Host Gene Expression Kinetics During Treatment of Tuberculosis in HIV-Coinfected Individuals Is Independent of Highly Active Antiretroviral Therapy

Gebremicael, Gebremedhin; Kassa, Desta; Quinten, Edwin; Alemayehu, Yodit; Gebreegziaxier, Atsbeha; Belay, Yohannes; Baarle, Debbie van; Ottenhoff, Tom H. M.; Cliff, Jacqueline M.; Haks, Mariëlle C.

doi:10.1093/infdis/jiy404

Cited by 15 publications

(21 citation statements)

References 32 publications

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“…This is the first multi-site, prospective study analyzing unstimulated whole blood-derived RNA expression profiles of four endemic populations using dcRT-MLPA, a focused gene expression profiling platform for monitoring gene expression in large cohorts 29,34 . We showed that host RNA expression levels discriminate various stages of disease thereby offering potential for leprosy diagnostics.…”

Section: Discussionmentioning

confidence: 99%

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Whole blood RNA signatures in leprosy patients identify reversal reactions before clinical onset: a prospective, multicenter study

Tió-Coma

Hooij

Bobosha

et al. 2019

Sci Rep

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Early diagnosis of leprosy is challenging, particularly its inflammatory reactions, the major cause of irreversible neuropathy in leprosy. Current diagnostics cannot identify which patients are at risk of developing reactions. This study assessed blood RNA expression levels as potential biomarkers for leprosy. Prospective cohorts of newly diagnosed leprosy patients, including reactions, and healthy controls were recruited in Bangladesh, Brazil, Ethiopia and Nepal. RNA expression in 1,090 whole blood samples was determined for 103 target genes for innate and adaptive immune profiling by dual color Reverse-Transcription Multiplex Ligation-dependent Probe Amplification (dcRT-MLPA) followed by cluster analysis. We identified transcriptomic biomarkers associated with leprosy disease, different leprosy phenotypes as well as high exposure to Mycobacterium leprae which respectively allow improved diagnosis and classification of leprosy patients and detection of infection. Importantly, a transcriptomic signature of risk for reversal reactions consisting of five genes (CCL2, CD8A, IL2, IL15 and MARCO) was identified based on cross-sectional comparison of RNA expression. In addition, intra-individual longitudinal analyses of leprosy patients before, during and after treatment of reversal reactions, indicated that several IFN-induced genes increased significantly at onset of reaction whereas IL15 decreased. This multi-site study, situated in four leprosy endemic areas, demonstrates the potential of host transcriptomic biomarkers as correlates of risk for leprosy. Importantly, a prospective five-gene signature for reversal reactions could predict reversal reactions at least 2 weeks before onset. Thus, transcriptomic biomarkers provide promise for early detection of these acute inflammatory episodes and thereby help prevent permanent neuropathy and disability in leprosy patients.

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Section: Discussionmentioning

confidence: 99%

“…Techniques such as RNA-Seq and microarray are costly, technically challenging and require high RNA concentrations which limits their application for large cohorts. Therefore, a selection of genes related to immune-mediated inflammatory pathways, which play a role in the immunopathology of leprosy can be assessed by dcRT-MLPA 29,34 .…”

Section: Introductionmentioning

confidence: 99%

Whole blood RNA signatures in leprosy patients identify reversal reactions before clinical onset: a prospective, multicenter study

Tió-Coma

Hooij

Bobosha

et al. 2019

Sci Rep

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“…Considering the importance of IFN-γ-producer cells in typical TB granuloma formation, we therefore hypothesize that individuals with a defective NLRC4/IL18 axis are not able to effectively contain mycobacteria within granulomas, leading to eventual extra-pulmonary dissemination. Accordingly, at least in HIV-infected patients, the expression of NLRC4 significantly increased in the blood of individuals with a more severe form of TB (41). Moreover, it is interesting to remember that lossof-function SNVs in NLRC4 have been found in HIV patents with severe TB (36) and in patients with cystic fibrosis affected by severe lung infections (42), reinforcing the important and poorly investigated role of NLRC4 in lung immunity and pulmonary diseases.…”

Section: Discussionmentioning

confidence: 94%

Combining Host Genetics and Functional Analysis to Depict Inflammasome Contribution in Tuberculosis Susceptibility and Outcome in Endemic Areas

et al. 2020

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The interplay between M. tuberculosis (Mtb) and humans is multifactorial. The susceptibility/resistance profile and the establishment of clinical tuberculosis (TB) still remains elusive. The gain-of-function variant rs10754558 in the NLRP3 gene (found in 30% of the world population) confers protection against the development of TB, indicating a prominent role played by NLRP3 inflammasome against Mtb. Through genotype-guided assays and various Mtb strains (BCG, H37Rv, Beijing-1471, MP287/03), we demonstrate that Mtb strains activate inflammasome according to the NLRP3/IL-1ß or NLRC4/IL18 preferential axis. NLRP3 and NLRC4 genetic variants contribute to the presentation of TB. For the first time, we have shown that loss-of-function variants in NLRC4 significantly contribute to the development of extra-pulmonary TB. The analysis of inflammasome activation in a cohort of TB patients and their "household contacts" (CNT) revealed that plasma IL-1ß/IFN-α ratio lets us distinguish patients from Mtb-exposed-but-healthy individuals from an endemic region. Moreover, NLRP3 inflammasome seemed "exhausted" in TB patients compared to CNT, indicating a more efficient activation of inflammasome in resistant individuals. These findings suggest that inflammasome genetics as well as virulence-dependent level of inflammasome activation contribute to the onset of a susceptible/resistant profile among Mtb-exposed individuals.

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“…In addition, a recently described 7gene signature differentiated active TB from latent TB in subjects with concurrent HIV infection, regardless of HIV treatment status. 88 Importantly, these signatures are generalizable across diverse populations; one classifier that distinguished active TB from pneumonia had an AUC of 0.96 in an American cohort and 0.91 in a Sub-Saharan African cohort. 89 Given the widespread global disease burden of TB, the generalizability of these signatures is vital.…”

Section: Tuberculosismentioning

confidence: 99%

Host-Based Diagnostics for Acute Respiratory Infections

Ross

Zick²,

Tsalik

2019

Clinical Therapeutics

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Purpose: The inappropriate use of antimicrobials, especially in acute respiratory infections (ARIs), is largely driven by difficulty distinguishing bacterial, viral, and noninfectious etiologies of illness. A new frontier in infectious disease diagnostics looks to the host response for disease classification. This article examines how host responseebased diagnostics for ARIs are being used in clinical practice, as well as new developments in the research pipeline. Methods: A limited search was conducted of the relevant literature, with emphasis placed on literature published in the last 5 years (2014e2019). Findings: Advances are being made in all areas of host responseebased diagnostics for ARIs. Specifically, there has been significant progress made in single protein biomarkers, as well as in various "omics" fields (including proteomics, metabolomics, and transcriptomics) and wearable technologies. There are many potential applications of a host responseebased approach; a few key examples include the ability to discriminate bacterial and viral disease, presymptomatic diagnosis of infection, and pathogen-specific host response diagnostics, including modeling disease progression. Implications: As biomarker measurement technologies continue to improve, host responseebased diagnostics will increasingly be translated to clinically available platforms that can generate a holistic characterization of an individual's health. This knowledge, in the hands of both patient and provider, can improve care for the individual patient and help fight rising rates of antibiotic resistance. (Clin Ther.

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Host Gene Expression Kinetics During Treatment of Tuberculosis in HIV-Coinfected Individuals Is Independent of Highly Active Antiretroviral Therapy

Abstract: Blood transcriptomic profiles can potentially be used as biomarkers to discriminate the different clinical stages of tuberculosis in HIV-coinfected individuals and to monitor tuberculosis treatment responses in both HAART recipients and untreated individuals.

Cited by 15 publications

References 32 publications

Whole blood RNA signatures in leprosy patients identify reversal reactions before clinical onset: a prospective, multicenter study

Whole blood RNA signatures in leprosy patients identify reversal reactions before clinical onset: a prospective, multicenter study

Combining Host Genetics and Functional Analysis to Depict Inflammasome Contribution in Tuberculosis Susceptibility and Outcome in Endemic Areas

Host-Based Diagnostics for Acute Respiratory Infections

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