The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

Abstract

Tyrosine kinases are checkpoints for multiple cellular pathways and dysregulation induces malignancies, most notably chronic myeloid leukemia (CML). Inhibition of Abltyrosine kinases has evolved as a new concept for the treatment of CML and other malignant diseases. Due to the multiple immune-modulatory pathways controlled by tyrosine kinases, treatment with tyrosine kinase inhibitors (TKIs) will not only affect the biology of malignant cells but also modulate physiological immune functions. To understand the effects of TKIs on host defense against intracellular bacteria, we investigated the immunological impact of the dual Abl/Src TKI dasatinib on the cellular immune response to Mycobacterium tuberculosis (Mtb). Our results demonstrate that dasatinib impaired proliferation, cytokine release (IFN-γ, TNF-α, GM-CSF), expression of granulysin and degranulation of cytotoxic effector molecules of human Mtb-specific T-lymphocytes by inhibition of lymphocyte-specific protein tyrosine kinase (Lck) phosphorylation. Despite this profound inhibition of T-cell function, dasatinib suppressed growth of virulent Mtb in human macrophages co-cultured with autologous Mtb-specific T-cells (49±15%). Functional analysis suggested that growth inhibition is due to dasatinib-triggered lysosomal acidification inMtb-infected macrophages. These results highlight the significance of innate immune responses, i.e. acidification of lysosomes, which control the multiplication of intracellular bacteria despite the lack of efficient T-cell support. Keywords: Human primary cells r infection immunology r infection immunology r tuberculosis r T-cells r Tyrosine kinase inhibitorAdditional supporting information may be found online in the Supporting Information section at the end of the article.

Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy

“…In addition, no clear difference was observed in the secretion of key cytokine in the treated and untreated mice. Our findings are in agreement with Wehrstedt et al [66], who used a dual Abl/Src TKI dasatinib, which restricted the growth of intracellular M. tb .…”

Targeting Host Tyrosine Kinase Receptor EPHA2 Signaling Affects Uropathogen Infection in Human Bladder Epithelial Cells

“…Dasatinib has previously been shown to suppress several infections, such as chlamydial infection [ 24 ], reduce the growth of intracellular Mycobacterium tuberculosis [ 62 ] and inhibit HIV replication [ 63 ] and HCV infection [ 27 ]. Similarly, ALW-II-41-27, an Eph receptor tyrosine kinase inhibitor with an IC50 of 11 nM for EPHA2, was effective in inhibiting oxidative stress and inflammation in Trichinella spiralis -infected mice [ 48 ].…”

Zastosowanie ponatynibu u pacjenta po wcześniejszym niepowodzeniu leczenia imatynibem i toksyczności dazatynibu

“…Istnieją pojedyncze doniesienia dotyczące wystąpienia gruźlicy w trakcie przyjmowania DA, który raczej zwiększa skłonność pacjentów do reaktywacji zakażeń wirusowych, głównie wirusem cytomegalii (CMV, cytomegalovirus) i zapalenia wątroby typu B (HBV, hepatitis B virus) [11]. Co interesujące, wykazano, że in vitro DA wspiera mechanizmy komórkowej odpowiedzi immunologicznej przeciwko prątkom gruźlicy [12]. U opisywanego pacjenta gruźlica płuc wystąpiła jednoczasowo z wysiękiem w jamie opłucnej.…”