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Cytomegalovirus infection is a risk factor for tuberculosis disease in infants
Julius Müller, … , Helen McShane, Helen A. Fletcher
Julius Müller, … , Helen McShane, Helen A. Fletcher
Published November 7, 2019
Citation Information: JCI Insight. 2019;4(23):e130090. https://doi.org/10.1172/jci.insight.130090.
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Research Article Inflammation Vaccines

Cytomegalovirus infection is a risk factor for tuberculosis disease in infants

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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.

Authors

Julius Müller, Rachel Tanner, Magali Matsumiya, Margaret A. Snowden, Bernard Landry, Iman Satti, Stephanie A. Harris, Matthew K. O’Shea, Lisa Stockdale, Leanne Marsay, Agnieszka Chomka, Rachel Harrington-Kandt, Zita-Rose Manjaly Thomas, Vivek Naranbhai, Elena Stylianou, Stanley Kimbung Mbandi, Mark Hatherill, Gregory Hussey, Hassan Mahomed, Michele Tameris, J. Bruce McClain, Thomas G. Evans, Willem A. Hanekom, Thomas J. Scriba, Helen McShane, Helen A. Fletcher

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Figure 1

Study design for immune correlates analysis.

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Study design for immune correlates analysis.
Infants who were enrolled i...
Infants who were enrolled in an efficacy trial of the candidate TB vaccine MVA85A were included in this study (4). Infants were randomized at 16–24 weeks of age to receive a single intradermal dose of MVA85A or placebo (Candin, a candida skin test antigen) (4). Boxes indicate the number of case infant (red) or control infant (gray) samples available for combined Day 0 (D0) and D28 analysis. Analysis was restricted to infants where a frozen PBMC sample was available and live cells in PBMC were > 50% (or PHA IFN-γ ELISPOT ≥ 1000 SFC/million), as well as to infants where a sample was available for analysis from both the D0 and D28 time points. Control infants were excluded if the corresponding matched case was not in the analysis. QFT, QuantiFERON-TB Gold test; HH, household.

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