CELL-CELL COMMUNICATION PRIZE TITLE: Alteration of Cell to cell interaction; Promoting Host-Directed Therapy during Macrophage and Mycobacteria Interaction Problem or question being addressed Tuberculosis treatment is lengthy, and drug resistance is common, meaning that new treatment approaches are urgently needed [1]. Mycobacterium tuberculosis (Mtb) is housed by Macrophages [2]. Understanding the communication between the macrophage and the mycobacteria would have benefits in TB therapy. Host-directed therapy has been acknowledged in terms of cell-cell communication context to help fight antimicrobial resistance. During M.tb infection, it has been documented that there is a shift in the macrophage phenotype/polarization during M.tb infection [3,4]. According to a previous study, altering the macrophage phenotype could be hostile to the mycobacteria. Unfortunately, there is no study that has analyzed the function of nanoparticles (NPs) capsulated with immune-modulatory compounds during M.tb infection. Rationale for your approach Immunomodulatory compounds (IMCs) have been previously studied in the context of host-directed therapy against the use of antibiotics which could possibly cause the development of drug resistance [5]. The IMCs will be used to alter the macrophage phenotype during M.tb infection. Flow cytometry and RNA sequencing could be used to better understand the transcriptional details [6] and gene expression of the macrophages [7] as a result of interaction with the M.tb and the impact of the capsulated NPs. Details of the suggested approach IMCs such as lecithin and curdlan have previously been proven to cause the production of IFN-gamma, IL-12, and induction of intracellular Calcium respectively which is expected to stimulate or affect macrophage phenotype/polarization [8]. In this approach, we will be assessing both IMCs which will be capsulated on bacterio-mimetic NPs. The objective of the IMCs is to alter the macrophage polarization/phenotype while the NPs serve as the IMCs-carrier for effective delivery into the macrophages. The functional control of macrophages largely happens at the transcriptional level [9]. Hence, we will be using flow cytometry to assess selected transcriptional biomarkers together with RNA sequencing for comparison and deeper transcriptional analysis [6]. How it will affect the broader field Although conventional drugs for TB are relatively ineffective against drug-sensitive strains of M.tb [1]. The increasing incidence of drug-resistant strains of M.tb remains a global concern in TB therapy. Previous research has shown that NPs can restrict the growth of M.tb inside macrophages through a host-dependent mechanism.[8] Therefore, alteration of the macrophage phenotype/polarization [10] and the use of NPs provide an attractive opportunity for host-directed therapy for TB. A key advantage of this would be the much-reduced risk of the development of drug resistance. In addition to being noble research, understanding the potential shift of macrophage polarization/phenotype could provide more information about the efficacy of the NPs for future study. References 1. WHO. Global Tuberculosis Report 2021. 2. D'Souza S, Du Plessis SM, Egieyeh S, et al. Physicochemical and Biological Evaluation of Curdlan-Poly(Lactic-Co-Glycolic Acid) Nanoparticles as a Host-Directed Therapy Against Mycobacterium Tuberculosis. J Pharm Sci 2022;111(2):469-478. DOI: 10.1016/j.xphs.2021.09.012. 3. Huang Z, Luo Q, Guo Y, et al. Mycobacterium tuberculosis-Induced Polarization of Human Macrophage Orchestrates the Formation and Development of Tuberculous Granulomas In Vitro. PLoS One 2015;10(6):e0129744. DOI: 10.1371/journal.pone.0129744. 4. Marino S, Cilfone NA, Mattila JT, et al. Macrophage polarization drives granuloma outcome during Mycobacterium tuberculosis infection. Infect Immun 2015;83(1):324-38. Epub 2014/11/05. DOI: 10.1128/IAI.02494-14. 5. Bekale RB, Du Plessis SM, Hsu NJ, et al. Mycobacterium tuberculosis and Interactions with the Host Immune System: Opportunities for Nanoparticle-Based Immunotherapeutics and Vaccines. Pharm Res 2018;36(1):8. DOI: 10.1007/s11095-018-2528-9. 6. Huang X, Li Y, Fu M, Xin HB. Polarizing Macrophages In Vitro. Methods Mol Biol 2018;1784:119-26. DOI: 10.1007/978-1-4939-7837-3_12. 7. Orecchioni M, Ghosheh Y, Pramod AB, Ley K. Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages. Front. Immunol 2019;10:1084. DOI: 10.3389/fimmu.2019.01084. 8. Tukulula M, Hayeshi R, Fonteh P, Meyer D, Ndamase A, Madziva MT, Khumalo V, Labuschagne P, Naicker B, Swai H, Dube A. Curdlan-Conjugated PLGA Nanoparticles Possess Macrophage Stimulant Activity and Drug Delivery Capabilities. Pharm Res. 2015;32(8):2713-26. Epub 2015/03/01. doi: 10.1007/s11095-015-1655-9. PubMed PMID: 25724161. 9. Wang S, Liu R, Yu Q, Dong L, Bi Y, Liu G. Metabolic reprogramming of macrophages during infections and cancer. Cancer Lett. 2019;452(March):14-22. doi:10.1016/j.canlet.2019.03.015 10. Ge G, Jiang H, Xiong J, et al. Progress of the Art of Macrophage Polarization and Different Subtypes in Mycobacterial Infection. Front Immunol. 2021;12(752657):1-7. doi:10.3389/fimmu.2021.752657