Tuberculosis最新文献

Mycobacterium tuberculosis, the causative agent of human tuberculosis (hTB), is a close evolutionary relative of Mycobacterium bovis, which causes bovine tuberculosis (bTB), one of the most damaging infectious diseases to livestock agriculture. Previous studies have shown that the pathogenesis of bTB disease is comparable to hTB disease, and that the bovine and human alveolar macrophage (bAM and hAM, respectively) transcriptomes are extensively reprogrammed in response to infection with these intracellular mycobacterial pathogens. In this study, a multi-omics integrative approach was applied with functional genomics and GWAS data sets across the two primary hosts (Bos taurus and Homo sapiens) and both pathogens (M. bovis and M. tuberculosis). Four different experimental infection groups were used: 1) bAM infected with M. bovis, 2) bAM infected with M. tuberculosis, 3) hAM infected with M. tuberculosis, and 4) human monocyte-derived macrophages (hMDM) infected with M. tuberculosis. RNA-seq data from these experiments 24 h post-infection (24 hpi) was analysed using three computational pipelines: 1) differentially expressed genes, 2) differential gene expression interaction networks, and 3) combined pathway analysis. The results were integrated with high-resolution bovine and human GWAS data sets to detect novel quantitative trait loci (QTLs) for resistance to mycobacterial infection and resilience to disease. This revealed common and unique response macrophage pathways for both pathogens and identified 32 genes (12 bovine and 20 human) significantly enriched for SNPs associated with disease resistance, the majority of which encode key components of the NF-κB signalling pathway and that also drive formation of the granuloma.

Much of the high mortality in tuberculosis meningitis (TBM) is attributable to excessive inflammation, making it imperative to identify targets for host-directed therapies that reduce pathologic inflammation and mortality. In this study, we investigate how cytokines and metabolites in the cerebral spinal fluid (CSF) associate with TBM at diagnosis and during TBM treatment. At diagnosis, TBM patients (n = 17) demonstrate significant increases of cytokines and chemokines that promote inflammation and cell migration including IL-17A, IL-2, TNFα, IFNγ, and IL-1β versus asymptomatic controls without known central nervous system pathology (n = 20). Inflammatory immune signaling had a strong positive correlation with immunomodulatory metabolites including kynurenine, lactic acid, and carnitine and strong negative correlations with tryptophan and itaconate. Inflammatory immunometabolic networks were only partially reversed with two months of effective TBM treatment and remained significantly different compared to CSF from controls. Together, these data highlight a critical role for host metabolism in regulating the inflammatory response to TBM and indicate the timeline for restoration of immune homeostasis in the CSF is prolonged.

Bacillus Calmette–Guérin (BCG) remains as the only vaccine employed to prevent tuberculosis (TB) during childhood. Among factors likely contributing to the variable efficacy of BCG is the variation in its antigenic repertoire that may arise from in vitro growth conditions. Our vaccine candidate, BCGΔBCG1419c, improved protection against TB in mice and guinea pigs with bacteria grown in either 7H9 OADC Tween 80 and in Proskauer Beck Tween 80 media in independent studies. Here, we compared the proteomes of planktonic cultures of BCG and BCGΔBCG1419c, grown in both media. Further to this, we compared systemic immunogenicity ex vivo elicited by both types of BCG strains and cultures when used to vaccinate BALB/c mice. Both the parental strain BCG Pasteur ATCC 35734, and its isogenic mutant BCGΔBCG1419c, had several medium-dependent changes. Moreover, ex vivo immune responses to a multiantigenic (PPD) or a single antigenic (Ag85A) stimulus were also medium-dependent. Then, not only the presence or absence of the BCG1419c gene in our strains under study affected the proteome produced in vitro but also that this was affected by culture medium, potentially leading to changes in the capacity to induce ex vivo immune responses.

The nucleic acid amplification tests (NAATs) such as Xpert MTB/RIF have transformed the TB diagnostic field by significantly increasing the case detection. However, newer improved diagnostic assays are still needed to meet the WHO targets to end TB. Present study is based on a novel approach of utilizing the in-vivo expressed specific mycobacterial transcriptomic biomarkers for the diagnosis of pulmonary tuberculosis (PTB). A total of 61 subjects were recruited including smear positive (smear+, n = 15), smear negative (smear-, n = 30) PTB patients and disease controls (n = 16). Transcripts of three mycobacterial genes Rv0986, Rv0971c and Rv3121 were analyzed using real time PCR (qRT-PCR) in sputum samples. qRT-PCR with Rv0986, Rv0971c and Rv3121 identified smear + PTB patients with 100 %, 78.6 % and 86.7 % sensitivity respectively. In smear- PTB patients, both Rv0986 and Rv0971c based qRT-PCR resulted in 63 %, sensitivity whereas Rv3121 identified these patients with ∼40 % sensitivity only. The sensitivity of the assay for smear-patients increased to 85 % when combinatorial analysis of qRT-PCR data for all the three genes was used. Thus, in-vivo expressed mycobacterial transcripts have promising potential as biomarkers for PTB diagnosis.

The aim of our paper is to demonstrate and discuss in detail the endocranial bony changes suggestive of tuberculous meningitis (TBM) that were recorded in an adult female's (SPF15) skeleton. The bone remains were uncovered from a solitary grave from the Hun period (5th-century-CE) archaeological site of Solt–Polya-fok (Bács-Kiskun county, Hungary). During the macromorphological examination of the very incomplete and poorly preserved skeleton of SPF15, the inner surface of the skull displayed abnormally pronounced digital impressions (APDIs) and granular impressions (GIs). Recently, it was confirmed that endocranial GIs can be considered as specific signs of TBM; and thus, they are sufficient enough on their own to make a definitive diagnosis of the disease in the palaeopathological practice. On the other hand, APDIs are not specific to TBM but can be tuberculous in origin; their concomitant presence with GIs in SPF15 makes their tuberculous origin very likely. Based on the above, it seems that the adult female from the 5th-century-CE archaeological site of Solt–Polya-fok suffered from TBM. SPF15 is the first reported probable case with tuberculosis (TB) from the Hun period of the present-day territory of Hungary, who gives us invaluable information about the spatio-temporal distribution of the disease in the past. Furthermore, it highlights the paramount importance of diagnostics development, especially the identification and refinement of diagnostic criteria, as without the application of APDIs and GIs, the diagnosis of TB could not have been established in SPF15.

In 1932, skeletal remains of two Neanderthal individuals, a young adult female and a 3–4–year-old child, were discovered in Subalyuk Cave in Northern Hungary [1,2]. Results of the anthropological examination were published some years after this important discovery. Methodological progress encouraged re-examination of the material during the last few years. Radiocarbon dating revealed a chronological age of 39,732–39,076 cal. BP for the adult female and 36,117–35,387 cal. BP for the child [3]. Morphological paleopathological studies of these Neanderthal remains uncovered distinct evidence of skeletal infections. Alterations of the adult individual's sacrum suggest probable early-stage sacroiliitis, while several vertebral bodies indicate superficial osseous remodelling of infectious origin. Traces of pathological lesions were observed on the endocranial surface of the child's skull, reflecting a reaction of meningeal tissues, a consequence of a probable TB-related meningeal infectious process. Results of recent paleomicrobiological examinations – lipid biomarker and aDNA studies – support the morphological diagnosis of probable TB infections [4].

This paper is dedicated to the memory of Professor David Ernest Minnikin (1939–2021). David was one of the key scientists who pioneered the field of Mycobacterium tuberculosis cell envelope research for over half a century. From the classification, identification, and extraction of the unusual lipids of the mycobacterial cell wall, to exploiting them as characteristic lipid biomarkers for sensitive detection, his ideas enlightened a whole world of possibilities within the tuberculosis (TB) field. In addition, his definition of the intricate models now forms a key milestone in our understanding of the M. tuberculosis cell envelope and has resolved many unanswered questions on the evolution of M. tuberculosis.

Many sampling protocols have been established to successfully retrieve human DNA from archaeological remains, however the systematic detection of ancient pathogens remains challenging. Here, we present a first assessment of the intra-bone variability of metagenomic composition in human skeletal remains and its effect on the sampling success for Mycobacterium tuberculosis (MTB) and human endogenous DNA. For this purpose, four bone samples from published peer-reviewed studies with PCR-based evidence for ancient MTB DNA were selected. Two bone samples of a Neolithic individual from Halberstadt, Germany and two ribs of two 18th-century Hungarian church mummies were sampled at multiple locations for equal amounts, followed by DNA extraction and library construction. Shotgun sequencing data was generated for taxonomic profiling as well as quantitative and qualitative evaluation of MTB and human endogenous DNA. Despite low variance in microbial diversity within and across samples, intra-bone variability of up to 36.45- and 62.88-fold for authentic ancient MTB and human reads, respectively, was detected. This study demonstrates the variable sampling success for MTB and human endogenous DNA within single skeletal samples despite relatively consistent microbial composition and highlights how a multisampling approach can facilitate the detection of hotspots with highly concentrated pathogen and human endogenous DNA.

The daily increasing sequencing of Mycobacterium tuberculosis has made it possible to establish an advanced phylogeny of this bacterium. It currently includes 9 lineages mainly affecting humans, completed by animal lineages, which form the Mycobacterium tuberculosis complex. Inherited from various historical approaches, this phylogeny is now based on Single Nucleotide Polymorphisms (SNPs), of which updates are frequently proposed. We present here evidence that the task needs refinements: some lineages have currently suboptimal defining SNPs, and many sublineages still need to be named and characterized. These findings are based on a new tool specifically designed to index the entire existing sequencing data. In this article, we focus on lineages 4.5, 4.7, 6 and 7. We take the opportunity to present some evidence that TB-annotator shows strong relevance, identifying well supported sublineages, as well as good global agreement with previous findings.

Humans and Mycobacterium tuberculosis have co-evolved together for thousands of years. Many individuals are infected with the bacterium, but few show signs and symptoms of tuberculosis (TB). Pharmacotherapy to treat those who develop disease is useful, but drug resistance and non-adherence significantly impact the efficacy of these treatments. Prior to the introduction of antibiotic therapies, public health strategies were used to reduce TB mortality. This work shows how these strategies were able to reduce TB mortality in 19th and 20th century populations, compared with antibiotic treatments.

Previously published mortality data from historical records for several populations (Switzerland, Germany, England and Wales, Scotland, USA, Japan, Brazil and South Africa) were used. Curvilinear regression was used to examine the reduction in mortality before and after the introduction of antibiotic treatments (1946).

A strong decline in TB mortality was already occurring in Switzerland, Germany, England and Wales, Scotland and the USA prior to the introduction of antibiotic treatment. This occurred following many public health interventions including improved sanitation, compulsory reporting of TB cases, diagnostic techniques and sanatoria treatments. Following the introduction of antibiotics, mortality rates declined further, however, this had a smaller effect than the previously employed strategies. In Japan, Brazil and South Africa, reductions in mortality rates were largely driven by antibiotic treatments that caused rapid decline of mortality, with a smaller contribution from public health strategies.

For the development of active disease, immune status is important. Individuals infected with the bacterium are more likely to develop signs and symptoms if their immune function is reduced. Effective strategies against TB can therefore include enhancing immune function of the population by improving nutrition, as well as reducing transmission by improving living conditions and public health. This has been effective in the past. Improving immunity may be an important strategy against drug resistant TB.