Trained innate immunity and resistance to Mycobacterium tuberculosis infection

Abstract

a b s t r a c tBackground: Some individuals, even when heavily exposed to an infectious tuberculosis patient, develop neither active nor latent tuberculosis infection (LTBI). This 'early clearance' of Mycobacterium tuberculosis is associated with a history of bacillus CalmetteeGu erin (BCG) vaccination. As BCG vaccination can boost innate immune responses through a process termed 'trained immunity', we hypothesize that BCGinduced trained innate immunity contributes to early clearance of M. tuberculosis. Objectives: We describe the epidemiological evidence and biological concepts of early clearance and trained immunity, and the possible relation between these two processes through BCG vaccination. Sources: Relevant data from published reports up to November 2018 were examined in the conduct of this review. Content: Several observational studies and one recent randomized trial support the concept that boosting innate immunity contributes to protection against M. tuberculosis infection, with BCG vaccination providing approximately 50% protection. The molecular mechanisms mediating early clearance remain largely unknown, but we propose that trained immunity, characterized by epigenetic and metabolic reprogramming of innate immune cells such as monocytes or macrophages, is at least partially responsible for eliminating the mycobacteria and inducing early clearance. Implications: Future studies should examine if BCG revaccination increases early clearance of M. tuberculosis through induction of trained immunity. Epigenetic or metabolic modulation may further boost BCG-induced trained innate immunity to promote tuberculosis prevention. New tuberculosis vaccine candidates should also be examined for their capacity to improve protection against M. tuberculosis infection and induce trained immunity. V.A.C.M. Koeken, Clin Microbiol Infect 2019;25:1468

Innate immune memory of tissue-resident macrophages and trained innate immunity: Re-vamping vaccine concept and strategies

“…Notwithstanding, the central role by AM in taking up M.tb , particularly in early phases of infection 43,45 offers an opportunity to exploit the concept of TII to immunologically manipulate the phenotype of AM prior to M.tb exposure 2,3,10,55–57 . For instance, immunologically rewiring the metabolic profile of AM 13 toward a highly glycolytic capacity represents such a strategy amenable to robust bactericidal control of M.tb 42 .…”

“…In so doing, trained AM will be able to overcome the innate immune tolerogenic/suppressive effects of M.tb upon exposure for enhanced innate protection. Indeed, it has been observed that up to 20% of the human house contacts exposed to M.tb could quickly clear infection (early clearers) as judged by lack of conversion in the interferon‐gamma‐release assay and purified protein derivative skin test, 55 and such protection is associated with increased innate immune responses and BCG vaccination 58,59 …”

Heterologous effects of vaccination and trained immunity

“…Benn and Aaby [9] describe in an historical review how epidemiologic studies in many industrialized and low-income countries led to the concept of beneficial nonspecific effects of BCG and other live human vaccines. Koeken et al [10] discuss the epidemiologic evidence and biologic concepts of early clearance of M. tuberculosis by BCG vaccination. They hypothesize that vaccination with BCG or other strategies to induce trained immunity could prevent TB contacts from becoming infected.…”

Therapeutic host-directed strategies to improve outcome in tuberculosis

“…Results indicate that BCG re-vaccination reduces the rate of sustained Quanti-FERON (QFT) conversion and displays improved long-term innate or trained immunity and adaptive responses, thus leading to effective control of mycobacterial infection. [123][124][125][126][127][128][129] A comprehensive review by Schaible et al in 2017 evaluates strategies to improve vaccine efficacy against TB by targeting innate INF-γ interferon-γ, TNF-α tumor necrosis factor-α, GM-CSF granulocyte/macrophage-colony stimulating factor, VEGF vascular endothelial growth factor, Ang angiopoietin, IL interleukin, DCs dendritic cells, CD cluster of differentiation, JAK-STAT Janus tyrosine kinase-signal transducer and activator of transcription, TGF-β transforming growth factor-β; BCG = Bacille Calmette Guerin, CFU colony-forming units, MGIT Mycobacteria Growth Indicator Tube a No clinical trial data as evidence for therapeutic intervention potential and outcome in TB disease immunity. 130 Here, they propose that short-term modulation of the local immune response to BCG vaccination may result in longterm protective immunity against Mtb infection.…”