title: Understanding PGE2, LXA4 and LTB4 balance during Mycobacterium tuberculosis infection through mathematical model.
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 PGE2, LXA4 and LTB4 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, [PGE2] 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.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg 110067, New Delhi, India. Electronic address: gabriele@icgeb.res.in.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pedruzzi
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg 110067, New Delhi, India. Electronic address: phonimath@gmail.com.
authors.forename: Phonindra Nath
authors.initials: PN
authors.lastname: Das
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg 110067, New Delhi, India. Electronic address: kanury@icgeb.res.in.
authors.forename: Kanury Vs
authors.initials: KV
authors.lastname: Rao
authors.affiliation: Translational Health Science and Technology Institute, Drug Discovery Research Centre, NCR Biotech Science Cluster, 3rd Milestone, Faridabad - Gurgaon Express Way, Faridabad 121001, Haryana, India. Electronic address: samrat.chatterjee@thsti.res.in.
authors.forename: Samrat
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D017209:Apoptosis; D003198:Computer Simulation; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D007975:Leukotriene B4 / Q000378:metabolism*; D044045:Lipoxins / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008962:Models, Theoretical; D009164:Mycobacterium Infections / Q000378:metabolism*; D009169:Mycobacterium tuberculosis; D009336:Necrosis; D010641:Phenotype; D016896:Treatment Outcome; D014774:Virulence
chemical_list: D044045:Lipoxins; C040527:lipoxin A4; D007975:Leukotriene B4; D015232:Dinoprostone
keywords: Differential equations; Host–pathogen interaction; LXA(4):LTB(4); Mycobacterium tuberculosis; PGE(2)