The Troika Host–Pathogen–Extrinsic Factors in Tuberculosis: Modulating Inflammation and Clinical Outcomes

Bastos, Hélder Novais; Osório, Nuno S.; Gagneux, Sébastien; Comas, Iñaki; Saraiva, Margarida

doi:10.3389/fimmu.2017.01948

Cited by 20 publications

(28 citation statements)

References 155 publications

(145 reference statements)

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“…A total of 3112 unique polymorphisms (SNPs and InDels) were found in comparison with the inferred sequence of the MTBC ancestor 5 . The maximum pairwise distance between any two clinical isolates was 456 mutations, as expected for M. tuberculosis strains from the same lineage 9 . Five possible transmission clusters were identified ( Supplementary Fig.…”

supporting

confidence: 63%

“…The human adapted tuberculosis (TB)-causing bacteria are part of the Mycobacterium tuberculosis complex (MTBC), and can be divided into seven distinct lineages that exhibit a strong phylogeographical structure 6 . Despite harboring little DNA sequence variation as compared to other bacteria 8 , strains of the MTBC differ in their capacity to modulate the immune response 9 . Pathogen diversity within the MTBC also impacts the clinical manifestation of TB 7,9 .…”

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confidence: 99%

“…Despite harboring little DNA sequence variation as compared to other bacteria 8 , strains of the MTBC differ in their capacity to modulate the immune response 9 . Pathogen diversity within the MTBC also impacts the clinical manifestation of TB 7,9 . What remains unknown, however, is the interaction between pathogen-induced immune-modulation and disease severity.…”

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confidence: 99%

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Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production

et al. 2020

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Genetic diversity of Mycobacterium tuberculosis affects immune responses and clinical outcomes of tuberculosis (TB). However, how bacterial diversity orchestrates immune responses to direct distinct TB severities is unknown. Here we study 681 patients with pulmonary TB and show that M. tuberculosis isolates from cases with mild disease consistently induce robust cytokine responses in macrophages across multiple donors. By contrast, bacteria from patients with severe TB do not do so. Secretion of IL-1β is a good surrogate of the differences observed, and thus to classify strains as probable drivers of different TB severities. Furthermore, we demonstrate that M. tuberculosis isolates that induce low levels of IL-1β production can evade macrophage cytosolic surveillance systems, including cGAS and the inflammasome. Isolates exhibiting this evasion strategy carry candidate mutations, generating sigA recognition boxes or affecting components of the ESX-1 secretion system. Therefore, we provide evidence that M. tuberculosis strains manipulate host-pathogen interactions to drive variable TB severities.

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confidence: 63%

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confidence: 99%

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Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production

et al. 2020

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“…Since different bacterial lineages display different rates of mixed samples (Fig. 4), as well as different biological behaviours, 24 we conducted separate analyses for the most common lineage circulating in the UK, lineage-4 and for other lineages (Fig. 5A, B).…”

Section: Resultsmentioning

confidence: 99%

M. tuberculosis microvariation is common and is associated with transmission: analysis of three years prospective universal sequencing in England

Wyllie

Nikolayevskyy

et al. 2019

Preprint

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BackgroundThe prevalence, association with disease status, and public health impact of infection with mixtures of M. tuberculosis strains is unclear, in part due to limitations of existing methods for detecting mixed infections.MethodsWe developed an algorithm to identify mixtures of M. tuberculosis strains using next generation sequencing data, assessing performance using simulated sequences. We identified mixed M. tuberculosis strains when there was at least one mixed nucleotide position, and where both the mixture’s components were present in similar isolates from other individuals. We determined risk factors for mixed infection among isolations of M. tuberculosis in England using logistic regression. We used survival analyses to assess the association between mixed infection and putative transmission.Findings6,560 isolations of TB were successfully sequenced in England 2016-2018. Of 3,691 (56%) specimens for which similar sequences had been isolated from at least two other individuals, 341 (9.2%) were mixed. Infection with lineages other than Lineage 4 were associated with mixed infection. Among the 1,823 individuals with pulmonary infection with Lineage 4 M. tuberculosis, mixed infection was associated with significantly increased risk of subsequent isolation of closely related organisms from a different individual (HR 1.43, 95% CI 1.05,1.94), indicative of transmission.InterpretationMixtures of transmissible strains occur in at least 5% of tuberculosis infections in England; when present in pulmonary disease, such mixtures are associated with an increased risk of tuberculosis transmission.FundingPublic Health England; NIHR Health Protection Research Unit Oxford; European Union.Research in ContextEvidence Before This StudyWe searched Pubmed using the search terms ‘tuberculosis’ and ‘mixed’ or ‘mixture’ for English Language articles published up to 1 April 2019. Studies, most performed without the benefit of genomic sequencing, report mixed TB infection from a range of medium and high prevalence areas and show it to be associated with delayed treatment response. Modelling suggests detection and treatment of mixed TB infection is an important goal for TB eradication campaigns. Although routine DNA sequencing of M. tuberculosis isolates is becoming widespread, efficient methods for detecting mixed infection from such data are underdeveloped, and the true prevalence of mixed infection and its association with transmission is unclear.Added Value of This StudyThis study investigated a large series of TB isolations obtained as part of a routine Mycobacterial sequencing program by two reference laboratories, in a low incidence area, England. We developed an efficient generalisable approach to identify transmitted mixed M. tuberculosis infection; our approach is capable of sensitive and specific detection of a single mixed nucleotide position. We identified mixed infection of similar strains (‘microvariation’) in about 9.2% of the M. tuberculosis samples which we were able to assess, and found evidence of increased transmission from individuals with mixed infection.Implications of All the Available EvidenceTB microvariation is a risk factor for TB transmission, even in the low incidence area studied. Although an efficient and highly specific technique identifying microvariation exists, it relies on comparison with similar sequences isolated from other patients. Sharing of sequence data from the many TB sequencing programs being deployed globally will increase the sensitivity of microvariation detection, and may assist targeted public health interventions.

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“…There is also likely to be an overestimation of the risk of LTBI by participants in our first occupational exposure investigation. Additionally, considering the complex interactions between pathogen exposure and the immune response to the microbe, host susceptibility may play a role in contracting LTBI …”

Section: Discussionmentioning

confidence: 99%

First assessment of interferon gamma release assay results among healthcare workers at a general hospital in China

Guo

Jiang

Liu

et al. 2018

Clinical Respiratory J

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Introduction China has a very high tuberculosis (TB) burden. The interferon‐gamma release assay (IGRA) is more specific for the diagnosis of latent tuberculosis infection (LTBI) than the tuberculin skin test, especially among populations with a high degree of coverage by the BCG vaccine. Objectives To evaluate the first screening of healthcare workers (HCW) for LTBI using the IGRA at a general hospital in Beijing. Methods A pilot screening program for LTBI was triggered by accidental contact between HCW and two patients with active TB in the emergency department (ED). Given the necessity of estimating the overall LTBI prevalence in the institution, a sample of 518 HCW was enrolled in our cross‐sectional study. The second IGRA was repeated with 43 of the 121 HCW in the ED after exposure to index TB cases. Data on putative risk factors were collected with a self‐administered questionnaire. Results The prevalence of LTBI in the targeted population was 21.8%. Differences in the prevalence of LTBI were significantly related to age, employment duration, and history of occupational exposure. A lack of childhood BCG vaccination was independently associated with the prevalence of LTBI (adjusted OR: 1.686, 95% CI: 1.045‐2.723, P = .0325). No new LTBI was diagnosed 12 weeks postexposure. No HCW adopted the preventive treatment for LTBI. Conclusions Considering the high morbidity of LTBI among HCW even in general hospitals, it is essential to formulate government policies and institutional operation protocols for the systematic screening, registration, and administration of prophylaxes for the control of LTBI.

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The Troika Host–Pathogen–Extrinsic Factors in Tuberculosis: Modulating Inflammation and Clinical Outcomes

Cited by 20 publications

References 155 publications

Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production

Mycobacterium tuberculosis associated with severe tuberculosis evades cytosolic surveillance systems and modulates IL-1β production

M. tuberculosis microvariation is common and is associated with transmission: analysis of three years prospective universal sequencing in England

First assessment of interferon gamma release assay results among healthcare workers at a general hospital in China

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