Human newborn bacille Calmette–Guérin vaccination and risk of tuberculosis disease: a case-control study

Fletcher, Helen A.; Filali‐Mouhim, Ali; Nemes, Elisa; Hawkridge, Anthony; Keyser, Alana; Njikan, Samuel; Hatherill, Mark; Scriba, Thomas J.; Abel, Brian; Kagina, Benjamin M.; Veldsman, Ashley; Agudelo, Nancy Marín; Kaplan, Gilla; Hussey, Gregory; Sékaly, Rafick‐Pierre; Hanekom, Willem A.

doi:10.1186/s12916-016-0617-3

Cited by 51 publications

(59 citation statements)

References 34 publications

(48 reference statements)

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“…Extremes in the ratio of peripheral blood to monocyte lymphocytes were found to be associated with increased risk of TB in HIV infected adults in South Africa and suggested to be a tool to stratify risk of TB [36]. In a separate study in infants who received BCG vaccination at birth and had higher monocyte to T cell ratios, transcriptional profiles were associated with an activated macrophage phenotype likely involved in pathogenesis of risk of TB disease suggesting that a phenotype of activated monocytes may be detrimental to the host [37]. It is thus important to classify the monocyte subsets behind this IL-1β response in further studies as well as measure associated soluble markers of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 1-Beta (IL-1β) Production by Innate Cells Following TLR Stimulation Correlates With TB Recurrence in ART-Treated HIV-Infected Patients

Thobakgale

Naidoo

McKinnon

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background Tuberculosis (TB) remains a major cause of global morbidity and mortality, especially in the context of HIV co-infection, since immunity is not completely restored following antiretroviral therapy (ART). The identification of immune correlates of risk for TB disease could help in the design of host-directed therapies and clinical management. This study aimed to identify innate immune correlates of TB recurrence in HIV+ ART-treated individuals with a history of previous successful TB treatment. Methods Twelve participants with a recurrent episode of TB (cases) were matched for age, sex, time on ART, pre-ART CD4 count with 12 participants who did not develop recurrent TB in 60 months of follow-up (controls). Cryopreserved peripheral blood mononuclear cells from time points prior to TB recurrence were stimulated with ligands for Toll like receptors (TLR) including TLR-2, TLR-4, and TLR-7/8. Multi-color flow cytometry and intracellular cytokine staining was used to detect IL-1β, TNF-α, IL-12 and IP10 responses from monocytes and myeloid dendritic cells (mDCs). Results Elevated production of IL-1β from monocytes following TLR-2, TLR-4 and TLR-7/8 stimulation was associated with reduced odds of TB recurrence. In contrast, production of IL-1β from both monocytes and mDCs following Bacillus Calmette-Guérin (BCG) stimulation was associated with increased odds of TB recurrence (risk of recurrence increased by 30% in monocytes and 42% in mDCs respectively). Conclusion Production of IL-1β by innate immune cells following TLR and BCG stimulations correlated with differential TB recurrence outcomes in ART-treated patients and highlights differences in host response to TB.

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Section: Discussionmentioning

confidence: 99%

Interleukin 1-Beta (IL-1β) Production by Innate Cells Following TLR Stimulation Correlates With TB Recurrence in ART-Treated HIV-Infected Patients

Thobakgale

Naidoo

McKinnon

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…The need for improved 4 strategies to control childhood TB has led to studies to identify risk factors for 5 TB disease in children. The longitudinal data collected during infant TB vaccine 6 efficacy trials in South Africa with the vaccines BCG and Modified Vaccinia 7 Virus Ankara expressing Antigen 85A (MVA85A) 1,7 have enabled the 8 identification of correlates of TB disease risk in infants 3,8 . Using samples 9 collected at enrolment from infants into the MVA85A efficacy trial in the Western 10 Cape Province of South Africa 1 , we reported that CD4+ T-cell activation in 4-6 11 month old infants and adolescents, measured as HLA-DR expression, was 12 associated with increased risk of TB disease over the following 3 years of life 8 .…”

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus infection is a risk factor for TB disease in Infants

Müller

Matsumiya

Snowden

et al. 2017

Preprint

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Immune activation is associated with increased risk of tuberculosis (TB) disease in infants. We performed a case-control analysis to identify drivers of immune activation and disease risk. Among 49 infants who developed TB disease over the first two years of life, and 129 matched controls who remained healthy, we found the cytomegalovirus (CMV) stimulated IFN-γ response at age 4-6 months to be associated with CD8+ T-cell activation (Spearman’s rho, p=6×10−8). A CMV specific IFN-γ response was also associated with increased risk of developing TB disease (Conditional Logistic Regression, p=0.043, OR 2.2, 95% CI 1.02-4.83), and shorter time to TB diagnosis (Log Rank Mantel-Cox p=0.037). CMV positive infants who developed TB disease had lower expression of natural killer cell associated gene signatures and a lower frequency of CD3-CD4-CD8-lymphocytes. We identified transcriptional signatures predictive of risk of TB disease among CMV ELISpot positive (AUROC 0.98, accuracy 92.57%) and negative (AUROC 0.9, accuracy 79.3%) infants; the CMV negative signature validated in an independent infant study (AUROC 0.71, accuracy 63.9%). Understanding and controlling the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.

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“…Initial priming of the immune system upon first mycobacterial contact seems increasingly important. Gene expression analysis revealed that BCG vaccination in young infants induced two dichotomous responses, likely involving differential monocyte activation [76]. Similarly, dichotomous responses to primary BCG vaccination were also observed in adults [77].…”

Section: Protection Mediated By Trained Immunitymentioning

confidence: 90%

Friends and foes of tuberculosis: modulation of protective immunity

Brighenti

Joosten

2018

J Intern Med

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Protective immunity in tuberculosis (TB) is subject of debate in the TB research community, as this is key to fully understand TB pathogenesis and to develop new promising tools for TB diagnosis and prognosis as well as a more efficient TB vaccine. IFN-γ producing CD4 T cells are key in TB control, but may not be sufficient to provide protection. Additional subsets have been identified that contribute to protection such as multifunctional and cytolytic T-cell subsets, including classical and nonclassical T cells as well as novel innate immune cell subsets resulting from trained immunity. However, to define protective immune responses against TB, the complexity of balancing TB immunity also has to be considered. In this review, insights into effector cell immunity and how this is modulated by regulatory cells, associated comorbidities and the host microbiome, is discussed. We systematically map how different suppressive immune cell subsets may affect effector cell responses at the local site of infection. We also dissect how common comorbidities such as HIV, helminths and diabetes may bias protective TB immunity towards pathogenic and regulatory responses. Finally, also the composition and diversity of the microbiome in the lung and gut could affect host TB immunity. Understanding these various aspects of the immunological balance in the human host is fundamental to prevent TB infection and disease.

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Human newborn bacille Calmette–Guérin vaccination and risk of tuberculosis disease: a case-control study

Cited by 51 publications

References 34 publications

Interleukin 1-Beta (IL-1β) Production by Innate Cells Following TLR Stimulation Correlates With TB Recurrence in ART-Treated HIV-Infected Patients

Interleukin 1-Beta (IL-1β) Production by Innate Cells Following TLR Stimulation Correlates With TB Recurrence in ART-Treated HIV-Infected Patients

Cytomegalovirus infection is a risk factor for TB disease in Infants

Friends and foes of tuberculosis: modulation of protective immunity

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