Anti‑CXCR4 chemokine receptor, motixafortide, as an adjunct treatment with anti‑TB drugs decreases the bacterial burden by improving drug distribution

Abstract

C-X-C motif chemokine receptor 4 (CXCR4) is involved in the migration of bloodcells and the formation of blood vessels. It is expressed on blood cells and other immune cells such as dendritic cells and lymphocytes. Mycobacterium tuberculosis (M. tb) induces granuloma-associated angiogenesis, which is associated with the mycobacterial-induced expression of CXCR4. However, the significance of pathogen-induced angiogenesis remains elusive. The aim of the present study was to investigate the role and expression levels of CXCR4 during M.tb infection. To inhibit CXCR4, motixafortide, an antagonist for CXCR4, was used. The effect of motixafortide on M.tb dissemination, attenuation of bacterial growth and immunological responses in a guinea pig animal model was extensively studied using immunohistochemistry, as well as immunological and colony enumeration assays. The pharmacokinetics of first-line drugs in plasma, the lungs, and granuloma were evaluated following the inhibition of the expression of CXCR4 through motixafortide therapy. The results revealed that CXCR4 stimulation induced the expression of vascular endothelial growth factor-A (VEGFA) in M.tb-infected guinea pigs. Improvement in the pharmacokinetic parameters and early bacterial clearance in the spleen were observed in motixafortide anti-tuberculosis (TB) drug therapy in contrast to therapy with first-line drugs alone. G ranulomatous capture of first line drugs combined with motixafortide may have significant implications through different mechanisms. In the present study, it was demonstrated that CXCR4 inhibitors may be used as a therapeutic strategy to combat granuloma-angiogenesis by interfering with VEGFA signalling and controlling the spread of M.tb infection.