The Roles of Immune Memory and Aging in Protective Immunity and Endogenous Reactivation of Tuberculosis

Finding more effective vaccines against tuberculosis (TB) and improved preventive treatments against endogenous reactivation of latent TB is strategic to block transmission and reach the WHO goal of eliminating TB by 2050. Key related open questions in TB research include: i) what are the determinants of a strong memory response upon primary infection? ii) what is the role of cytokines towards protective memory response against a secondary infection? iii) what are the mechanisms responsible for the increased risk of reactivation in elderly individuals? To address these questions, we explored a computational model of the immune response to Mycobacterium tuberculosis including a mathematical description of immunosenescence and the generation and maintenance of immune memory. Sensitivity analysis techniques, together with extensive model characterization and in silico experiments, were applied to identify key mechanisms controlling TB reactivation and immunological memory. Key findings of this study are summarized by the following model predictions: i) increased strength and duration of memory protection is associated with higher levels of Tumor Necrosis Factor-alpha (TNF) during primary infection; ii) production of TNF, but not of interferon-gamma, by memory T cells during secondary infection is a major determinant of effective protection; iii) impaired recruitment of CD4+ T cells may promote reactivation of latent TB infections in aging hosts. This study is a first attempt to consider the immune dynamics of a persistent infection throughout the lifetime of the host, taking into account immunosenescence and memory. While the model is TB specific, the results are applicable to other persistent bacterial infections and can aid in the development, evaluation and refinement of TB treatment and/or vaccine protocols.