Low Doses of Imatinib Induce Myelopoiesis and Enhance Host Anti-microbial Immunity

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Host-directed therapeutics (HDTs) for infectious diseases target cellular mechanisms used by pathogens to move into, through, or out of cells. The Abl tyrosine kinase (TK) inhibitor and cancer therapeutic imatinib mesylate (Gleevec), for example, has activity against bacterial and viral pathogens via effects on pathogen entry (polyomaviruses), intracellular transit (Mycobacteria) and exit (poxviruses and filoviruses). Other HDTs target the host immune system by suppressing or activating circulating innate and adaptive cells. Here we report that imatinib at doses that are effective in clearing Mycobacterial infections but which are 10-fold lower than those used for cancer, mimics a physiological innate response to infection in the bone marrow, called the “emergency response,” in which hematopoietic stem cells and multipotent progenitors expand and differentiate into mature myeloid cells that migrate to peripheral sites. Imatinib effects occur in part via partial inhibition of c-Kit, suggesting a mechanism by which c-Kit controls the earliest stages of hematopoiesis. Mimicking a physiological antimicrobial response may make imatinib broadly useful. Accordingly, imatinib also has efficacy against infections caused by Franciscella spp., which do not use imatinib-sensitive TKs for pathogenesis. These observations identify myelopoiesis as an important target for HDTs, and provide information on how to dose imatinib for clinical use.

Vyšlo v časopise: Low Doses of Imatinib Induce Myelopoiesis and Enhance Host Anti-microbial Immunity. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004770
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004770

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