Impaired neutrophil function in patients with pulmonary tuberculosis and its normalization in those undergoing specific treatment,except the HIV-coinfected cases

Our study investigated whether the respiratory burst (RB) of polymorphonuclear neutrophils from tuberculosis (TB) patients was related with the disease severity or treatment, as well as the circulating levels of TNF-alpha. The sample comprised 57 patients with moderate (n=21) or advanced disease (n=36, 13 of them with HIV coinfection, TB-HIV) and 12 controls. Patients were newly diagnosed (n=27) or under treatment (moderate=14, advanced=10, TB-HIV=6). Cytometric analysis showed that untreated patients had a depressed RB in response to Candida albicans, being more pronounced in the advanced group and nearly absent in TB-HIV cases. A recovered RB was observed in treated patients, except for the TB-HIV cases that continued to show a poor response. TNF-alpha serum levels were increased in untreated patients, mostly in the advanced and TB-HIV groups, and showed an inverse and significant correlation with the RB. Disease severity and anti-TB therapy exerted negative and positive influences on the reactive oxygen intermediates production, respectively.     

Variants of the CD40 ligand gene are not associated with increased susceptibility to tuberculosis in West Africa

Evidence for linkage between tuberculosis and human chromosomal region Xq26 has previously been described. The costimulatory molecule CD40 ligand, encoded by TNFSF5 and located at Xq26.3, is a promising positional candidate. Interactions between CD40 ligand and CD40 are involved in the development of humoral- and cell-mediated immunity, as well as the activation of macrophages, which are the primary host and effector cells for Mycobacterium tuberculosis. We hypothesised that common variation within TNFSF5 might affect susceptibility to tuberculosis disease and, thus, might be responsible for the observed linkage to Xq26. Sequencing 32 chromosomes from a Gambian population identified nine common polymorphisms within the coding, 3 and 5 regulatory sequences of the gene. Six single nucleotide polymorphisms (SNPs) and a 3 microsatellite were genotyped in 121 tuberculosis patients and their available parents. No association with tuberculosis was detected for these variants using a transmission disequilibrium test, although one SNP at –726 showed some evidence of association in males. This finding, however, did not replicate in a separate case control study of over 1,200 West African individuals. We conclude that common genetic variation in TNFSF5 is not likely to affect tuberculosis susceptibility in West Africa and the linkage observed in this region is not due to variation in TNFSF5.Sadly, Professor Steve Bennett passed away in March 2003     

CpG oligonucleotides partially inhibit growth of Mycobacterium tuberculosis, but not Salmonella or Listeria, in human monocyte-derived macrophages

Immunostimulatory DNA sequences and their synthetic oligonucleotide analogs (CpG-ODN) activate innate immunity and can stimulate antibacterial effects against numerous intracellular pathogens. While it has been shown previously that CpG-ODN inhibit growth of Mycobacterium avium in murine and human macrophages, we now report that Mycobacterium tuberculosis growth can be inhibited by CpG-ODN treatment of human monocyte-derived macrophages (hMDM). This inhibitory effect was reversed by IFN-gamma, which has been shown repeatedly to enhance the growth of virulent M. tuberculosis in cultured hMDM. The antibacterial effect of CpG-ODN in human macrophages was specific for M. tuberculosis when compared to other intracellular pathogens including Listeria monocytogenes and Salmonella enterica serovar Dublin. These data indicate that CpG-ODN can improve the ability of hMDM to contain growth of virulent M. tuberculosis.     

Synthesis and in vitro anti-mycobacterial activity of 5-substituted pyrimidine nucleosides

Mycobacterium tuberculosis and Mycobacterium avium infections cause the two most important mycobacterioses, leading to increased mortality in patients with AIDS. Various 5-substituted 2′-deoxyuridines, uridines, 2′-O-methyluridine, 2′-ribofluoro-2′-deoxyuridines, 3′-substituted-2′,3′-dideoxy uridines, 2′,3′-dideoxyuridines, and 2′,3′-didehydro-2′,3′-dideoxyuridines were synthesized and evaluated for their in vitro inhibitory activity against M. bovis and M. avium. 5-(C-1 Substituted)-2′-deoxyuridine derivatives emerged as potent inhibitors of M. avium (MIC₉₀ = 1–5 μg/mL range). The nature of C-5 substituents in the 2′-deoxyuridine series appeared to be a determinant of anti-mycobacterial activity. This new class of inhibitors could serve as useful compounds for the design and study of new anti-tuberculosis agents.     

Polymorphism in NOD2, Crohn's disease, and susceptibility to pulmonary tuberculosis

The nucleotide oligomerization binding domain 2 gene (NOD2) encodes an intracellular receptor for bacterial components, which is expressed in monocytes and is associated with Crohn's Disease (CD). This finding, along with epidemiological evidence, supports a role for infection in the pathogenesis of CD. Speculation that mycobacteria are involved in CD led us to investigate NOD2 in susceptibility to tuberculosis (TB), a global public health problem caused by Mycobacterium tuberculosis. CD-associated NOD2 variants were absent in a case-control study of 640 Gambians, where CD is rare. Novel NOD2 promoter polymorphisms were identified but showed no association with TB in this African population sample.     

Production of a fusion protein consisting of the enterotoxigenic<Emphasis Type="Italic"> Escherichia coli</Emphasis> heat-labile toxin B subunit and a tuberculosis antigen in<Emphasis Type="Italic"> Arabidopsis thaliana</Emphasis>

Transgenic plants are potentially safe and inexpensive vehicles to produce and mucosally deliver protective antigens. However, the application of this technology is limited by the poor response of the immune system to non-particulate, subunit vaccines. Co-delivery of therapeutic proteins with carrier proteins could increase the effectiveness of the antigen. This paper reports the ability of transgenic Arabidopsis thaliana plants to produce a fusion protein consisting of the B subunit of the Escherichia coli heat-labile enterotoxin and a 6 kDa tuberculosis antigen, the early secretory antigenic target ESAT-6. Both components of the fusion protein were detected using GM1-ganglioside-dependent enzyme-linked immunosorbant assay. This suggested the fusion protein retained both its native antigenicity and the ability to form pentamers.Abbreviations ELISA Enzyme linked immunosorbant assay - ESAT-6 Early secretory antigenic target (6 kDa) - ETEC Enterotoxigenic Escherichia coli - LTB B subunit of E. coli heat-labile enterotoxin Communicated by W.A. Parrott     

PCR法快速检测临床标本中结核杆菌DNA

应用聚合酶链反应（ＰＣＲ）快速检测临床标本（脑脊液、胸水、腹水、血、痰液）中的结核杆菌ＤＮＡ,特异性扩增片段１２３ｂｐ,为结核杆菌的特异性重复序列ＩＳ６１１０部分基因。ＰＣＲ检测人型结核杆菌的敏感性达１０ｆｇＤＮＡ。临床标本的ＰＣＲ检测阳性率（２３．３％）明显高于抗酸染色涂片（２．９％）和细菌培养（５．７％）的阳性率（Ｐ〈０．０５）。通过设立对照系统及对扩增产物酶切分析,表明该法无假阴性结果（特异     

Calprotectin (MRP8/14 protein complex) release during mycobacterial infection in vitro and in vivo

The calprotectin (MRP8/14) protein complex belongs to the S100 family of Ca2+ binding proteins and is expressed during myelomonocytic differentiation. MRP8/14 plasma levels were determined by ELISA in 35 patients with active pulmonary tuberculosis (TB) showing mild (n = 12), moderate (n = 11) or severe (n = 12) disease, 13 patients with active pulmonary sarcoidosis (SR) and 21 healthy controls. TB patients had significantly increased plasma levels of MRP8/14 in comparison with SR and controls, which significantly depended on the volume of lung tissue involved in the inflammatory process. In TB patients, there was no correlation between plasma levels of MRP8/14 and total white blood cell (WBC) count, and blood polymorphonuclear neutrophil (PMN) count. In SR patients, MRP8/14 plasma levels were twofold higher in comparison with controls, but were lower compared with mild TB, and correlated with PMN and WBC counts. Human monocytes infected and cultured for 7 days with Mycobacterium bovis bacillus Calmette-Guérin showed fivefold higher MRP8/14 levels in supernatants compared with unstimulated or purified protein derivative-stimulated cells. Human MRP8/14 significantly increased Mycobacterium tuberculosis H37Rv growth in liquid medium in a dose- and time-dependent manner. These findings suggest that MRP8/14 plays an important role in the immunopathogenesis of tuberculosis.     

Chemokines and tuberculosis

Mycobacterium tuberculosis is a respiratory pathogen responsible for tuberculosis. A primary pathologic feature of M. tuberculosis infection is the formation of a granuloma. Immune cells migrate to the lung and then through the lung to the site of infection to form a granuloma. This structure contains the infection, and is often maintained for a long period of time. The signals responsible for granuloma formation and maintenance are largely unknown. Since chemokines and chemokine receptors direct cells to specific sites within the tissues, it is plausible that these cells participate in granuloma formation. In this review, the current literature on chemokines and M. tuberculosis infection, as well as the specific role that tumor necrosis factor alpha (TNF-) plays in granuloma formation and chemokine expression are discussed.