Naffie Top Poster 2023

Naffie Top

Mrs Naffie Top

MRCG@LSHTM, Gambia

The role of macrophage differentiation on Mycobacterium tuberculosis complex lineages response to Tyrosine kinase inhibitors.

Poster Abstract

N. Top1*., Mberkadji SN1,2*, SM. Colley1, LD Tientcheu1,3

Background: Mycobacterium tuberculosis complex (MTBC) success in evading the host immune response is key to its survival. It uses the tyrosine kinase (TK) signalling system to enter and survive in macrophages by phosphorylating STAT3 and altering it to a favorable phenotype. We investigated the effect of TK inhibitors as Host directed therapeutics (HDT) that will target bacterial entry, survival, and manipulation of macrophages.

Method: Venous blood from healthy donors was used for monocyte extraction. Monocytes were differentiated into M1/IFN-γ, M2/IL-4, and M2/IL-13 by incubating with GM-CSF and M-CSF for 6 days, followed by either IFN-γ, IL-4, or IL-13. The different phenotypes were infected with reporter-gene-tagged clinical isolates of M.tuberculosis lineage2 (Mtb-L2), lineage4 (Mtb-L4), and M.africanum lineage6 (Maf-L6) at a multiplicity of infection of 5  in the presence or absence of TK inhibitors drugs, Imatinib, Gefitinib, and Erlotinib. Bacterial load quantification done daily by measuring fluorescence, luminescence, and absorbance using SpectraMax i3x.

Results: Our data show that M1/IFN-γ controls Mtb-L4 growth significantly compared to Mtb-L2 and Maf-L6. M2/IL-4 control Maf-L6 growth better than Mtb-L4 and Mtb-L2 (P=0.0005), although M2/IL-13 were relatively permissive to all three MTBC lineages.  Imatinib stimulated M1/IFN-γ control of all the intracellular MTBC lineages; in contrast, Gefitinib and Erlotinib impair M1/IFN-γ control of MTBC infection by increasing permissiveness (P=<0.0001). M2/IL-13 alone and in the presence of Imatinib has poor control of MTBC intracellular growth. However,Gefitinib and Erlotinib enhanced M2/IL-13 intracellular control of all three MTBC lineages (P=0.0001).

Conclusion: Our study shows macrophage differentiation affects their response to different clinical MTBC lineages infection. The phenotype's capacity to control intracellular MTBC growth also differed in response to TK inhibitor drugs. The development of new HDT should account for macrophage subsets and different circulating MTBC lineages.

 

Biography

I am a young scientist who is passionate about bringing change to the world of tuberculosis treatment. My vision is to contribute significantly to the development of novel treatment strategies against tuberculosis in Africa. This vision has been shaped by my current position and the experience of the fatal impact of TB within my neighborhood community. I believe I am in the right place and time to make this vision a reality.