Dynamic changes of interferon gamma release assay results with latent tuberculosis infection treatment

Xin, Henan; Cao, Xuefang; Zhang, H.; Liu, J.; Pan, Shouguo; Li, X.; Guan, Ling; Shen, Fei; Liu, Z.; Wang, D.; Guan, Xueling; Yan, Jiaoxia; Li, H.; Feng, Boxuan; Zhang, Meng; Yang, Qianting; Jin, Qi; Gao, Lei

doi:10.1016/j.cmi.2020.02.009

Cited by 10 publications

(17 citation statements)

References 24 publications

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“…It is therefore possible that these CoRs were detecting ISGs provoked by stimuli other than Mtb infection. The Mtb -specific cellular responses that define LTBI are well-known to persist despite LTBI treatment or spontaneous clearance of Mtb infection [ 40 , 41 ], and therefore persons identified as LTBI in this study may not have had differential ISG or other gene expression measured concurrently in that sample or at the time of HIV exposure.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis infection, immune activation, and risk of HIV acquisition

et al. 2022

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Background Although immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses to M. tuberculosis (Mtb) infection, are not well characterized. Methods We conducted a nested case-control study using cryopreserved samples from persons who did and did not acquire HIV during the multinational Step clinical trial of the MRKAd5 HIV-1 vaccine. PBMCs from the last HIV-negative sample from incident HIV cases and controls were stimulated with Mtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining and scored with COMPASS. We measured inflammatory profiles with five Correlates of TB Risk (CoR) transcriptomic signatures. Our primary analysis examined the association of latent Mtb infection (LTBI; IFNγ+CD4+ T cell frequency) or RISK6 CoR signature with HIV acquisition. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether TB-associated immune markers were associated with HIV acquisition. Results Among 465 participants, LTBI prevalence (21.5% controls vs 19.1% cases, p = 0.51) and the RISK6 signature were not higher in those who acquired HIV. In exploratory analyses, Mtb antigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.78 (0.61, 0.98)), were associated with HIV acquisition. The transcriptomic pattern used to differentiate active vs latent TB (Sweeney3) was most strongly associated with acquiring HIV. Conclusions LTBI, Mtb polyfunctional antigen-specific CD4+ T cell activation, and RISK6 were not identified as risks for HIV acquisition. In exploratory transcriptomic analyses, two CoR signatures were associated with HIV risk after adjustment for known behavioral and clinical risk factors. We identified host gene expression signatures associated with HIV acquisition, but the observed effects are likely not mediated through Mtb infection.

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Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis infection, immune activation, and risk of HIV acquisition

et al. 2022

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“…Because LTBI was not independently associated with any of the 5 CoRs in this cohort, especially RISK6, Suliman4, or Maetzdorf4, it is likely that there was little incipient TB in the Step study, and so these CoRs were detecting ISGs provoked by stimuli other than Mtb infection. The Mtb -specific cellular responses that define LTBI are well-known to persist despite LTBI treatment or spontaneous clearance of Mtb infection[41, 42], and therefore persons with LTBI may not been expressing differential ISG or other gene transcription.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosisinfection, immune activation, and risk of HIV acquisition

Ignacio

Long

Saha

et al. 2021

Preprint

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BackgroundAlthough immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses to M. tuberculosis (Mtb) infection, are not well characterized.MethodsWe conducted a nested case-control study within the Step MRKAd5 HIV-1 vaccine study. PBMCs from the last HIV-negative sample from incident HIV cases and controls who did not acquire HIV were stimulated with Mtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining.Combinatorial polyfunctionality analysis of antigen-specific T-cell subsets (COMPASS) determined overall Mtb-antigen-specific T cell activation. We measured inflammatory profiles with five Correlates of TB Risk (CoR) peripheral blood transcriptomic signatures. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether either cellular markers of TB-associated immune activation or transcriptomic predictors of TB disease states were associated with HIV acquisition.ResultsAmong 465 participants, latent Mtb infection (LTBI) prevalence (21.5% controls vs 19.1% cases, p=0.51) and Mtb antigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.76 (0.60, 0.95)), were associated with HIV acquisition in multivariable analysis. The Sweeney3 signature best predicted odds of acquiring HIV in unadjusted and adjusted analyses, including when restricted to LTBI-negative participants.ConclusionsLTBI and Mtb polyfunctional antigen-specific CD4+ T cell immune activation were not identified as risk factors for HIV acquisition, but transcriptomic analyses demonstrated that two CoR signatures predicted HIV risk after adjustment for known behavioral and clinical risk factors. CoR signatures can demonstrate host gene expression associated with HIV acquisition, but the observed effects are likely not mediated through Mtb infection.

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“…Some relevant proteins might be excluded. Third, IGRAs are immunological tests to identify infections, but the testing results using a single cut-off value are unstable due to the influence of the host immune level (Xin et al, 2019(Xin et al, , 2020. Although we used a more strict definition of QFT reversion to evaluate the effect of preventive treatment, misclassification of infection status could not be comprehensively excluded.…”

Section: Figure 3 |mentioning

confidence: 99%

“…IGRA was frequently studied to monitor the treatment efficacy of active TB (Carrara et al, 2004;Lee et al, 2010;Chiappini et al, 2012). Our previous study found QuantiFERON-TB Gold In-Tube (QFT) reversion also occurred in the untreated group, however, it was indeed related to a low risk of TB development as compared with QFT persistent positives (Xin et al, 2020). Additionally, although some studies have been engaged in exploring the potential biomarkers for reflecting LTBI treatment efficacy, very few have been well-validated and further used in practice.…”

Section: Introductionmentioning

confidence: 99%

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

Xin

Cao

et al. 2022

Front. Microbiol.

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BackgroundIdentifying host plasma exosome proteins associated with host response to latent tuberculosis infection (LTBI) treatment might promote our understanding of tuberculosis (TB) pathogenesis and provide useful tools for implementing the precise intervention.MethodsBased on an open-label randomized controlled trial (RCT) aiming to evaluate the short-course regimens for LTBI treatment, plasma exosomes from pre- and post-LTBI treatment were retrospectively detected by label-free quantitative protein mass spectrometry and validated by a parallel reaction monitoring method for participants with changed or not changed infection testing results after LTBI treatment. Eligible participants for both screening and verification sets were randomly selected from the based-RCT in a 1:1 ratio by age and gender. Reversion was defined as a decrease in IFN-γ levels from >0.70 IU/ml prior to treatment to 0.20 IU/ml within 1 week of treatment. The predictive ability of the candidate proteins was evaluated by receiver operating characteristic (ROC) analysis.ResultsTotally, two sample sets for screening (n = 40) and validation (n = 60) were included. Each of them included an equal number of subjects with persistent positive or reversed QuantiFERON-TB Gold In-Tube (QFT) results after LTBI. A total of 2,321 exosome proteins were detected and 102 differentially expressed proteins were identified to be associated with QFT reversion. Proteins with high confidence and original values intact were selected to be further verified. Totally, 9 downregulated proteins met the criteria and were validated. After verification, C4BPA and S100A9 were confirmed to be still significantly downregulated (fold change <0.67, p < 0.05). The respective areas under the ROC curve were 0.73 (95% CI: 0.57–0.89) and 0.69 (95% CI: 0.52–0.86) for C4BPA and S100A9, with a combined value of 0.78 (95% CI: 0.63–0.93). The positive and negative predictive values for combined markers were 70.10% (95% CI: 50.22–86.30%) and 55.63% (95% CI: 29.17–61.00%).ConclusionOur findings suggest that downregulated C4BPA and S100A9 in plasma exosomes might be associated with a host positive response to LTBI treatment. Further studies are warranted to verify the findings and potential underlying mechanisms in varied populations with a larger sample size.

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Dynamic changes of interferon gamma release assay results with latent tuberculosis infection treatment

Cited by 10 publications

References 24 publications

Mycobacterium tuberculosis infection, immune activation, and risk of HIV acquisition

Mycobacterium tuberculosis infection, immune activation, and risk of HIV acquisition

Mycobacterium tuberculosisinfection, immune activation, and risk of HIV acquisition

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

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