Mycobacterium abscessus Glycopeptidolipid Prevents Respiratory Epithelial TLR2 Signaling as Measured by HβD2 Gene Expression and IL-8 Release

Davidson, Lisa B.; Nessar, Rachid; Kempaiah, Prakasha; Perkins, Douglas J; Byrd, Thomas F.

doi:10.1371/journal.pone.0029148

Cited by 60 publications

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References 36 publications

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“…A rough clinical isolate persisted in the lungs of experimentally infected mice and disseminated into the spleen, whereas a smooth isolate was cleared from the lungs within 3 weeks (16). An isogenic mutant of M. abscessus that lacked GPL production lost biofilm formation but gained the ability to replicate inside macrophages, stimulate Toll-like receptor 2, and induce cytokine production (17,18). It has also been suggested that the rough morphotype is more virulent in humans (19).…”

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confidence: 99%

Characterization of Rough and Smooth Morphotypes of Mycobacterium abscessus Isolates from Clinical Specimens

et al. 2014

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Mycobacterium abscessus, which consists of the two subspecies M. abscessus subspecies abscessus and M. abscessus subspecies bolletii, can produce rough or smooth colony morphologies. Here we analyzed 50 M. abscessus isolates cultured from the respiratory specimens of 34 patients, 28 (82%) of whom had cystic fibrosis (CF), with respect to their colony morphologies and antibiotic susceptibilities. The overall proportions of occurrences of the two morphotypes were similar, with specimens from 50% of the patients showing a rough and 38% showing a smooth morphotype. A total of 12% of the specimens from the patients showed both morphotypes simultaneously. At the subspecies level, the proportions of rough and smooth morphotypes differed substantially; 88% of rough morphotypes belonged to M. abscessus subspecies abscessus, and 85% of smooth morphotypes belonged M. abscessus subspecies bolletii. Inducible clarithromycin resistance due to the Erm(41) methylase, as well as high-level resistance to clarithromycin due to mutations within the rrl gene, occurred independently of the morphotype. The MIC 50 s of amikacin and cefoxitin were identical for the two morphotypes, whereas the MIC 50 s of tigecycline were 0.25 g/ml for the rough morphotype and 2.0 g/ml for the smooth morphotype. Our results show that the smooth morphotype was more dominant in respiratory specimens from CF patients than previously thought. With respect to resistance, colony morphology did not affect the susceptibility of Mycobacterium abscessus to the first-line antibiotics clarithromycin, amikacin, and cefoxitin.T he genus Mycobacterium contains more than 100 different species which belong either to the Mycobacterium tuberculosis complex or to the large group of nontuberculous mycobacteria (NTMs). M. abscessus is an NTM, and clinical studies have begun to shed light on its epidemiology. M. abscessus is involved in soft tissue infections and is a dominant respiratory pathogen in patients with cystic fibrosis (CF). It is the second-most-common NTM species isolated from CF patients in the United States and the most common NTM species isolated from CF patients in Europe (1-6). Fatal infections with M. abscessus have been reported, especially after lung transplantation (7). M. abscessus has been subdivided in type I and type II, which, together with Mycobacterium chelonae, share identical 16S rRNA genes but show differences within the hsp65 gene (8, 9). Based on multilocus sequence analysis of hsp65, rpoB, secA, and the 16S-23S internal transcribed spacer (ITS) region, M. abscessus was further subdivided into three species, M. abscessus (sensu stricto), M. bolletii, and M. massiliense (10, 11). Recently, uniting M. bolletii and M. massiliense as M. abscessus subspecies bolletii (the former type II) and separating that subspecies from M. abscessus subspecies abscessus (the former type I) have been proposed (12).M. abscessus colonies on agar plates grow with either a rough or a smooth morphology (13,14). M. abscessus can show cord formation when visualized mic...

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Characterization of Rough and Smooth Morphotypes of Mycobacterium abscessus Isolates from Clinical Specimens

et al. 2014

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“…We have previously verified the specificity of HβD2 as a readout for M. abscessus TLR2 stimulation by siRNA knockdown of TLR2 which abrogated HβD2 release in response to M. abscessus [6]. In addition, we have reported that phosphatidyl inositol mannosides (PIMs) are one of the M. abscessus ligands for TLR2.…”

Section: Resultsmentioning

confidence: 91%

“…These cells are among the various cell types which express toll-like receptors (TLRs); receptors which mediate the innate immune response to invading pathogens [3]. Both interleukin-8 (IL-8) and human β-defensin 2 (HβD2) are expressed by respiratory epithelial cells in response to TLR stimulation [4–6]. …”

Section: Introductionmentioning

confidence: 99%

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Cystic fibrosis CFBE41o‐ cells contain TLR1 SNP I602S and fail to respond to Mycobacterium abscessus

Kempaiah

Davidson

Perkins

et al. 2013

Journal of Cystic Fibrosis

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Background Mycobacterium abscessus causes lung infection in patients with cystic fibrosis. M. abscessus stimulates the host innate immune response via TLR2 on respiratory epithelial cells. Signaling through TLR2 requires the formation of TLR2/TLR1 heterodimers on the cell surface. Methods The ability of M. abscessus to stimulate the innate immune response of cystic fibrosis CFBE41o- respiratory epithelial cells was measured as expression of HβD2 by RT PCR, and release of IL-8 by ELISA. Genotyping of CFBE41o- TLR polymorphisms was carried out. Results CFBE41o- cells are hyporesponsive to M. abscessus. They are homozygous for the TLR1 SNP I602S which has been demonstrated to cause diminished cellular responses to TLR2 agonists. Conclusions Homozygosity for I602S is prevalent in Western Europeans and North American Caucasians, the same demographic in which the ΔF508 mutation is present. This SNP may play a role in the pathogenesis of M. abscessus lung infection in patients with cystic fibrosis.

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“…This led to the hypothesis that GPL on the outer cell wall of M. abscessus allows the bacillus to initially avoid inducing immunity by avoiding TLR2 triggering, but when it is not present, this unmasks other materials, possibly phosphatidylinositol mannosides or lipoarabinomannans, that are known to be TLR2 agonists. More recently, disruption of the mmpL4b gene, which is involved in GPL biosynthesis, resulted in bacilli that could trigger TLR2 in macrophage cultures (85,86); these mutants lack GPL but also seem to upregulate the production of cell wall lipoproteins (87). What has yet to be explained, however, is why mechanisms other than TLR2 signaling do not compensate and prevent GPL Ϫ M. abscessus from so quickly killing mice.…”

Section: Immunity To M Abscessus An Emerging Pathogenmentioning

confidence: 99%

Host Response to Nontuberculous Mycobacterial Infections of Current Clinical Importance

Orme

Ordway

2014

Infect Immun

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The nontuberculous mycobacteria are a large group of acid-fast bacteria that are very widely distributed in the environment. While Mycobacterium avium was once regarded as innocuous, its high frequency as a cause of disseminated disease in HIV-positive individuals illustrated its potential as a pathogen. Much more recently, there is growing evidence that the incidence of M. avium and related nontuberculous species is increasing in immunocompetent individuals. The same has been observed for M. abscessus infections, which are very difficult to treat; accordingly, this review focuses primarily on these two important pathogens. Like the host response to M. tuberculosis infections, the host response to these infections is of the TH1 type but there are some subtle and as-yet-unexplained differences.A lthough nontuberculous mycobacteria have long been recognized, there is far less information regarding their pathogenicity than that of their more famous relatives Mycobacterium tuberculosis and Mycobacterium leprae. It is becoming increasingly clear, however, that the incidence of certain members of the nontuberculous mycobacterial family may be increasing, an observation not related simply to better recognition, typing, and diagnosis. Of this family, the host response to M. avium is perhaps the best understood, but even here there are interesting differences in the expression of immunity that have yet to be explained. NOMENCLATUREOne cannot begin to address this issue without considering the current nomenclature, a morass in itself. We are using here the term "nontuberculous mycobacteria" (NTM) but could easily use "atypical mycobacteria," "environmental mycobacteria," the subset "rapidly growing mycobacteria" (RGM), "mycobacteria other than M. tuberculosis," or even the "quasi-too-complex" term that can be applied to M. avium and M. abscessus. NTM is perhaps the most widely used, but one has to realize that "tuberculous" refers to "not tuberculosis" not "no tubercles." ECOLOGY AND EPIDEMIOLOGYNTM were suspected as potential causes of human infections in the sanatorium era, but it was not until the 1950s that direct evidence became available. Even then, NTM were initially regarded as simple saprophytes of limited, if any, virulence occurring only in people with other predisposing lung conditions (as discussed further below). This opinion, of course, changed dramatically when M. avium complex (MAC) species emerged as major opportunistic infections in patients with HIV and more recently with observations of increases in infections with other NTM such as M. abscessus in elderly patients.Because of extensive research, including seminal work by Falkinham, we now know that NTM are widely distributed in the environment and can cause opportunistic infections in multiple mammals, fish, and birds (particularly poultry) (1). In fact, it seems that NTM can grow essentially anywhere (2) and thrive where competing microbes are destroyed, such as in chlorinated water (3). In untreated water, NTM can even parasitize amoebae (4, 5). Eve...

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Mycobacterium abscessus Glycopeptidolipid Prevents Respiratory Epithelial TLR2 Signaling as Measured by HβD2 Gene Expression and IL-8 Release

Cited by 60 publications

References 36 publications

Characterization of Rough and Smooth Morphotypes of Mycobacterium abscessus Isolates from Clinical Specimens

Characterization of Rough and Smooth Morphotypes of Mycobacterium abscessus Isolates from Clinical Specimens

Cystic fibrosis CFBE41o‐ cells contain TLR1 SNP I602S and fail to respond to Mycobacterium abscessus

Host Response to Nontuberculous Mycobacterial Infections of Current Clinical Importance

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