Abstract
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 2 years of life, and 129 healthy matched controls, we found the cytomegalovirus-stimulated (CMV-stimulated) IFN-γ response 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+ infants who developed TB disease had lower expression of NK cell–associated gene signatures and a lower frequency of CD3–CD4–CD8– lymphocytes. We identified transcriptional signatures predictive of TB disease risk among CMV ELISpot–positive (area under the receiver operating characteristic [AUROC], 0.98, accuracy, 92.57%) and –negative (AUROC, 0.9; accuracy, 79.3%) infants; the CMV– signature was validated in an independent infant study (AUROC, 0.71; accuracy, 63.9%). A 16-gene signature that previously identified adolescents at risk of developing TB disease did not accurately classify case and control infants in this study. Understanding the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.
Highlights
There are an estimated 1 million cases of childhood tuberculosis (TB) each year and in 2015, 210,000 children died of TB [1]
Using samples collected from 4- to 6-month-old infants at enrollment into the Modified Vaccinia Virus Ankara expressing Antigen 85A (MVA85A) efficacy trial in the Western Cape Province of South Africa [4], we reported that CD4+ T cell activation was associated with increased risk of TB disease over the following 3 years of life [6]
Activated CD8+ T cells are associated with TB disease risk and correlate with CMV-specific IFN-γ response
Summary
There are an estimated 1 million cases of childhood tuberculosis (TB) each year and in 2015, 210,000 children died of TB [1]. Using samples collected from 4- to 6-month-old infants at enrollment into the MVA85A efficacy trial in the Western Cape Province of South Africa [4], we reported that CD4+ T cell activation (measured as HLA-DR expression) was associated with increased risk of TB disease over the following 3 years of life [6]. This finding was validated in an independent cohort of Mycobacterium tuberculosis– infected (M.tb–infected) adolescents [6]. Recognition that T cell activation is a feature of HIV immunopathogenesis is guiding the development of new interventions for the management of HIV, such as the use of statins or Maraviroc as an adjunct to antiretroviral therapy (ART) or switching ART regimens [16,17,18]
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