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A Functional Toll-Interacting Protein Variant Is Associated with Bacillus Calmette-Guerin-Specific Immune Responses and Tuberculosis.

ABSTRACT: The molecular mechanisms that regulate tuberculosis susceptibility and bacillus Calmette-Guérin (BCG)-induced immunity are mostly unknown. However, induction of the adaptive immune response is a critical step in host control of Mycobacterium tuberculosis. Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune responses, including Toll-like receptor signaling, which initiate adaptive immunity. TOLLIP variation is associated with susceptibility to tuberculosis, but the mechanism by which it regulates tuberculosis immunity is poorly understood.To identify functional TOLLIP variants and evaluate the role of TOLLIP variation on innate and adaptive immune responses to mycobacteria and susceptibility to tuberculosis.We used human cellular immunology approaches to characterize the role of a functional TOLLIP variant on monocyte mRNA expression and M. tuberculosis-induced monocyte immune functions. We also examined the association of TOLLIP variation with BCG-induced T-cell responses and susceptibility to latent tuberculosis infection.We identified a functional TOLLIP promoter region single-nucleotide polymorphism, rs5743854, which was associated with decreased TOLLIP mRNA expression in infant monocytes. After M. tuberculosis infection, TOLLIP-deficient monocytes demonstrated increased IL-6, increased nitrite, and decreased bacterial replication. The TOLLIP-deficiency G/G genotype was associated with decreased BCG-specific IL-2+ CD4+ T-cell frequency and proliferation. This genotype was also associated with increased susceptibility to latent tuberculosis infection.TOLLIP deficiency is associated with decreased BCG-specific T-cell responses and increased susceptibility to tuberculosis. We hypothesize that the heightened antibacterial monocyte responses after vaccination of TOLLIP-deficient infants are responsible for decreased BCG-specific T-cell responses. Activating TOLLIP may provide a novel adjuvant strategy for BCG vaccination.

SUBMITTER: Shah JA

PROVIDER: S-EPMC5564674 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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A Functional Toll-Interacting Protein Variant Is Associated with Bacillus Calmette-Guérin-Specific Immune Responses and Tuberculosis.

Shah Javeed A JA Musvosvi Munyaradzi M Shey Muki M Horne David J DJ Wells Richard D RD Peterson Glenna J GJ Cox Jeffery S JS Daya Michelle M Hoal Eileen G EG Lin Lin L Gottardo Raphael R Hanekom Willem A WA Scriba Thomas J TJ Hatherill Mark M Hawn Thomas R TR

American journal of respiratory and critical care medicine 20170801 4

<h4>Rationale</h4>The molecular mechanisms that regulate tuberculosis susceptibility and bacillus Calmette-Guérin (BCG)-induced immunity are mostly unknown. However, induction of the adaptive immune response is a critical step in host control of Mycobacterium tuberculosis. Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune responses, including Toll-like receptor signaling, which initiate adaptive immunity. TOLLIP variation is associated with susceptibil ...[more]

PMID: 28463648

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Project description:INTRODUCTION:Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (M.TB) and other species of the Mycobacterium tuberculosis complex. Globally, TB is ranked as the ninth leading cause of death and the leading cause of death from a single infectious agent. The bacille Calmette-Guerin (BCG) vaccine has been used globally since 1921 for the prevention of TB in humans, and was derived from an attenuated strain of Mycobacterium bovis. Evidence from previous randomised trials show that the efficacy of primary BCG vaccination against pulmonary TB ranged from no protection to very high protection. In addition, some studies suggest a benefit of BCG revaccination. For example, a recent trial conducted in South Africa showed that BCG revaccination of adolescents could reduce the risk of TB infection by half. However, we are not aware of any recent systematic reviews of the effects of BCG revaccination. Thus, the need for this systematic review of the effects of BCG revaccination on protection against TB infection and disease. METHOD AND ANALYSIS:We will search PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, WHO International Clinical Trials Registry Platform and reference lists of relevant publications for potentially eligible studies. We will screen search outputs, select eligible studies, extract data and assess risk of bias in duplicate. Discrepancies will be resolved by discussion and consensus or arbitration. We will use the Grading of Recommendations Assessment, Development and Evaluation method to assess the certainty of the evidence. The planned systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) in August 2018. ETHICS AND DISSEMINATION:Publicly available data will be used, hence no formal ethical approval will be required for this review. The findings of the review will be disseminated through conference presentations and publication in an open-access peer-reviewed journal. PROSPERO REGISTRATION NUMBER:CRD42018105916.

Project description:BackgroundThe Bacillus Calmette-Guerin (BCG) vaccine has been in use for 99 years, and is regarded as one of the oldest human vaccines known today. It is recommended primarily due to its effect in preventing the most severe forms of tuberculosis, including disseminated tuberculosis and meningeal tuberculosis in children; however, its efficacy in preventing pulmonary tuberculosis and TB reactivation in adults has been questioned. Several studies however have found that asides from its role in tuberculosis prevention, the BCG vaccine also has protective effects against a host of other viral infections in humans, an effect which has been termed: heterologous, non-specific or off-target.ObjectivesAs we approach 100 years since the discovery of the BCG vaccine, we review the evidence of the non-specific protection offered by the vaccine against viral infections, discuss the possible mechanisms of action of these effects, highlight the implications these effects could have on vaccinology and summarize the recent epidemiological correlation between the vaccine and the on-going COVID-19 pandemic.ResultsSeveral epidemiological studies have established that BCG does reduce all-cause mortality in infants, and also the time of vaccination influences this effect significantly. This effect has been attributed to the protective effect of the vaccine in preventing unrelated viral infections during the neonatal period. Some of such viral infections that have been investigated include: herpes simplex virus (HSV), human Papilloma virus (HPV), yellow fever virus (YFV), respiratory syncytial virus (RSV) and influenza virus type A (H1N1). These effects are thought to be mediated via induction of innate immune memory as well as heterologous lymphocytic activation. While epidemiological studies have suggested a correlation, the potential protection of the BCG vaccine against COVID-19 transmission and mortality rates is currently unclear. Ongoing clinical trials and further research may shed more light on the subject in the future.ConclusionBCG is a multifaceted vaccine, with many numerous potential applications to vaccination strategies being employed for current and future viral infections. There however is a need for further studies into the immunologic mechanisms behind these non-specific effects, for these potentials to become reality, as we usher in the beginning of the second century since the vaccine's discovery.

Dataset Information

A Functional Toll-Interacting Protein Variant Is Associated with Bacillus Calmette-Guerin-Specific Immune Responses and Tuberculosis.

Publications

A Functional Toll-Interacting Protein Variant Is Associated with Bacillus Calmette-Guérin-Specific Immune Responses and Tuberculosis.

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