Cytomegalovirus infection is a risk factor for tuberculosis disease in infants
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
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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Research Article Inflammation Vaccines

Cytomegalovirus infection is a risk factor for tuberculosis disease in infants

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 4

Transcriptomic correlates of risk of TB disease are different in CMV+ and CMV– infants.

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Transcriptomic correlates of risk of TB disease are different in CMV+ an...
Volcano plots showing magnitude and significance of differential expression between all case and control infants (A), CMV+ case and control infants (B), and CMV– case and control infants (C). The top 50 significant genes are labeled, and horizontal and vertical dashed lines indicate 20% FDR and 5% change in gene expression, respectively. Log2 FC color code: blue, downregulated in cases vs. controls; gray, unchanged; red, upregulated in cases vs. controls. (D) Enriched modules for differential expression in case and control infants among all, CMV+, and CMV– infants. Each row contains 1 module with the number of genes indicated. Each significantly enriched module at a P < 0.05 is shown as a pie chart. The size of the pie corresponds to the AUROC in the cerno test, and intensity of the color corresponds to the enrichment q value. The red and blue color indicates the amount of significantly up- and downregulated genes, respectively, and gray color indicates the remaining nonsignificant genes within the category. The interaction term evaluates the statistical difference between changes in CMV+ and CMV– infants. (E and F) AUROC of the classification performance of the artificial neural network model, which was trained using approximately 70% of the data, and risk of TB was predicted on the withheld 30% of the data (Supplemental Figure 3A). The process was repeated 50 times with random splits into training and test set (bootstrapping), and the AUROC was recorded for each round for CMV+ (E) and CMV– (F) infants.