| Pulmonary tuberculosis (TB) is a serious chronic infectious disease caused byMycobacterium tuberculosis (MTB) that mainly invade the lung, which recently hasbecame a harmful global public health problem. On a global level, an estimated8.8million new cases were diagnosed and1.45million deaths from pulmonary TBoccurred in2010. With the widespread usage of antibiotics, drug resistance of MTB isbecoming an increasingly serious problem and the consequent multi-drug resistanttuberculosis (MDR-TB), especially extensively drug-resistant tuberculosis (XDR-TB)has became the main threat to the control of TB. Normal TB can be cured after atreatment with first-line anti-TB drugs of half a year, contrast to which, the drugresistant TB need more than18years with a limited therapeutic effect and great sideeffects. So, selection of an efficient and safe anti-TB drug is an essential factor in thetreatment of drug resistant TB. Meanwhile, it is imminent to development newanti-TB drugs aimed at effective targets. What’s more, the virulence genes of MTBare complex and horizontal gene transfer (HGT) is the main driver for pathogenicityof MTB, in the process of evolution. Pathogenicity islands (PAIs) are a distinct classof genomic islands acquired by microorganisms through horizontal gene transfer thatwould realize the complementary and integration of gene functions through theeffective coupling of a quantity of functional genes, which is a new method for theevolution of pathogenic virulence evolution. And the rapid development ofhigh-throughput bio-computing technology makes high-throughput screening of PAIspossible. Hence, the genome-wide scanning and functional assignment of MTB PAIswould lay a molecular foundation of comprehensive comments on the pathogenicmechanism, which has a vital role in the diagnosis of TB and the development ofanti-TB vaccines and drugs.MDR-TB is hard to cure, and carries a cost burden and mortality rate greater thanthat of drug-susceptible TB. There is no recognized effective treatment for MDR-TB,although there are a number of publications that have reported positive results forMDR-TB. We performed a network meta-analysis to assess the efficacy andacceptability of potential new antitubercular drugs. We conducted aBayesian-framework, multiple-treatments network meta-analysis of randomized controlled clinical trials to compare the efficacy and acceptability of six antituberculardrugs, bedaquiline, delamanid, linezolid, levofloxacin, metronidazole, moxifloxacinand placebo in the treatment of MDR-TB. We systematically reviewed13suitabletrials from12journal articles and8clinical trials from ClinicalTrials.gov, with datafor1549participants. We used the odds ratios (OR) as a measure of effect size. Ourresults indicated no statistically significant difference between each comparedintervention although linezolid has the potential for being very efficacious, followedby bedaquiline, delamanid, levofloxacin, moxifloxacin and metronidazole in thatorder.M. tuberculosis is one of the most dreaded diseases of the last few centuries, andmany aspects of M. tuberculosis physiology and pathogenesis still remain elusive. Ithas developed a complex matrix of virulence genes which attack the host organismsfrom various mechanisms, which makes its diagnosis and treatment extremelydifficult. Point mutation, gene recombination and horizontal gene transfer (HGT)represent three major strategies in forming the pathogenic landscape of the modern M.tuberculosis strains. In particular, HGT facilitates the dynamics of pathogenicfunctional modules of modern M. tuberculosis strains, by rapid exchanging geneticmaterials with the environmental microbes. A PAI is just a genomic region withpathogenic genes that was acquired through the horizontally transferring from anothermicrobial genome. In addition, the acquisition of PAIs was supposed to play anessential role in the adaptive evolution of a microbe, by giving the PAI-receivingmicrobe novel virulent modules. The purpose of this study was to screen thepathogenicity islands (PAIs) in M. tuberculosis using the genomic barcodevisualization technique and to characterize the functions of the detected PAIs. Byvisually screening the barcode image of the M. tuberculosis chromosomes, threecandidate PAIs were detected as MPI-1, MPI-2and MPI-3, among which MPI-2andMPI-3were known to harbor pathogenesis genes, and MPI-1represents a novelcandidate. Based on the functional annotations of Pfam domains and GO categories,both MPI-2and MPI-3carry genes encoding PE/PPE family proteins, MPI-2encodesthe type VII secretion system, and MPI-3encodes genes for mycolic acid synthesis inthe cell wall. Some of these genes were already widely used in early diagnosis ortreatment of M. tuberculosis. The novel candidate PAI MPI-1encodes CRISPR-Casfamily proteins, which are known to be associated with persistent infection of M. tuberculosis. Our data represents a molecular basis and protocol for comprehensiveannotating the pathogenic systems of M. tuberculosis, and will also facilitate thedevelopment of diagnosis and vaccination techniques of M. tuberculosis. |
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