Dataset Information

Self-clearance of Mycobacterium tuberculosis infection: implications for lifetime risk and population at-risk of tuberculosis disease.

ABSTRACT: Background: it is widely assumed that individuals with Mycobacterium tuberculosis (Mtb) infection remain at lifelong risk of tuberculosis (TB) disease. However, there is substantial evidence that self-clearance of Mtb infection can occur. We infer a curve of self-clearance by time since infection and explore its implications for TB epidemiology. Methods and findings: data for self-clearance were inferred using post-mortem and tuberculin-skin-test reversion studies. A cohort model allowing for self-clearance was fitted in a Bayesian framework before estimating the lifetime risk of TB disease and the population infected with Mtb in India, China and Japan in 2019. We estimated that 24.4% (17.8-32.6%, 95% uncertainty interval (UI)) of individuals self-clear within 10 years of infection, and 73.1% (64.6-81.7%) over a lifetime. The lifetime risk of TB disease was 17.0% (10.9-22.5%), compared to 12.6% (10.1-15.0%) assuming lifelong infection. The population at risk of TB disease in India, China and Japan was 35-80% (95% UI) smaller in the self-clearance scenario. Conclusions: the population with a viable Mtb infection may be markedly smaller than generally assumed, with such individuals at greater risk of TB disease. The ability to identify these individuals could dramatically improve the targeting of preventive programmes and inform TB vaccine development, bringing TB elimination within reach of feasibility.

SUBMITTER: Emery JC

PROVIDER: S-EPMC7893269 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Malaria and tuberculosis (Tb) are two of the main causes of death from infectious diseases globally. The pathogenic agents, Plasmodium parasites and Mycobacterium tuberculosis, are co-endemic in many regions in the world, however, compared to other co-infections like HIV/Tb or helminth/Tb, malaria/Tb has been given less attention both in clinical and immunological studies. Due to the lack of sufficient human data, the impact of malaria on Tb and vice versa is difficult to estimate but co-infections are likely to occur very frequently. Due to its immunomodulatory properties malaria might be an underestimated risk factor for latent or active Tb patients particularly in high-endemic malaria settings were people experience reinfections very frequently. In the present study, we used the non-lethal strain of Plasmodium yoelii to investigate, how one episode of self-resolving malaria impact on a chronic M. tuberculosis infection. P. yoelii co-infection resulted in exacerbation of Tb disease as demonstrated by increased pathology and cellular infiltration of the lungs which coincided with elevated levels of pro- and anti-inflammatory mediators. T cell responses were not impaired in co-infected mice but enhanced and likely contributed to increased cytokine production. We found a slight but statistically significant increase in M. tuberculosis burden in co-infected animals and increased lung CFU was positively correlated with elevated levels of TNF? but not IL-10. Infection with P. yoelii induced the recruitment of a CD11c(+) population into lungs and spleens of M. tuberculosis infected mice. CD11c(+) cells isolated from P. yoelii infected spleens promoted survival and growth of M. tuberculosis in vitro. 170 days after P. yoelii infection changes in immunopathology and cellular immune responses were no longer apparent while M. tuberculosis numbers were still slightly higher in lungs, but not in spleens of co-infected mice. In conclusion, one episode of P. yoelii co-infection transiently exacerbated disease severity but had no long-term consequences on disease progression and survival of M. tuberculosis infected mice.

Project description: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 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.ResultsAmong 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.ConclusionsLTBI, 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.

Project description:Tuberculosis results from an interaction between a chronically persistent pathogen counteracted by IFN-g-mediated immune responses. Modulation of IFN-g signaling could therefore constitute a major immune evasion mechanism for M. tuberculosis. SOCS1 plays a major role in the inhibition of IFN-g-mediated responses. We found that M. tuberculosis infection stimulates SOCS1 expression in mouse and human myeloid cells. Significantly higher levels of SOCS1 were induced after in vitro or in vivo infection with virulent M. tuberculosis-than with attenuated M. bovis BCG. Different innate and adaptive immune mechanisms participated in infection-induced SOCS1 expression. SOCS1 hampered M. tuberculosis clearance both in macrophages and during murine infection in vivo. On the other hand, SOCS1 protected the host from an infection-induced inflammation. Despite SOCS1 expression, mycobacteria-infected macrophages were not tolerant to IFN-g. Instead, an impaired IFN-g secretion by macrophages, associated to lower responses to IL-12, accounted for the increased mycobacterial intracellular growth in presence of SOCS1. SOCS1 attenuated the expression of the majority of genes modulated by infection of macrophages (6,1% of the transcriptome), indicating the relevance of the molecule in the outcome of infection with M. tuberculosis. We suggest that SOCS1 is expressed during M. tuberculosis infection to establish a successful chronic infection, and dampen inflammatory damage. Difference in genotype and TB infection comparison Relative gene expressions were determined by normalized intensity values. GeneSpring analysis was performed using the Treg transcriptome data with following comparisons: no GvHD d90 versus no GvHD d150, no GvHD d90 versus acute GvHD, no GvHD d150 versus chronic GvHD, acute GvHD versus chronic GvHD, acute GvHD versus GvHD d90 and chronic GvHD versus GvHD d150 (Figure 2). Cut-off was a transcript fold change of +2 or -2 in at least one comparison. Student´s t-test was used to identify significant expression changes.

Project description:BACKGROUND: Molecular genotyping methods have shown infection with more than one Mycobacterium tuberculosis strain genotype in a single sputum culture, indicating mixed infection. AIM: This study aimed to develop a PCR-based genotyping tool to determine the population structure of M. tuberculosis strain genotypes in primary Mycobacterial Growth Indicator Tubes (MGIT) and Löwenstein-Jensen (LJ) cultures to identify mixed infections and to establish whether the growth media influenced the recovery of certain strain genotypes. METHOD: A convenience sample of 206 paired MGIT and LJ M. tuberculosis cultures from pulmonary tuberculosis patients resident in Khayelitsha, South Africa were genotyped using an in-house PCR-based method to detect defined M. tuberculosis strain genotypes. RESULTS: The sensitivity and specificity of the PCR-based method for detecting Beijing, Haarlem, S-family, and LAM genotypes was 100%, and 75% and 50% for detecting the Low Copy Clade, respectively. Thirty-one (15%) of the 206 cases showed the presence of more than one M. tuberculosis strain genotype. Strains of the Beijing and Haarlem genotypes were significantly more associated with a mixed infection (on both media) when compared to infections with a single strain (Beijing MGIT p = 0.02; LJ, p<0.01) and (Haarlem: MGIT p<0.01; LJ, p = 0.01). Strains with the Beijing genotype were less likely to be with "other genotype" strains (p<0.01) while LAM, Haarlem, S-family and LCC occurred independently with the Beijing genotype. CONCLUSION: The PCR-based method was able to identify mixed infection in at least 15% of the cases. LJ media was more sensitive in detecting mixed infections than MGIT media, implying that the growth characteristics of M. tuberculosis on different media may influence our ability to detect mixed infections. The Beijing and Haarlem genotypes were more likely to occur in a mixed infection than any of the other genotypes tested suggesting pathogen-pathogen compatibility.

Dataset Information

Self-clearance of Mycobacterium tuberculosis infection: implications for lifetime risk and population at-risk of tuberculosis disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets