Submission
| Title: | Agent based model of latent and naïve in vitro M. Tuberculosis early infection dynamics shows synergistic interactions between CD4+ T cell and macrophage activation |
| Presenter: | Alexis Hoerter |
| Institution: | Purdue University |
| Authors: | Alexa Petrucciani – Purdue University Israel Guerrero – Texas Biomedical Research Institute Charles Renshaw – Texas Biomedical Research Institute Maria Montoya – Texas Biomedical Research Institute Eusondia Arnett – Texas Biomedical Research Institute Larry S. Schlesinger – Texas Biomedical Research Institute Elsje Pienaar – Purdue University; Regenstrief Center for Healthcare Engineering |
Abstract
| Background/Significance/Rationale: | Tuberculosis (TB) remains a prevalent global health challenge with 10.6 million infections and 1.6 million deaths in 2021. Granulomas – clusters of immune cells and bacteria – are the hallmark of TB infection. Early infection interactions during granuloma formation have been shown to be impacted by the host immune status. Cells from individuals with latent TB infection (LTBI) have improved bacterial growth control and cellular proliferation and faster granuloma formation compared to cells from unexposed (naïve) individuals. |
| Methods: | We developed a computational agent-based model to analyze mechanistic differences in early infection dynamics between LTBI and naïve individuals. We simulate macrophages, bacteria, and CD4+ T cells as agents along with TNFα and IFNγ. Virtual interactions between our agents include bacterial growth, macrophage phagocytosis and infection, CD4+ T cell and macrophage activation, bacterial killing, cytokine secretion, diffusion and degradation. We calibrate the model to published experimental data for bacterial and total cell fold change and timing of first granuloma appearance. |
| Results/Findings: | Our results indicate that the earliest interactions between activated CD4+ T cells and activated infected macrophages in LTBI cells inhibit bacterial growth by seeding granuloma-like structures with fewer bacteria. The granulomas produced in the simulations promote TB-specific CD4+ T cell proliferation, macrophage activation and continue to inhibit bacterial growth. Differences in baseline killing rates (reminiscent of trained immunity) between LTBI and naïve cells also contribute significantly to bacterial control. |
| Conclusions/Discussion: | Our findings suggest that LTBI cells have quicker macrophage activation, better bacterial clearance and higher chance to promote rapid T cell proliferation. These findings support the use of host directed therapies that promote macrophage activation such as IFNγ and enhanced macrophage autophagy before infection to support innate immune clearance of the bacteria. |
| Translational/Human Health Impact: | This work highlights the need for more research into the initial interactions between macrophages and Mtb to identify preventative strategies in TB endemic regions. |
