Africa-wide evaluation of host biomarkers in QuantiFERON supernatants for the diagnosis of pulmonary tuberculosis.

We investigated host-derived biomarkers that were previously identified in QuantiFERON supernatants, in a large pan-African study. We recruited individuals presenting with symptoms of pulmonary TB at seven peripheral healthcare facilities in six African countries, prior to assessment for TB disease. We then evaluated the concentrations of 12 biomarkers in stored QuantiFERON supernatants using the Luminex platform. Based on laboratory, clinical and radiological findings and a pre-established algorithm, participants were classified as TB disease or other respiratory diseases(ORD). Of the 514 individuals included in the study, 179(34.8%) had TB disease, 274(51.5%) had ORD and 61(11.5%) had an uncertain diagnosis. A biosignature comprising unstimulated IFN-γ, MIP-1ß, TGF-α and antigen-specific levels of TGF-α and VEGF, identified on a training sample set (n = 311), validated by diagnosing TB disease in the test set (n = 134) with an AUC of 0.81(95% CI, 0.76-0.86), corresponding to a sensitivity of 64.2%(95% CI, 49.7-76.5%) and specificity of 82.7%(95% CI, 72.4-89.9%). Host biomarkers detected in QuantiFERON supernatants can contribute to the diagnosis of active TB disease amongst people presenting with symptoms requiring investigation for TB disease, regardless of HIV status or ethnicity in Africa.

Epigenetics and Proteomics Join Transcriptomics in the Quest for Tuberculosis Biomarkers.

UNLABELLED: An estimated one-third of the world's population is currently latently infected with Mycobacterium tuberculosis. Latent M. tuberculosis infection (LTBI) progresses into active tuberculosis (TB) disease in ~5 to 10% of infected individuals. Diagnostic and prognostic biomarkers to monitor disease progression are urgently needed to ensure better care for TB patients and to decrease the spread of TB. Biomarker development is primarily based on transcriptomics. Our understanding of biology combined with evolving technical advances in high-throughput techniques led us to investigate the possibility of additional platforms (epigenetics and proteomics) in the quest to (i) understand the biology of the TB host response and (ii) search for multiplatform biosignatures in TB. We engaged in a pilot study to interrogate the DNA methylome, transcriptome, and proteome in selected monocytes and granulocytes from TB patients and healthy LTBI participants. Our study provides first insights into the levels and sources of diversity in the epigenome and proteome among TB patients and LTBI controls, despite limitations due to small sample size. Functionally the differences between the infection phenotypes (LTBI versus active TB) observed in the different platforms were congruent, thereby suggesting regulation of function not only at the transcriptional level but also by DNA methylation and microRNA. Thus, our data argue for the development of a large-scale study of the DNA methylome, with particular attention to study design in accounting for variation based on gender, age, and cell type. IMPORTANCE: DNA methylation modifies the transcriptional program of cells. We have focused on two major populations of leukocytes involved in immune response to infectious diseases, granulocytes and monocytes, both of which are professional phagocytes that engulf and kill bacteria. We have interrogated how DNA methylation, gene expression, and protein translation differ in these two cell populations between healthy individuals and patients suffering from TB. To better understand the underlying biologic mechanisms, we harnessed a statistical enrichment analysis, taking advantage of predefined and well-characterized gene sets. Not only were there clear differences on various levels between the two populations, but there were also differences between TB patients and healthy controls in the transcriptome, proteome, and, for the first time, DNA methylome in these cells. Our pilot study emphasizes the value of a large-scale study of the DNA methylome taking into account our findings.

Diagnostic biomarkers are hidden in the infected host's epigenome.

The success of our immune system depends on its ability to react efficiently, which in turn is supported by a large degree of plasticity as well as memory. Some aspects of this plasticity and memory are now known to be under epigenetic control - determined both by default, during differentiation, and by responses to environmental factors, including infectious agents. Thus, epigenetic marks in the immune system can occur as predetermined or as responsive marks and as such can potentially serve as diagnostic markers for disease susceptibility and disease progression or treatment response. Here, the authors review some examples of epigenetic control and epigenetic marks during the differentiation process of the immune system and memory formation, followed by some examples of epigenetic marks in the immune system subsequent to infection. These are used to illustrate the potential use of epigenetic marks as diagnostic markers in adverse immune system conditions and treatment thereof.

Can the battle against tuberculosis gain from epigenetic research?

A healthy immune system needs to be highly plastic to cope with host defense and surveillance. What mechanisms provide this plasticity? Considering the threat of infectious diseases to a large part of the world's population, can these mechanisms possibly be of use in the ongoing battle against infectious diseases? Against the backdrop of the pandemic nature of tuberculosis, we discuss whether and how epigenetic mechanisms can shed light on our understanding of infectious disease, and if epigenetic marks can be employed to monitor latent infection, disease reactivation or treatment response.