with Mycobacterium marinum, a close genetic relative of Mtb that forms tail granulomas, we report that imatinib does not fundamentally alter the anti-mycobacteria immune response, but rather accelerates it. In addition, imatinib regulates gene signatures associated with cell death, and limits granuloma formation and growth, an effect abrogated in mice lacking caspase 8, a key regulator of cell survival and death. These data highlight imatinib as a possible HDT for mycobacterial infections, including TB, with the capacity to augment the immune response in at-risk individuals, and limit granuloma growth, thereby limiting tissue damage and post-treatment morbidity.

Automated summary

Infections caused by MTC and NTM can lead to widespread morbidity and mortality. Imatinib mesylate may be a new therapeutic approach for mycobacterial infections, reducing lesion size and inflammation, accelerating immune response, and inhibiting granuloma formation and growth, thereby mitigating lung damage and morbidity.