Mycobacterium abscessus causes chronic skin infections, lung diseases, and systemic or disseminated infections. Here we investigated whether the virulence of M. abscessus clinical isolates could be ...evaluated by calculating the median lethal dose (LD50) in a silkworm infection model. M. abscessus subsp. abscessus cells were injected into the silkworm hemolymph. When reared at 37˚C, the silkworms died within 2 days post-infection with M. abscessus subsp. abscessus. Viable cell numbers of M. abscessus increased in the hemolymph of silkworms injected with M. abscessus. Silkworms were not killed by injections with heat-killed M. abscessus cells. The administration of clarithromycin, an antibacterial drug used to treat the infection in humans, prolonged the survival time of silkworms injected with M. abscessus. The LD50 values of 7 clinical isolates in the silkworm infection model were differed by up to 9-fold. The Mb-17 isolate, which was identified as a virulent strain in the silkworm infection model, induced more detachment of human THP-1-derived macrophages during infection than the Mb-10 isolate. These findings suggest that the silkworm M. abscessus infection model can be used to quantitatively evaluate the virulence of M. abscessus clinical isolates in a short time period.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mycobacteria possess various immunomodulatory molecules on the cell wall. Mannose-capped lipoarabinomannan (Man-LAM), a major lipoglycan of Mycobacterium tuberculosis, has long been known to have ...both inhibitory and stimulatory effects on host immunity. However, the direct Man-LAM receptor that explains its pleiotropic activities has not been clearly identified. Here, we report that a C-type lectin receptor Dectin-2 (gene symbol Clec4n) is a direct receptor for Man-LAM. Man-LAM activated bone-marrow-derived dendritic cells (BMDCs) to produce pro- and anti-inflammatory cytokines, whereas it was completely abrogated in Clec4n–/– BMDCs. Man-LAM promoted antigen-specific T cell responses through Dectin-2 on DCs. Furthermore, Man-LAM induced experimental autoimmune encephalitis (EAE) as an adjuvant in mice, whereas Clec4n–/– mice were resistant. Upon mycobacterial infection, Clec4n–/– mice showed augmented lung pathology. These results demonstrate that Dectin-2 contributes to host immunity against mycobacterial infection through the recognition of Man-LAM.
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•Dectin-2 recognizes mycobacterial Man-LAM•Man-LAM induces both pro- and anti-inflammatory cytokine production through Dectin-2•IL-10 production during mycobacterial infection is abrogated in Clec4n−/− DCs•Man-LAM induces EAE as an adjuvant through Dectin-2-FcRγ signaling axis
Mycobacterial lipoarabinomannan is a well-known immunomodulatory component. Yamasaki and colleagues demonstrate that Dectin-2 is a direct receptor for this lipoglycan.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Scotochromogenic slow-growing mycobacteria were isolated from the sputum or bronchoalveolar lavage fluid of 12 patients in Japan. From a comparison of the whole-genome sequences, the representative ...strain IWGMT90018-18076
and the unknown strains obtained from the patients were found to represent a novel species related to the
complex. The average nucleotide identity values of IWGMT90018-18076
with
,
and
were 86.7, 82.5 and 82.2 %, respectively. The genome size of the representative strain IWGMT90018-18076
was approximately 6.3 Mbp, and the genomic DNA G+C content was 67.1 %. The major fatty acid methyl esters were C
(37.71 %), C
ω9
(29.5 %) and C
ω7
(10.32 %). In this study, we performed phylogenetic analyses, physiological and biochemical characteristic tests, drug susceptibility tests and fatty acid profiling of the clinical isolates. On the basis of the results obtained, we propose that the unknown clinical isolates represent a novel species, '
sp. nov,' with the type strain being IWGMT90018-18076
(=JCM 34837
=KCTC 49725
).
Buruli ulcer (BU) is a skin disease caused by
Mycobacterium ulcerans
infection that requires long-term antibiotic treatment and/or surgical excision. In this study, we investigated the therapeutic ...efficacy of the rifamycin derivative, rifalazil (RLZ) (also known as KRM-1648), in an advanced
M
.
ulcerans
infection model. Six-week-old female BALB/c mice were infected with 3.25 x 10
4
colony-forming units (CFU) of
M
.
ulcerans
subcutaneously into the bilateral hind footpads. At 33 days post-infection, when the footpads exhibited significant redness and swelling, mice were treated orally with 5 or 10 mg/kg of RLZ for up to 15 weeks. Mice were followed for an additional 15 weeks following treatment cessation. Untreated mice exhibited a progressive increase in footpad redness, swelling, and erosion over time, and all untreated mice reached to endpoint within 5–8 weeks post-bacterial injection. In the RLZ-treated mice, footpad redness and swelling and general condition improved or completely healed, and no recurrence occurred following treatment cessation. After 3 weeks of treatment, the CFU counts from the footpads of recovered RLZ-treated mice showed a 10
4
decrease compared with those of untreated mice. We observed a further reduction in CFU counts to the detection limit following 6 to 15 weeks of treatment, which did not increase 15 weeks after discontinuing the treatment. Histopathologically, bacteria in the treated mice became fragmented one week after RLZ-treatment. At the final point of the experiment, all the treated mice (5mg/kg/day; n = 6, 10mg/kg/day; n = 7) survived and had no signs of
M
.
ulcerans
infection. These results indicate that the rifamycin analogue, RLZ, is efficacious in the treatment of an advanced
M
.
ulcerans
infection mouse model.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Buruli ulcer (BU) is a skin disease caused by Mycobacterium ulcerans infection that requires long-term antibiotic treatment and/or surgical excision. In this study, we investigated the therapeutic ...efficacy of the rifamycin derivative, rifalazil (RLZ) (also known as KRM-1648), in an advanced M. ulcerans infection model. Six-week-old female BALB/c mice were infected with 3.25 x 104 colony-forming units (CFU) of M. ulcerans subcutaneously into the bilateral hind footpads. At 33 days post-infection, when the footpads exhibited significant redness and swelling, mice were treated orally with 5 or 10 mg/kg of RLZ for up to 15 weeks. Mice were followed for an additional 15 weeks following treatment cessation. Untreated mice exhibited a progressive increase in footpad redness, swelling, and erosion over time, and all untreated mice reached to endpoint within 5–8 weeks post-bacterial injection. In the RLZ-treated mice, footpad redness and swelling and general condition improved or completely healed, and no recurrence occurred following treatment cessation. After 3 weeks of treatment, the CFU counts from the footpads of recovered RLZ-treated mice showed a 104 decrease compared with those of untreated mice. We observed a further reduction in CFU counts to the detection limit following 6 to 15 weeks of treatment, which did not increase 15 weeks after discontinuing the treatment. Histopathologically, bacteria in the treated mice became fragmented one week after RLZ-treatment. At the final point of the experiment, all the treated mice (5mg/kg/day; n = 6, 10mg/kg/day; n = 7) survived and had no signs of M. ulcerans infection. These results indicate that the rifamycin analogue, RLZ, is efficacious in the treatment of an advanced M. ulcerans infection mouse model.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Since 2010, mycobacterial examination results have been used widely to survey nontuberculous mycobacteria (NTM) lung disease.
To reveal the clinical and epidemiological status of NTM lung disease in ...Japan.
All data on the isolation and identification of mycobacteria in 2012 and 2013 were obtained from three dominant commercial laboratories in Japan. Pulmonary NTM disease was defined on the basis of bacteriological diagnostic criteria issued by the American Thoracic Society/Infectious Diseases Society of America. The coverage population was estimated using the ratio between national tuberculosis registration data and laboratory results for each of the eight regions of Japan.
A total of 113,313 mycobacterial specimens from 4,710 institutes were collected, and specimens from 26,059 patients tested positive for NTM cultures at least once. Among patients with positive cultures, 7,167 (27.5%) satisfied the American Thoracic Society/Infectious Diseases Society of America criteria for NTM lung disease, resulting in a 2-year prevalence rate of 24.0 per 100,000. Mycobacterium avium complex (MAC) was the most commonly isolated species (93.3%), and 29.0% of the patients from whom MAC was isolated satisfied the criteria for NTM lung disease. Individuals older than 70 years of age accounted for the majority of cases, and 65.5% of cases involved females. After MAC, Mycobacterium kansasii and Mycobacterium abscessus exhibited the highest (43.6%) and second-highest (37.1%) incidence per isolation, respectively. The prevalence of M. kansasii was highest in the Kinki region (P < 0.05), and M. abscessus had the greatest prevalence in the Kyushu-Okinawa region (P < 0.005). The proportion of Mycobacterium intracellulare in MAC cases was higher in the southwestern part of Japan than in other regions. The period prevalence was highest in the southwestern part of Japan, and the standardized prevalence ratio was highest in central regions. Evaluations of clarithromycin susceptibility revealed a clear binomial distribution.
This investigation is the first laboratory-based study in which a large number of NTM isolated from clinical samples in Japan have been assessed. Although the calculated prevalence of NTM disease might be underestimated, the approach may prove useful for monitoring relative epidemiological data for NTM lung disease.
The management of macrolide-resistant Mycobacterium avium complex (MR-MAC) pulmonary disease is difficult and is thought to be analogous to that of multidrug-resistant tuberculosis (MDR-TB).
This ...study aimed to clarify the cause of MR-MAC, to see how its management affected outcome, and to compare its prognosis with that of MDR-TB.
The medical records of 102 consecutive cases with MR-MAC pulmonary disease at three tertiary hospitals for mycobacteriosis in metropolitan Tokyo and one in Aichi prefecture from 2005 to 2014 were reviewed. The data of 311 consecutive cases with MDR-TB were extracted from the medical data at Fukujuji Hospital.
Of the 90 patients who met the criteria, 53 (58.9%) received inappropriate first-line treatment, and 28 (31.1%) deviated from the standard treatment because of the adverse effects of ethambutol. The survival rates for MR-MAC disease and MDR-TB were not significantly different (P = 0.6). Multivariate analysis showed that the combination of aminoglycoside and surgery resulted in the best treatment outcome (P = 0.02), although neither of the two factors reached significance by themselves. The continuation of clarithromycin and the addition of fluoroquinolones did not improve the outcome for the treatment of disease caused by MR-MAC.
Inappropriate prescription patterns and deviations from the standard treatment because of adverse drug reactions appeared to be the main causes of macrolide resistance in this patient series. Drug sensitivity testing should be performed at diagnosis to identify macrolide resistance and patients who may benefit from other therapy.
Buruli ulcer is an emerging chronic infectious skin disease caused by Mycobacterium ulcerans. Mycolactone, an exotoxin produced by the bacterium, is the only identified virulence factor so far, but ...the functions of this toxin and the mechanisms of disease progression remain unclear. By interfering Sec61 translocon, mycolactone inhibits the Sec61-dependent co-translational translocation of newly synthesized proteins, such as induced cytokines and immune cell receptors, into the endoplasmic reticulum. However, in regard to IL-1β, which is secreted by a Sec61-independent mechanism, mycolactone has been shown to induce IL-1β secretion via activation of inflammasomes. In this study, we clarified that cytokine induction, including that of IL-1β, in infected macrophages was suppressed by mycolactone produced by M. ulcerans subsp. shinshuense, despite the activation of caspase-1 through the inflammasome activation triggered in a manner independent of mycolactone. Intriguingly, mycolactone suppressed the expression of proIL-1β as well as TNF-α at the transcriptional level, suggesting that mycolactone of M. ulcerans subsp. shinshuense may exert additional inhibitory effect on proIL-1β expression. Remarkably, constitutively produced IL-18 was cleaved and mature IL-18 was actually released from macrophages infected with the causative mycobacterium. IL-18-deficient mice infected subcutaneously with M. ulcerans exhibited exacerbated skin inflammation during the course of disease progression. On the other hand, IL-1β controls bacterial multiplication in skin tissues. These results provide information regarding the mechanisms and functions of the induced cytokines in the pathology of Buruli ulcer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We herein report a 59-year-old woman with a 2-year history of chronic bursitis of the hand who took 50 mg/day prednisolone for several autoimmune diseases. Mycobacteroides abscessus subsp. ...massiliense was isolated from the abscess and blood culture. Combination therapy (imipenem/cilastatin, amikacin, and clarithromycin) was administered for a month. Two months later, M. massiliense was detected from a blood culture again, and disseminated lesions were found. Clarithromycin and sitafloxacin were administered following eight weeks of the same regimen. Six months after the diagnosis, M. massiliense was isolated from a blood culture, and she expired due to multiple organ failure.
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