Mycolactone toxin induces an inflammatory response by targeting the IL-1β pathway: Mechanistic insight into Buruli ulcer pathophysiology

Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans, the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by M. ulcerans induced the production of IL-1β, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3/1 inflammasomes. We show our data to be relevant in a physiological context. The in vivo injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1β, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account.     

Functional significance of manganese catalase in Lactobacillus plantarum.

A strain of Lactobacillus plantarum which was unable to produce manganese (Mn)catalase (ATCC 8014) grew somewhat more rapidly and to a slightly higher plateau density than did an Mn catalase-positive strain (ATCC 14421), and this was the case during aerobic or anaerobic growth. However, when maintenance of viability was measured during the stationary phase of the growth cycle, the advantage provided by Mn catalase was obvious. Thus, the viability of ATCC 14431 was undiminished over 21 h of aerobic incubation, during the stationary phase, whereas that of ATCC 8014 decreased by seven orders of magnitude. Addition of catalase to the medium or growth in the presence of hemin, which allows catalase synthesis, protected ATCC 8014 against this loss of viability. Suppression of Mn catalase within ATCC 14431 by treatment with NH2OH caused the cells to lose viability when exposed to 4 mM H2O2.     

Epidemiological problems of ozena and the means for controlling this infection

Clinical, bacteriological, serological and epidemiological studies of ozena morbidity among the population of Minsk were carried out in 1970-1980. On January 1, 1981, the ozena morbidity rate among the inhabitants of Minsk was 26.72%. Ozena was found to affect mainly children and women. A wide spread of the family foci of this disease (31.68%) was revealed. The results of this study indicate that the source of K. ozaenae is a sick person who begins to excrete the bacteria in the prodromal period of the disease and may continue to excrete them for many years. The transfer of K. ozaenae occurs probably by droplet or contact infection. The droplet infection is less active in the absence of symptoms (coughing, sneezing) facilitating excretion of the infective agent into the air and in cases of the low susceptibility of persons to ozena. The main measures for controlling ozena are the timely detection and sanitation of the sources of ozena, as well as the current disinfection of the infection foci in apartments.     

Mixed-species bird flocks in dipterocarp forest of north-central Burma (Myanmar)

We studied the bird community in deciduous, dipterocarp forest of north-central Burma (Myanmar) during December 1994, March 1996, and January 1997 and 1999. Most members of this community participated in mixed-species flocks. Seventy-three flocks were encountered during our study, containing 52 species. Of these, 25 species occurred in more than 10% of flocks, and were included in our analyses. There were 26 significant correlations among species pairs, 25 of which were positive. Cluster analysis indicated that there were three principal types of flocks: one consisting mostly of small passerines and picids, commonly including Common Wood-Shrike, Small Minivet and White-browed Fantail, among others; a second type consisting mainly of sylviids, e.g. Arctic, Dusky and Radde's Warblers; and a third type which generally centred around Greater and Lesser Necklaced Laughingthrushes. Bird-eating hawks were numerous at these sites, and we witnessed several attacks on flocks during the study. Thus we infer that enhanced protection from predation is an important benefit conferred by flock membership. In contrast, there was little overlap in foraging behaviour among species, suggesting that foraging facilitation is a relatively minor benefit enjoyed by flock members, although we did observe White-browed Fantails and Greater Racket-tailed Drongos kleptoparasitizing other species on occasion.     

Capsular contracture and steroid-related complications after augmentation mammaplasty. A preliminary study.

Ninety-one patients who had had augmentation mammaplasties were evaluated retrospectively. The intra-implant use of steroids appeared to reduce the incidence of breast firmness--at least over the short follow-up period--but there were complications from this which appear to be dose related (mg of Solu-Medrol/100 cc saline). A long-term evaluation of such patients is desirable. Meanwhile, our limited data strongly suggest that the intra-implant use of steroids should be used only with caution as to the dose and with a careful follow-up.     

Kinetics of adrenodoxin reductase oxidation by non-physiologic electron acceptors

The reactions of NADPH oxidation by quinones and inorganic complexes catalyzed by NADPH: adrenodoxin reductase were studied. The catalytic constant for the enzyme at pH 7.0 is 20-25 s-1; the oxidative constants for the quinones vary from 5 X 10(5) to 1.1 X 10(3) M-1 s-1 and show an increase with a rise in the one-electron acceptor reduction potential. The mode of adrenodoxin reductase interaction with oxyquinones differs from that of the enzyme interaction with alkyl-substituted quinones and inorganic complexes. NADPH competitively inhibits electron acceptors, whereas NADP+ is a competitive inhibitor of NADPH and a uncompetitive inhibitor of electron acceptors. (Ki = 25 microM). The depth of FAD incorporation into the enzyme molecule as calculated according to the outer sphere electron transfer theory is 6.1 A.     

Use of spin-labelled substrate analogs for a comparative study of microsomal cytochrome P-450 and P-448

The previously described, iodine-labeled alkylating stable nitroxyl radicals located at different distances between the N-O. group and the iodine atom were used for a comparative study of the structure of microsomal cytochromes P-450 and P-448 active centers. The radicals were shown to change the optical spectra of Fe3+ located in the active site of the enzyme that are similar to those induced by cytochrome P-450 substrates. Some differences in the type of the radicals binding to control, phenobarbital- and 3-methylcholanthrene-induced microsomes were revealed. The alkylating radical substrate analogs covalently bound to microsomal cytochrome P-450 in the vicinity of the active center, resulting in the inhibition of oxidation of type I and II substrates (e. g., aniline and naphthalene). The value of the spectral binding constant (Ks) for naphthalene in the presence of the radical covalently bound to the cytochrome P-450 active center showed a tendency to increase. Using the ESR technique, the interaction between Fe3+ and the radical localized in the active site of cytochrome P-450 was demonstrated. The contribution of Fe3+ to the relaxation of the radicals covalently bound to cytochrome P-450 was evaluated from the values of the spin label ESR spectra saturation curves at 77K. The distances between the N-O. group of these radicals and Fe3+ in the enzyme active center for the three types of microsomes were determined. The data obtained point to structural peculiarities of the active center of cytochrome P-450, depending on the microsomal type.     

Effect of adenine nucleotides on the activator function of streptokinase

The addition of ATP or 3,5-AMP (but not UTP, GTP, CTP, AMP, 2,3-AMP, ADP, inorganic pyrophosphate) at a final concentration of 10(-1) M into streptokinase solution, pH 7.0 or 9.5, causes a dramatic inhibition of streptokinase-induced fibrinolysis. The specificity of ATP effect is fully lost at pH 3.0, when all nucleotides completely inhibit the activating function of streptokinase. Ribose-5-phosphate causes a similar effect at pH 3.0. The character of nucleotide action on the activating function of streptokinase considerably differs from their influence on proteolytic reactions.     

Genetics of congenital esophageal defects

An analysis of 304 cases of esophageal atresia in fetuses and neonates showed that frequency of other congenital malformations is 43.1% including 10% of chromosomal disorders and monogenous syndromes. Summarizing the authors' own data and evidences from literature the genetic risk for sibs is calculated to be 0.88% and heredity--57.3 +/- 5.1%. The hypothesis that esophageal atresia is a malformation of multifactorial genesis with polygenic hereditary component is confirmed.