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

Abstract

Mycobacterial infections, including those 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. MTC members resistant to some or all antibiotics are estimated to account for a third of deaths from tuberculosis [TB], and newly developed antibiotics have already engendered resistance, pointing to 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 TB. Here, we use the murine Mycobacterium marinum [Mm] infection model, which forms quantifiable granulomas on the tails, in conjunction with transcriptomic analysis of the tail lesions. The data indicate that imatinib induces gene signatures indicative of immune activation 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. Moreover, focusing on the TNF pathway, which is induced by imatinib, we show that imatinib promotes cell survival in infected bone marrow-derived macrophages [BMDMs] in a manner that depends on caspase 8. Moreover, imatinib limits formation and growth of granulomas, an effect abrogated in mice lacking caspase 8. These data provide evidence for the utility of imatinib as an HDT for mycobacterial infections in accelerating immune responses, and limiting pathology associated with granulomas, and thus mitigating post-treatment morbidity. Author SummaryMycobacterial infections remain an important cause of morbidity and mortality in humans; for example, Mycobacterium tuberculosis [Mtb], the cause of tuberculosis [TB], kills [~]1.5 million and newly infects [~]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 mycobacteria. 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 limits granuloma formation and growth, an effect abrogated in mice lacking caspase 8. 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.