Stratification of Latent Mycobacterium tuberculosis Infection by Cellular Immune Profiling

Halliday, Alice; Whitworth, Hilary; Kottoor, Sherine Hermangild; Niazi, Umar; Menzies, Sarah; Kunst, Heinke; Bremang, Samuel; Badhan, Amarjit; Beverley, Peter C. L.; Kon, Onn Min; Lalvani, Ajit

doi:10.1093/infdis/jix107

Cited by 40 publications

(45 citation statements)

References 22 publications

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“…Indeed, our estimated cell type and pathway analyses suggest that both cellular and molecular signatures of immune activation associated with recent exposure and could be interrogated by other modalities such as epigenetics. Immune cell differences between recently acquired and remotely acquired infection have been reported by others in single cohorts without longitudinal sampling (20,48). The high enrichment of B cell signaling in our signature is interesting, and a recent case control study in a single cohort showed that several IgG and IgA antibodies to M.tb antigens strongly discriminated (AUC > 0.90) active TB contacts who converted on TST from non-converters both at first known conversion and 3 months prior (49).…”

Section: Discussionsupporting

confidence: 67%

“…Given that time since active TB exposure is the single strongest clinical risk factor for developing TB disease in immunocompetent persons, the finding that time since exposure and risk of TB, as predicted by the blood transcriptomic response, are independent in the GC6-74 study of healthy household contacts suggests that these signatures could be combined to possibly better predict risk of TB when the time of exposure is unknown (17,19,20). While the GC6-74 study was not powered for this particular secondary analysis, we assessed whether the highest 6gene score during longitudinal sampling allowed discrimination of subjects who did or did not progress to active TB disease during study follow-up.…”

Section: Application Of Reduced 6-gene Expression Signature Of Time Smentioning

confidence: 99%

“…Recent infection is the single strongest clinical risk factor for developing active TB disease in immunocompetent persons, who comprise the vast majority of LTBI and active TB cases (14)(15)(16)(17)(18)(19). However, time since exposure or infection is very difficult to ascertain in the clinical setting, and its estimate is often unreliable (20). Moreover, there are no known validated biomarkers of recent exposure or infection beyond conversion on a tuberculin skin test (TST) or IFN- release assay (IGRA), which requires longitudinal sampling.…”

Section: Introductionmentioning

confidence: 99%

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Blood RNA Signatures Predict Recent Tuberculosis Exposure in Mice, Macaques and Humans

Ault

Headley

Hare

et al. 2019

Preprint

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Tuberculosis (TB) is the leading cause of death due to a single infectious disease.Knowing when a person was infected with Mycobacterium tuberculosis (M.tb) is critical as recent infection is the strongest clinical risk factor for progression to TB disease in immunocompetent individuals. However, time since M.tb infection is challenging to determine in routine clinical practice. To define a biomarker for recent TB exposure, we determined whether gene expression patterns in blood RNA correlated with time since M.tb infection or exposure.First, we found RNA signatures that accurately discriminated early and late time periods after experimental infection in mice and cynomolgus macaques. Next, we found a 6-gene blood RNA signature that identified recently exposed individuals in two independent human cohorts, including adult household contacts of TB cases and adolescents who recently acquired M.tb infection. Our work supports the need for future longitudinal studies of recent TB contacts to determine whether biomarkers of recent infection can provide prognostic information of TB disease risk in individuals and help map recent transmission in communities.

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Section: Discussionsupporting

confidence: 67%

Section: Application Of Reduced 6-gene Expression Signature Of Time Smentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Blood RNA Signatures Predict Recent Tuberculosis Exposure in Mice, Macaques and Humans

Ault

Headley

Hare

et al. 2019

Preprint

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“…In a recent report from the UK, the presence of TNF‐α‐only T effector cells was found to distinguish between individuals believed to have acquired TB either recently or remotely, as determined by epidemiologic and clinical data . While this study was relatively small, with only 59 total participants enrolled, and was conducted in a low‐burden setting, the prospect of a cellular immune signature capable of reliably identifying recent infection is exciting and warrants further study in other cohorts and high‐burden settings.…”

Section: Tools To Study Tb Transmissionmentioning

confidence: 89%

Where is tuberculosis transmission happening? Insights from the literature, new tools to study transmission and implications for the elimination of tuberculosis

et al. 2018

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More than 10 million new cases of tuberculosis (TB) are diagnosed worldwide each year. The majority of these cases occur in low- and middle-income countries where the TB epidemic is predominantly driven by transmission. Efforts to 'end TB' will depend upon our ability to halt ongoing transmission. However, recent studies of new approaches to interrupt transmission have demonstrated inconsistent effects on reducing population-level TB incidence. TB transmission occurs across a wide range of settings, that include households and hospitals, but also community-based settings. While home-based contact investigations and infection control programmes in hospitals and clinics have a successful track record as TB control activities, there is a gap in our knowledge of where, and between whom, community-based transmission of TB occurs. Novel tools, including molecular epidemiology, geospatial analyses and ventilation studies, provide hope for improving our understanding of transmission in countries where the burden of TB is greatest. By integrating these diverse and innovative tools, we can enhance our ability to identify transmission events by documenting the opportunity for transmission-through either an epidemiologic or geospatial connection-alongside genomic evidence for transmission, based upon genetically similar TB strains. A greater understanding of locations and patterns of transmission will translate into meaningful improvements in our current TB control activities by informing targeted, evidence-based public health interventions.

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“…However, real-time, definitive diagnosis of recent exposure to Mtb at the individual level is not possible with any of the currently available tests (eg, TST, IGRA, chest X-ray, sputum analysis). Yet there are several recent reports of promising new approaches to identifying recent exposure, including a T-cell immune signature capable of differentiating recent from remote tuberculosis infection and a blood transcriptomic signature associated with greater risk of progression to active tuberculosis disease [ 41 , 42 ]. Although these signatures need to be validated in other settings, this type of biomarker of recent exposure would enable precisely targeted preventive therapy (akin to ring prophylaxis) and accelerate identification of tuberculosis “hotspots”—areas of high tuberculosis incidence—for earlier and more effective implementation of infection control measures [ 43 ].…”

Section: Current Transmission Research Needsmentioning

confidence: 99%

Research Roadmap for Tuberculosis Transmission Science: Where Do We Go From Here and How Will We Know When We’re There?

Auld

Kasmar

Dowdy

et al. 2017

The Journal of Infectious Diseases

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High rates of tuberculosis transmission are driving the ongoing global tuberculosis epidemic, and there is a pressing need for research focused on understanding and, ultimately, halting transmission. The ongoing tuberculosis–human immunodeficiency virus (HIV) coepidemic and rising rates of drug-resistant tuberculosis in parts of the world add further urgency to this work. Success in this research will require a concerted, multidisciplinary effort on the part of tuberculosis scientists, clinicians, programs, and funders and must span the research spectrum from biomedical sciences to the social sciences, public health, epidemiology, cost-effectiveness analyses, and operations research. Heterogeneity of tuberculosis disease, both among individual patients and among communities, poses a substantial challenge to efforts to interrupt transmission. As such, it is likely that effective interventions to stop transmission will require a combination of approaches that will vary across different epidemiologic settings. This research roadmap summarizes key gaps in our current understanding of transmission, as laid out in the preceding articles in this series. We also hope that it will be a call to action for the global tuberculosis community to make a sustained commitment to tuberculosis transmission science. Halting transmission today is an essential step on the path to end tuberculosis tomorrow.

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Stratification of Latent Mycobacterium tuberculosis Infection by Cellular Immune Profiling

Cited by 40 publications

References 22 publications

Blood RNA Signatures Predict Recent Tuberculosis Exposure in Mice, Macaques and Humans

Blood RNA Signatures Predict Recent Tuberculosis Exposure in Mice, Macaques and Humans

Where is tuberculosis transmission happening? Insights from the literature, new tools to study transmission and implications for the elimination of tuberculosis

Research Roadmap for Tuberculosis Transmission Science: Where Do We Go From Here and How Will We Know When We’re There?

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