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 two years of life, and 129 matched controls who remained healthy, we found the cytomegalovirus (CMV) stimulated IFN-γ response at age 4-6 months 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 positive infants who developed TB disease had lower expression of natural killer cell associated gene signatures and a lower frequency of CD3-CD4-CD8-lymphocytes. We identified transcriptional signatures predictive of risk of TB disease among CMV ELISpot positive (AUROC 0.98, accuracy 92.57%) and negative (AUROC 0.9, accuracy 79.3%) infants; the CMV negative signature validated in an independent infant study (AUROC 0.71, accuracy 63.9%). Understanding and controlling the microbial drivers of T cell activation, such as CMV, could guide new strategies for prevention of TB disease in infants.
Footnotes
The introduction and discussion now include reference to supportive data from independent studies which have 1) Shown the epidemiological overlap between CVM and tuberculosis disease and 2) Have shown that CMV responses are elevated in TB patients. 1) Cobelens, F., Nagelkerke, N. & Fletcher, H. The convergent epidemiology of tuberculosis and human cytomegalovirus infection. F1000Res 7, 280, doi:10.12688/f1000research.14184.2 (2018). 2) Stockdale, L. et al. Human cytomegalovirus epidemiology and relationship to tuberculosis and cardiovascular disease risk factors in a rural Ugandan cohort. PloS one 13, e0192086 (2018).