Understanding PGE2, LXA4 and LTB4 balance during Mycobacterium tuberculosis infection through mathematical model. (21st January 2016)

• Record Type: Journal Article
• Authors: Pedruzzi, Gabriele; Das, Phonindra Nath; Rao, Kanury VS.; Chatterjee, Samrat
• Is Part Of: Journal of theoretical biology. Volume 389(2016)
• Page Start: 159
• Page End: 170
• Publication Date: 2016-01-21
• Subjects: Mycobacterium tuberculosis -- Host–pathogen interaction -- Differential equations -- PGE2 -- LXA4:LTB4; Biology -- Periodicals; Biological Science Disciplines -- Periodicals; Biology -- Periodicals; Biologie -- Périodiques; Theoretische biologie; Biology; Periodicals; 571.05
• DOI: 10.1016/j.jtbi.2015.10.025
• Languages: English
• ISSNs: 0022-5193

Abstract

Abstract: Infection of humans with Mycobacterium tuberculosis (Mtb) results in diverse outcomes that range from acute disease to establishment of persistence and to even clearance of the pathogen. These different outcomes represent the combined result of host heterogeneity on the one hand, and virulence properties of the infecting strain of pathogen on the other. From the standpoint of the host, the balance between PGE 2, LXA 4 and LTB 4 represents at least one of the factors that dictates the eventual pathophysiology. We therefore built an ODE model to describe the host–pathogen interaction and studied the local stability properties of the system, to obtain the parametric conditions that lead to different disease outcomes. We then modulated levels of the pro- and anti-inflammatory lipid mediators to better understand the convergence between host phenotype and factors that relate to virulence properties of the pathogen. Global sensitivity analysis, using the variance-based method of extended Fourier Amplitude Sensitivity Test (eFAST), revealed that disease severity was indeed defined by combined effects of phenotypic variability at the level of both host and pathogen. Interestingly here, [ PGE 2 ] was found to act as a switch between bacterial clearance and acute disease. Our mathematical model suggests that development of more effective treatments for tuberculosis will be contingent upon a better understanding of how the intrinsic variability at the level of both host and pathogen contribute to influence the nature of interactions between these two entities. Abstract : Highlights: Mathematical model describes the pro/anti-inflammatory balance during tuberculosis. PGE2 acts as a main switch between bacterial clearance and acute disease. Host increased susceptibility to disease was defined by deregulated LXA4 and LTB4 ratio.