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Interferon (IFN)-γ responsiveness to 12 purified protein derivative (PPD) and new tuberculin antigens from 9 species of mycobacteria was assessed, using a whole blood assay, in 616 young adults living in northern Malawi, where Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccination provides no protection against pulmonary tuberculosis. The prevalence of IFN-γ responsiveness was highest for PPDs of M. avium, M. intracellulare, and M. scrofulaceum (the MAIS complex). Correlations between responsiveness paralleled genetic relatedness of the mycobacterial species. A randomized, controlled trial was carried out, to assess the increase in IFN-γ responsiveness to M. tuberculosis PPD that can be attributed to M. bovis BCG vaccination. The BCG-attributable increase in IFN-γ response to M. tuberculosis PPD was greater for individuals with low initial responsiveness to MAIS antigens than for those with high initial responsiveness. Although not statistically significant, the trend is consistent with the hypothesis that prior exposure to environmental mycobacteria interferes with immune responses to BCG vaccination.

The distribution of Mycobacterium avium-intracellulare complex (MAC) in residences was examined. MAC was only recovered from bathrooms but not from other sites of residences. The appearance ratio in the bathrooms of patients with pulmonary MAC was significantly higher than that in healthy volunteers' bathrooms (P = .01). For 2 patients, the genotypes of environmental isolates were identical to their respective clinical isolates.

Many non-tuberculous mycobacteria synthesize abundant glycopeptidolipids (GPLs). These surface-located GPLs are involved in pathogenicity by interfering with the host immune system. In Mycobacterium avium subsp. avium ( Mav), GPLs consist of a lipopeptide core composed of a tetrapeptide O-linked to mono- and oligo-saccharides. The biosynthesis pathway of the simplest GPLs is now relatively well understood and involves probably more than fifteen genes. Whereas it is very obvious that most, if not all, of the Mav isolates produce GPLs, the picture is not as clear for M. avium subsp. paratuberculosis ( Map), the etiologic agent of Johne's disease in cattle, and several conflicting data have been produced. Biochemical analysis of a large set of characterized Map isolates showed that all Map strains tested produce a lipopentapeptide (L5P) instead of GPLs. To provide a genomic basis for the synthesis of this compound, the recently published genome sequence of Map was explored using in silico methods. Even though Map produces a lipopeptide rather than GPL, its genome contains nevertheless a locus highly similar to the GPL biosynthetic pathway of Mav. We showed that the module composition of the non-ribosomal protein synthase (Nrp) of Map, the enzyme involved in the synthesis of the peptidyl moiety, is dramatically different from that of other GPL producers such as M. smegmatis ( Ms) and Mav and is in agreement with the amino acid content of the L5P. We also showed that the peptidyl moiety of the L5P is a target for a strong specific humoral response in Map infected animals. These genomic and biochemical differences may help to unambiguously distinguish Map from Mav and also from M. bovis, to reclassify related strains of the Map species and to allow the convenient and specific diagnosis of paratuberculosis.

The insertion sequence IS900 has been considered specific for Mycobacterium avium subsp. paratuberculosis (M. paratuberculosis) and has, therefore, been used as the target gene for diagnostic PCR of M. paratuberculosis. From a healthy dairy cow we have isolated and characterised a Mycobacterium harbouring one copy of a sequence with 94% identity to IS900 at the nucleic acid level. The isolate was shown to be related to Mycobacterium cookii, as assessed by 16S rRNA sequencing. Strong amplifications were obtained with several PCR primers described for detection of IS900. This finding shows the need of alternative PCR systems based on other genes than IS900 to confirm the presence of M. paratuberculosis.

Mycobacterium avium subsp. hominissuis (MAH) causes mainly pulmonary infection in immunocompetent hosts, disseminated infection in immunocompromised hosts, such as individuals infected with human immunodeficiency virus (HIV), and infection in pigs. To examine the features of MAH isolates from different origins, we performed molecular epidemiological analysis and drug susceptibility testing using eight drugs, including clarithromycin, rifampicin, ethambutol, streptomycin, and amikacin. Phylogenetic analysis based on the allelic profile of whole-genome multi-locus sequence typing of 156 strains, including those from Japan, Europe, the United States, and Taiwan, revealed that 93.6% of isolates from patients with pulmonary MAH disease and 61.5% of isolates from HIV-positive patients formed clusters unique to Japanese strains, whereas the remaining isolates from HIV-positive patients and all isolates from pigs were included in other clusters formed by strains from Europe, the United States, and Taiwan. Thus, isolates from patients with pulmonary MAH disease and pigs were genetically distinct, and isolates from HIV-positive patients were classified into two distinct genetic types. Furthermore, isolates from patients with pulmonary MAH disease were significantly more resistant to seven drugs, excluding rifampicin, compared with other isolates. These results indicate that MAH isolates from three different origins in Japan have different genetic and drug susceptibility characteristics.

Background Among the non-tuberculous mycobacteria, Mycobacterium (M.) avium are important pathogens for humans and/or animals. Currently, there are four M. avium subspecies: subsp. hominissuis (Mah) , subsp. paratuberculosis (Map) , subsp. avium (Maa) , and subsp. silvaticum (Mas) . While sufficient data is available for the first three mentioned, only few reports exist on the isolation, epidemiology and even less on the genetic equipment of Mas . Results Here, Mas was isolated from an Egyptian goose that died of avian tuberculosis. Subspecies identification was based on the presence of IS 901 and IS 1245 as well as Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeat analysis demonstrating Mas specific profile INMV99 profile. During cultural isolation, Mas showed preference for media with mycobactin supplementation but was not limited to mycobactin-containing media. A closed genome sequence was assembled using short- and long-read sequencing technology. The genome sequence consisted of one circular chromosome of 4.84 Mb (GC content 69.3%) and no plasmid. It was highly similar to the only other available Mas sequence (ANI 99.98%, GGDC 99.7%) and eight Maa sequences (ANI ≥99.88%, GGDC ≥98.9%), although all Maa genomes were larger (approx. 5 Mb). In silico prediction of the metabolic pathways and gene content found that all Maa but no Mas should be able to synthetize ergothioneine and the carotenoid neurosporene. The analysis of the mycobactin cluster mbt -1 made it obvious that in Mas two of the eleven mbt genes ( mbtB and mbtE ) were probably dysfunctional due frameshift-based disruptions. Conclusions The first complete, high quality, closed genome sequence of a Mas isolate closes a knowledge gap. Even if the collection of further genome sequences is considered necessary, the now existing data set already enables a deeper analysis of M. avium . The found differences in the Mas gene content compared to the closest relative Maa seem to be stable and independent of spatial (France, UK, Germany) and temporal (>40 years) differences on their isolation. These data thus call into question the demand for merging the two subspecies Maa and Mas into one, but further genome sequences from other Mas strains are needed to answer this question conclusively.

Within a group of three captive lowland tapirs ( Tapirus terrestris ) suffering from clinically apparent mycobacteriosis, non-tuberculous Mycobacterium avium subsp. hominissuis (MAH) strains were isolated from the animals and the tapir’s enclosure. Based on MIRU-VNTR findings, which identified two closely related INMV profiles (124 and 246), a micro-evolutionary event was assumed, and four available MAH strains were submitted to whole genome sequencing (short- and long-read technologies). Surprisingly, the differences based on single nucleotide polymorphisms (SNPs) were exceptionally high between the four strains, i.e., between 841 and 11,166 bases, due to a strong impact of homologous recombination. Thus, an ad hoc core genome multilocus sequence typing (cgMLST) scheme was created and pangenome analysis was conducted for determining the genomic similarity between the strains. The INMV246 isolate obtained from sputum on the enclosure floor and one INMV124 isolate of tapir #2 showed the highest congruence, suggesting that both originated from a shared source. The other two INMV124 isolates were genomically distinct from these strains. Nevertheless, in all four strains two plasmids were detected, which were highly conserved between the strains. The study showed that the genomic variability between MAH strains isolated from the same site within a short period of time can be exceptionally high and the influence of homologous recombination needs to be considered when determining MAH strain relationships, particularly via SNP analyses.

Mycobacterium avium subsp. avium (MAA) is the main tuberculosis pathogen of poultry and wild birds. MAA can also infect mammals such as pigs, cattle, and horses and can pose a threat to people with low immunity. Here, we describe the first identification of MAA strain HJW isolated from a cow in Jilin Province, China. The isolate was completely sequenced and a phylogenetic analysis of its relationship to members of the Mycobacterium avium complex (MAC) was performed. The results revealed that strain HJW was type MAA based on the analysis of insertion sequence amplification and whole genome sequencing. The HJW genome size was 4,961,843 bp with a GC content of 69.28%. The strain was genetically most closely related to the Mycobacterium avium subsp. avium strain DSM 44156. This study suggests that MAA may pose an infection risk to cattle and provides data support for the phylogeny of Mycobacterium avium.

Background Mycobacterium intracellulare is a representative etiological agent of emerging pulmonary M. avium-intracellulare complex disease in the industrialized countries worldwide. The recent genome sequencing of clinical strains isolated from pulmonary M. avium-intracellulare complex disease has provided insight into the genomic characteristics of pathogenic mycobacteria, especially for M. avium ; however, the genomic characteristics of M. intracellulare remain to be elucidated. Results In this study, we performed comparative genomic analysis of 55  M. intracellulare and related strains such as M. paraintracellulare (MP), M. indicus pranii (MIP) and M. yonogonense . Based on the average nucleotide identity, the clinical M. intracellulare strains were phylogenetically grouped in two clusters: (1) the typical M. intracellulare (TMI) group, including ATCC13950 and virulent M.i.27 and M.i.198 that we previously reported, and (2) the MP-MIP group. The alignment of the genomic regions was mostly preserved between groups. Plasmids were identified between groups and subgroups, including a plasmid common among some strains of the M.i.27 subgroup. Several genomic regions including those encoding factors involved in lipid metabolism (e.g., fadE3 , fadE33 ), transporters (e.g., mce3 ), and type VII secretion system (genes of ESX-2 system) were shown to be hypermutated in the clinical strains. M. intracellulare was shown to be pan-genomic at the species and subspecies levels. The mce genes were specific to particular subspecies, suggesting that these genes may be helpful in discriminating virulence phenotypes between subspecies. Conclusions Our data suggest that genomic diversity among M. intracellulare , M. paraintracellulare , M. indicus pranii and M. yonogonense remains at the subspecies or genovar levels and does not reach the species level. Genetic components such as mce genes revealed by the comparative genomic analysis could be the novel focus for further insight into the mechanism of human pathogenesis for M. intracellulare and related strains.

Nontuberculous mycobacteria are an important cause of morbidity in the United States, although patient outcomes vary greatly by species. Currently, nationally representative data on the distribution of mycobacterial species from clinical isolates are limited. Using a national hospitalization database capturing microbiologic data for nearly 6 million patient encounters, we describe the geographic distribution of, and patient demographic features associated with, clinical mycobacterial isolates in the United States. Linked demographic and microbiologic data from the Premier Healthcare Database were extracted for all patient encounters from 2009 to 2013. Patients with at least one positive potentially pathogenic nontuberculous mycobacterial culture were identified as cases. The period prevalence was calculated, and patient-, encounter-, and hospital-level factors were analyzed. Regional differences in species distribution were analyzed; a subanalysis was conducted among patients with International Classification of Diseases, Ninth Revision, codes for pulmonary nontuberculous mycobacterial disease. Significant differences were assessed (P < 0.05). Of 5,928,830 unique patients included during the 5-year study period, 7,812 (0.13%) had at least one positive nontuberculous mycobacterial culture. The mean age of cases was 64 years (range, <1-89 yr), and most were female (52%) and white (70%). Hospitals with cases were more often labeled \"urban\" (96%), \"teaching\" (56%), and had at least 500 beds (78%). Species distribution differed significantly by geographic area. Mycobacterium avium complex ranged from 61 to 91% of isolates and were most frequent in the South and Northeast regions; M. abscessus/M. chelonae ranged from 2 to 18% of isolates and were most frequent in the West; and other species, including M. fortuitum and M. kansasii, ranged from 7 to 26% and were also most frequent in the West. Significant geographic variation exists in the distribution of nontuberculous mycobacterial species in the United States. Whereas M. avium complex was the most common species isolated in the South, M. abscessus/M. chelonae was proportionately higher in the West. Greater clinical awareness in regions with increased levels of harder-to-treat mycobacteria are needed, given differences in treatment options and implications for patient outcomes.