Imatinib decreases bacterial load of pathogenic <i>Francisella spp</i>. <i>in vivo</i>.

<p><b>(A-B)</b> C57Bl/6 mice were treated with imatinib at 66 mg/kg/d or water for 7d prior to infection and for the duration of the experiment, and then injected subcutaneously with either ~6x10⁶ Fn <b>(A)</b> or ~2x10⁵ LVS <b>(B)</b>. After 48h for Fn or 5d for LVS, skin and spleens were collected and CFU/gram of tissue was determined. The limit of detection of the assay was 100 CFUs. <b>(C)</b> Images of lesions on control or imatinib-treated mice infected with LVS. Hair was removed from injection site. The lesions are indicated by white arrows. <b>(D)</b> Quantitation of lesions from control or imatinib-treated mice. Lesions were scored on a scale of one to three, with a score of one denoting no visible lesion, two a visible lesion but without a break in the skin, and three an open wound. 15 animals were scored per condition. <b>(E)</b> Four days following infection with strain Ft Schu S4, CFU/gram of tissue was determined. The limit of detection of the assay was 100 CFU/gm for Ft. The line in each data set represents the median. A Mann-Whitney nonparametric test was used to determine significance. Combined data from three independent experiments are shown. <b>(F)</b> Effects of imatinib at 66mg/kg/d on neutrophils and monocytes upon infection with LVS. Data from a representative experiment are shown. <b>(G)</b> Summary of effects of Imatinib on myelopoiesis and migration of mature myeloid cells to the blood and organs. Imatinib at doses of 66 or 200 mg/kg/day induces activation, expansion, and maturation of hematopoietic stem cells (HSCs) and multipotent hematopoietic progenitors 1–4 (MPP1-4) in the bone marrow. Imatinib at these doses also stimulates a lineage determination step that induces MPPs to differentiatiate into myeloid precursors and then mature cells (green arrow), but not into cells of the lymphoid lineage (red arrow). Data with low doses of neutralizing antibodies against the c-Kit tyrosine kinase support the hypothesis that effects on HSCs and MPPs are mediated by partial inhibition of c-Kit, whereas effects of the drug on lineage determination appears to be independent of c-Kit. Ultimately, imatinib increases the numbers of mature myeloid cells in the bone marrow, an effect seen with drug alone; the accumulation of mature cells is not evident with the drug in context of infection, which itself appears to mobilize migration of mature cells from the bone marrow to the periphery. Notably, increased numbers of mature cells are only evident in the blood and tissues at lower doses (66mg/kg/d), suggesting that at low doses, Imatinib induces migration of mature cells out of the bone marrow; alternatively, the drug may inhibit migration at higher doses (200mg/kg/d). Importantly, Imatinib mimics the “emergency response” to infection, which likewise induces HSC activation, MPP expansion, myelopoiesis, and migration of mature myeloid cells from the bone marrow to the periphery (green arrows).