Müller, Julius; Tanner, Rachel; Matsumiya, Magali; Snowden, Margaret A; Landry, Bernard; Satti, Iman; Harris, Stephanie A; O'Shea, Matthew K; Stockdale, Lisa; Marsay, Leanne; +16 more... Chomka, Agnieszka; Harrington-Kandt, Rachel; Thomas, Zita-Rose Manjaly; Naranbhai, Vivek; Stylianou, Elena; Mbandi, Stanley Kimbung; Hatherill, Mark; Hussey, Gregory; Mahomed, Hassan; Tameris, Michele; McClain, J Bruce; Evans, Thomas G; Hanekom, Willem A; Scriba, Thomas J; McShane, Helen; Fletcher, Helen A; (2019) Cytomegalovirus infection is a risk factor for tuberculosis disease in infants. JCI insight, 4 (23). ISSN 2379-3708 DOI: https://doi.org/10.1172/jci.insight.130090
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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.
Item Type | Article |
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Faculty and Department | Faculty of Infectious and Tropical Diseases > Department of Infection Biology |
PubMed ID | 31697647 |
Elements ID | 141985 |
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Filename: Cytomegalovirus infection is a risk factor for tuberculosis disease in infants.pdf
Licence: Creative Commons: Attribution 3.0
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