Cytomegalovirus infection is a risk factor for tuberculosis disease in infants

• DOI: 10.1172/jci.insight.130090
• Publication Date: 2019-11-07T17:00:44Z
• 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...; Zita-Rose Manjaly...; Vivek Naranbhai; Elena Stylianou; Stanley Kimbung M...; 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
• Keywords: CD4-Positive T-Lymphocytes; Inflammation; Male; Cytomegalovirus; Infant; Mycobacterium tuberculosis; CD8-Positive T-Lymphocytes; Lymphocyte Activation; 3. Good health; Killer Cells, Natural; Interferon-gamma; South Africa; 03 medical and health sciences; 0302 clinical medicine; Risk Factors; Case-Control Studies; Cytomegalovirus Infections; BCG Vaccine; Humans; Tuberculosis; Female; Transcriptome; Research Article

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.