Genetic and Shared Environmental Influences on Interferon-γ Production in Response to Mycobacterium tuberculosis Antigens in a Ugandan Population

Tao, Liyuan; Zalwango, Sarah; Chervenak, Keith; Thiel, Bonnie; Malone, LaShaunda L.; Qiu, Feiyou; Mayanja‐Kizza, Harriet; Boom, W. Henry; Stein, Catherine M.

doi:10.4269/ajtmh.12-0670

Cited by 22 publications

(12 citation statements)

References 24 publications

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“…Nevertheless, despite lack of TST conversion, cytokine levels, particularly IP10, follwoing EC stimulation were higher than those of TSTCECS − , further supporting the importance of host factors in Mtb immune responses [38] . Studies in The Gambia and Uganda have shown that acquired immune responses to secreted Mtb antigens such as ESAT–6 and Ag85 but also the DTH response to PPD are influenced by genetic variance [39] , [40] and this should also be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

Broad Adaptive Immune Responses to M. tuberculosis Antigens Precede TST Conversion in Tuberculosis Exposed Household Contacts in a TB-Endemic Setting

et al. 2014

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BackgroundThe identification of Mycobacterium-tuberculosis (Mtb) infected individuals remains a challenge due to an insufficient understanding of immune responses detected with the current diagnostic tests for latent tuberculosis i.e. the tuberculin skin test (TST) or IFN–γ release assays (IGRAs) and an inability to distinguish infection stages with current immunologic assays. Further classification based on markers other than IFN–γ may help to define markers of early Mtb infection.MethodsWe assessed the TST status of Mtb-exposed household contacts at baseline and at 6 months. Contacts were classified into those with initial positive TST (TST+); those with baseline negative TST but TST conversion at 6 months (TST converters, TSTC) and those with persistently negative TST (PTST−). We assessed their short- and long-term immune responses to PPD and ESAT–6/CFP–10 (EC) via IFN–γ ELISPOT and a multiplex cytokine array in relation to TST status and compared them to those of TB cases to identify immune profiles associated with a spectrum of infection stages.ResultsAfter 1 and 6 days stimulation with EC, 12 cytokines (IFN–γ, IL–2, IP–10, TNF–α, IL–13, IL–17, IL–10, GMCSF, MIP–1β, MCP–3, IL–2RA and IL–1A) were not different in TSTC compared to TST+ suggesting that robust adaptive Mtb-specific immune responses precede TST conversion. Stratifying contacts by baseline IFN–γ ELISPOT to EC in combination with TST results revealed that IP–10 and IL–17 were highest in the group of TST converters with positive baseline ELISPOT, suggesting they might be markers for recent infection.ConclusionWe describe a detailed analysis of Mtb-specific biomarker profiles in exposed household contacts in a TB endemic area that provides insights into the dynamic immune responses to Mtb infection and may help to identify biomarkers for ‘at-risk’ populations beyond TST and IGRA.

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Section: Discussionmentioning

confidence: 99%

Broad Adaptive Immune Responses to M. tuberculosis Antigens Precede TST Conversion in Tuberculosis Exposed Household Contacts in a TB-Endemic Setting

et al. 2014

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“…Evaluation for new candidate genes for TB can be done through conduct of association studies such as case–control, family based, and/or case–parent studies. Heritability to TB can be determined using standard quantitative genetic approaches which can be based on host immune responses as intermediate phenotypes (Stein et al, 2005; Tao et al, 2013). Studies of HHCs have demonstrated that young children are at greater risk for developing TB and the clustering of cases within families does give hint at a familial susceptibility (Brailey, 1940; Puffer et al, 1952).…”

Section: Overview Of the Household Contact Study Designmentioning

confidence: 99%

The household contact study design for genetic epidemiological studies of infectious diseases

Stein¹,

Hall²,

Malone³

et al. 2013

Front. Genet.

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Most genetic epidemiological study designs fall into one of two categories: family based and population-based (case–control). However, recent advances in statistical genetics call for study designs that combine these two approaches. We describe the household contact study design as we have applied it in our several years of study of the epidemiology of tuberculosis. Though we highlight its applicability for genetic epidemiological studies of infectious diseases, there are many facets of this design that are appealing for modern genetic studies, including the simultaneous enrollment of related and unrelated individuals, closely and distantly related individuals, collection of extensive epidemiologic and phenotypic data, and evaluation of effects of shared environment and gene by environment interaction. These study design characteristics are particularly appealing for current sequencing studies.

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“…In addition, the presence of immune-related genetic variants likely affects test results of immune responses as indicators of M.tb infection. A report of the influence of genetic variance and shared environment on the production of IFNγ is an example in this context (Tao et al, 2013).…”

Section: Immune Diversity and The Challenge Of Global Tb Diagnostics mentioning

confidence: 99%

Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines

Azad

Lloyd

Sadée

et al. 2020

Front. Cell. Infect. Microbiol.

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Universal approaches to the prevention and treatment of human diseases fail to take into account profound immune diversity resulting from genetic variations across populations. Personalized or precision medicine takes into account individual lifestyle, environment, and biology (genetics and immune status) and is being adopted in several disease intervention strategies such as cancer and heart disease. However, its application in infectious diseases, particularly global diseases such as tuberculosis (TB), is far more complex and in a state of infancy. Here, we discuss the impact of human genetic variations on immune responses and how they relate to failures seen in current TB diagnostic, therapy, and vaccine approaches across populations. We offer our perspective on the challenges and potential for more refined approaches going forward.

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Genetic and Shared Environmental Influences on Interferon-γ Production in Response to Mycobacterium tuberculosis Antigens in a Ugandan Population

Cited by 22 publications

References 24 publications

Broad Adaptive Immune Responses to M. tuberculosis Antigens Precede TST Conversion in Tuberculosis Exposed Household Contacts in a TB-Endemic Setting

Broad Adaptive Immune Responses to M. tuberculosis Antigens Precede TST Conversion in Tuberculosis Exposed Household Contacts in a TB-Endemic Setting

The household contact study design for genetic epidemiological studies of infectious diseases

Challenges of Immune Response Diversity in the Human Population Concerning New Tuberculosis Diagnostics, Therapies, and Vaccines

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