Naffie Top Poster 2024

Naffie Top

Ms Naffie Top

MRC The Gambia at LSHTM, Gambia

Macrophages differentiation and Mycobacterium tuberculosis complex lineages influence the response to tyrosine kinase inhibitor Erlotinib.

 

Poster Abstract

Background
Mycobacterium tuberculosis complex (MTBC) success in evading the host immune response is key to its survival. MTBC phosphorylates tyrosine kinase (TK) such as STAT3 to alter macrophage differentiation into a permissive phenotype that promotes its intracellular survival. This project investigates how macrophage subsets control clinical MTBC lineages in response to new host-directed therapeutics (HDT) candidate Erlotinib.
 
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 2 days with either IFN-γ, IL-4, or IL-13. Macrophages subsets 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 inhibitor Erlotinib. Intracellular bacterial load quantification was done daily by measuring fluorescence, luminescence, and absorbance using SpectraMax i3x. Supernatant were collected, and concentration of key cytokines was tested.
 
Results
M1/IFN-γ macrophages exhibit heightened TNF-α, IL-6, and IL-12 expression, effectively controlling all MTBC lineages, notably Mtb-L4. Conversely, M2/IL-4 macrophages display superior control over Maf-L6 growth, while M2/IL-13 macrophages, with the lowest TNF-α, IL-6, and IL-12 expression, are permissive to all MTBC lineages. Erlotinib compromises M1/IFN-γ control, reducing TNF-α and IL-12 and increasing IL-10 expression. However, it enhances M2/IL-13 control of MTBC lineages, elevating IL-12 and S100A8/A9 expression in M2 macrophages. These findings shed light on Erlotinib's differential impact on macrophage responses to MTBC infection, offering insights into potential therapeutic strategies.
 
Conclusion
Our study shows macrophage differentiation subsets affect their response to different clinical MTBC lineages infection and their response to Erlotinb. The development of new HDT should account for macrophage subsets and different circulating MTBC lineages.

 

Biography

I am a young female scientist from the Gambia @ The London School of Hygiene and Tropical Medicine. I am 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 as a Scientific Officer under the project TB host-directed therapeutics for Africa group 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.