Bayesian Approach to Model CD137 Signaling in Human M. tuberculosis In Vitro Responses

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Immune responses are qualitatively and quantitatively influenced by a complex network of receptor-ligand interactions. Among them, the CD137:CD137L pathway is known to modulate innate and adaptive human responses against Mycobacterium tuberculosis. However, the underlying mechanisms of this regulati...

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Autores principales:	Fernández Do Porto, D.A., Auzmendi, J., Peña, D., García, V.E., Moffatt, L.
Formato:	Artículo publishedVersion
Lenguaje:	Inglés
Publicado:	2013
Materias:	CD137 antigen cytokine gamma interferon tuberculostatic agent tumor necrosis factor alpha antigen presenting cell article Bayes theorem cell survival clinical article culture medium cytokine production human immune response in vitro study lung tuberculosis Monte Carlo method Mycobacterium tuberculosis natural killer cell nonhuman nonlinear system probability qualitative analysis quantitative analysis T lymphocyte thermodynamics 4-1BB Ligand Adaptive Immunity Adult Antigen-Presenting Cells Antigens, CD137 Antigens, CD56 Bayes Theorem Cellular Microenvironment Cytokines Humans Immunity, Innate Intracellular Space Killer Cells, Natural Models, Biological Signal Transduction T-Lymphocytes Thermodynamics Tuberculosis Uncertainty
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_19326203_v8_n2_p_FernandezDoPorto
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paperaa:paper_19326203_v8_n2_p_FernandezDoPorto2023-06-12T16:51:44Z Bayesian Approach to Model CD137 Signaling in Human M. tuberculosis In Vitro Responses PLoS ONE 2013;8(2) Fernández Do Porto, D.A. Auzmendi, J. Peña, D. García, V.E. Moffatt, L. CD137 antigen cytokine gamma interferon tuberculostatic agent tumor necrosis factor alpha antigen presenting cell article Bayes theorem cell survival clinical article culture medium cytokine production human immune response in vitro study lung tuberculosis Monte Carlo method Mycobacterium tuberculosis natural killer cell nonhuman nonlinear system probability qualitative analysis quantitative analysis T lymphocyte thermodynamics 4-1BB Ligand Adaptive Immunity Adult Antigen-Presenting Cells Antigens, CD137 Antigens, CD56 Bayes Theorem Cellular Microenvironment Cytokines Humans Immunity, Innate Intracellular Space Killer Cells, Natural Models, Biological Mycobacterium tuberculosis Signal Transduction T-Lymphocytes Thermodynamics Tuberculosis Uncertainty Immune responses are qualitatively and quantitatively influenced by a complex network of receptor-ligand interactions. Among them, the CD137:CD137L pathway is known to modulate innate and adaptive human responses against Mycobacterium tuberculosis. However, the underlying mechanisms of this regulation remain unclear. In this work, we developed a Bayesian Computational Model (BCM) of in vitro CD137 signaling, devised to fit previously gathered experimental data. The BCM is fed with the data and the prior distribution of the model parameters and it returns their posterior distribution and the model evidence, which allows comparing alternative signaling mechanisms. The BCM uses a coupled system of non-linear differential equations to describe the dynamics of Antigen Presenting Cells, Natural Killer and T Cells together with the interpheron (IFN)-γ and tumor necrosis factor (TNF)-α levels in the media culture. Fast and complete mixing of the media is assumed. The prior distribution of the parameters that describe the dynamics of the immunological response was obtained from the literature and theoretical considerations Our BCM applies successively the Levenberg-Marquardt algorithm to find the maximum a posteriori likelihood (MAP); the Metropolis Markov Chain Monte Carlo method to approximate the posterior distribution of the parameters and Thermodynamic Integration to calculate the evidence of alternative hypothesis. Bayes factors provided decisive evidence favoring direct CD137 signaling on T cells. Moreover, the posterior distribution of the parameters that describe the CD137 signaling showed that the regulation of IFN-γ levels is based more on T cells survival than on direct induction. Furthermore, the mechanisms that account for the effect of CD137 signaling on TNF-α production were based on a decrease of TNF-α production by APC and, perhaps, on the increase in APC apoptosis. BCM proved to be a useful tool to gain insight on the mechanisms of CD137 signaling during human response against Mycobacterium tuberculosis. © 2013 Fernández Do Porto et al. Fil:Fernández Do Porto, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Auzmendi, J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Peña, D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:García, V.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Moffatt, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2013 info:eu-repo/semantics/article info:ar-repo/semantics/artículo info:eu-repo/semantics/publishedVersion application/pdf eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_19326203_v8_n2_p_FernandezDoPorto
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
language	Inglés
orig_language_str_mv	eng
topic	CD137 antigen cytokine gamma interferon tuberculostatic agent tumor necrosis factor alpha antigen presenting cell article Bayes theorem cell survival clinical article culture medium cytokine production human immune response in vitro study lung tuberculosis Monte Carlo method Mycobacterium tuberculosis natural killer cell nonhuman nonlinear system probability qualitative analysis quantitative analysis T lymphocyte thermodynamics 4-1BB Ligand Adaptive Immunity Adult Antigen-Presenting Cells Antigens, CD137 Antigens, CD56 Bayes Theorem Cellular Microenvironment Cytokines Humans Immunity, Innate Intracellular Space Killer Cells, Natural Models, Biological Mycobacterium tuberculosis Signal Transduction T-Lymphocytes Thermodynamics Tuberculosis Uncertainty
spellingShingle	CD137 antigen cytokine gamma interferon tuberculostatic agent tumor necrosis factor alpha antigen presenting cell article Bayes theorem cell survival clinical article culture medium cytokine production human immune response in vitro study lung tuberculosis Monte Carlo method Mycobacterium tuberculosis natural killer cell nonhuman nonlinear system probability qualitative analysis quantitative analysis T lymphocyte thermodynamics 4-1BB Ligand Adaptive Immunity Adult Antigen-Presenting Cells Antigens, CD137 Antigens, CD56 Bayes Theorem Cellular Microenvironment Cytokines Humans Immunity, Innate Intracellular Space Killer Cells, Natural Models, Biological Mycobacterium tuberculosis Signal Transduction T-Lymphocytes Thermodynamics Tuberculosis Uncertainty Fernández Do Porto, D.A. Auzmendi, J. Peña, D. García, V.E. Moffatt, L. Bayesian Approach to Model CD137 Signaling in Human M. tuberculosis In Vitro Responses
topic_facet	CD137 antigen cytokine gamma interferon tuberculostatic agent tumor necrosis factor alpha antigen presenting cell article Bayes theorem cell survival clinical article culture medium cytokine production human immune response in vitro study lung tuberculosis Monte Carlo method Mycobacterium tuberculosis natural killer cell nonhuman nonlinear system probability qualitative analysis quantitative analysis T lymphocyte thermodynamics 4-1BB Ligand Adaptive Immunity Adult Antigen-Presenting Cells Antigens, CD137 Antigens, CD56 Bayes Theorem Cellular Microenvironment Cytokines Humans Immunity, Innate Intracellular Space Killer Cells, Natural Models, Biological Mycobacterium tuberculosis Signal Transduction T-Lymphocytes Thermodynamics Tuberculosis Uncertainty
description	Immune responses are qualitatively and quantitatively influenced by a complex network of receptor-ligand interactions. Among them, the CD137:CD137L pathway is known to modulate innate and adaptive human responses against Mycobacterium tuberculosis. However, the underlying mechanisms of this regulation remain unclear. In this work, we developed a Bayesian Computational Model (BCM) of in vitro CD137 signaling, devised to fit previously gathered experimental data. The BCM is fed with the data and the prior distribution of the model parameters and it returns their posterior distribution and the model evidence, which allows comparing alternative signaling mechanisms. The BCM uses a coupled system of non-linear differential equations to describe the dynamics of Antigen Presenting Cells, Natural Killer and T Cells together with the interpheron (IFN)-γ and tumor necrosis factor (TNF)-α levels in the media culture. Fast and complete mixing of the media is assumed. The prior distribution of the parameters that describe the dynamics of the immunological response was obtained from the literature and theoretical considerations Our BCM applies successively the Levenberg-Marquardt algorithm to find the maximum a posteriori likelihood (MAP); the Metropolis Markov Chain Monte Carlo method to approximate the posterior distribution of the parameters and Thermodynamic Integration to calculate the evidence of alternative hypothesis. Bayes factors provided decisive evidence favoring direct CD137 signaling on T cells. Moreover, the posterior distribution of the parameters that describe the CD137 signaling showed that the regulation of IFN-γ levels is based more on T cells survival than on direct induction. Furthermore, the mechanisms that account for the effect of CD137 signaling on TNF-α production were based on a decrease of TNF-α production by APC and, perhaps, on the increase in APC apoptosis. BCM proved to be a useful tool to gain insight on the mechanisms of CD137 signaling during human response against Mycobacterium tuberculosis. © 2013 Fernández Do Porto et al.
format	Artículo Artículo publishedVersion
author	Fernández Do Porto, D.A. Auzmendi, J. Peña, D. García, V.E. Moffatt, L.
author_facet	Fernández Do Porto, D.A. Auzmendi, J. Peña, D. García, V.E. Moffatt, L.
author_sort	Fernández Do Porto, D.A.
title	Bayesian Approach to Model CD137 Signaling in Human M. tuberculosis In Vitro Responses
title_short	Bayesian Approach to Model CD137 Signaling in Human M. tuberculosis In Vitro Responses
title_full	Bayesian Approach to Model CD137 Signaling in Human M. tuberculosis In Vitro Responses
title_fullStr	Bayesian Approach to Model CD137 Signaling in Human M. tuberculosis In Vitro Responses
title_full_unstemmed	Bayesian Approach to Model CD137 Signaling in Human M. tuberculosis In Vitro Responses
title_sort	bayesian approach to model cd137 signaling in human m. tuberculosis in vitro responses
publishDate	2013
url	http://hdl.handle.net/20.500.12110/paper_19326203_v8_n2_p_FernandezDoPorto
work_keys_str_mv	AT fernandezdoportoda bayesianapproachtomodelcd137signalinginhumanmtuberculosisinvitroresponses AT auzmendij bayesianapproachtomodelcd137signalinginhumanmtuberculosisinvitroresponses AT penad bayesianapproachtomodelcd137signalinginhumanmtuberculosisinvitroresponses AT garciave bayesianapproachtomodelcd137signalinginhumanmtuberculosisinvitroresponses AT moffattl bayesianapproachtomodelcd137signalinginhumanmtuberculosisinvitroresponses
_version_	1769810303126601728

Bayesian Approach to Model CD137 Signaling in Human M. tuberculosis In Vitro Responses

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