Cytomegalovirus infection is a risk factor for tuberculosis disease in infants

JCI Insight. 2019 Dec 5;4(23):e130090. doi: 10.1172/jci.insight.130090.

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.

Trial registration: ClinicalTrials.gov NCT00953927.

Keywords: Inflammation; NK cells; Tuberculosis; Vaccines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BCG Vaccine
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Case-Control Studies
  • Cytomegalovirus
  • Cytomegalovirus Infections / complications*
  • Cytomegalovirus Infections / immunology*
  • Female
  • Humans
  • Infant
  • Inflammation
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / immunology
  • Lymphocyte Activation
  • Male
  • Mycobacterium tuberculosis
  • Risk Factors
  • South Africa
  • Transcriptome
  • Tuberculosis / complications*
  • Tuberculosis / immunology*

Substances

  • BCG Vaccine
  • Interferon-gamma

Associated data

  • ClinicalTrials.gov/NCT00953927