scholarly journals Mycobacterium tuberculosisLipoprotein and Lipoglycan Binding to Toll-Like Receptor 2 Correlates with Agonist Activity and Functional Outcomes

2018 ◽  
Vol 86 (10) ◽  
Author(s):  
Supriya Shukla ◽  
Edward T. Richardson ◽  
Michael G. Drage ◽  
W. Henry Boom ◽  
Clifford V. Harding
Keyword(s):  
Immune Responses ◽  
Agonist Activity ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Tlr2 Agonist ◽  
Content Type ◽  
Host Immune Responses ◽  
Extracellular Signal ◽  
Toll Like Receptor 2 ◽  
Tlr2 Signaling

ABSTRACTMycobacterium tuberculosiscauses persistent infection due to its ability to evade host immune responses.M. tuberculosisinduces Toll-like receptor 2 (TLR2) signaling, which influences immune responses toM. tuberculosis. TLR2 agonists expressed byM. tuberculosisinclude lipoproteins (e.g., LprG), the glycolipid phosphatidylinositol mannoside 6 (PIM6), and the lipoglycan lipomannan (LM). AnotherM. tuberculosislipoglycan, mannose-capped lipoarabinomannan (ManLAM), lacks TLR2 agonist activity. In contrast, PILAM, fromMycobacterum smegmatis, does have TLR2 agonist activity. Our understanding of howM. tuberculosislipoproteins and lipoglycans interact with TLR2 is limited, and binding of these molecules to TLR2 has not been measured directly. Here, we directly measuredM. tuberculosislipoprotein and lipoglycan binding to TLR2 and its partner receptor, TLR1. LprG, LAM, and LM were all found to bind to TLR2 in the absence of TLR1, but not to TLR1 in the absence of TLR2. Trimolecular interactions were revealed by binding of TLR2-LprG or TLR2-PIM6 complexes to TLR1, whereas binding of TLR2 to TLR1 was not detected in the absence of the lipoprotein or glycolipid. ManLAM exhibited low affinity for TLR2 in comparison to PILAM, LM, and LprG, which correlated with reduced ability of ManLAM to induce TLR2-mediated extracellular-signal-regulated kinase (ERK) activation and tumor necrosis factor alpha (TNF-α) secretion in macrophages. We provide the first direct affinity measurement and kinetic analysis ofM. tuberculosislipoprotein and lipoglycan binding to TLR2. Our results demonstrate that binding affinity correlates with the functional ability of agonists to induce TLR2 signaling.

scholarly journals Staphylococcus aureus Releases Proinflammatory Membrane Vesicles To Resist Antimicrobial Fatty Acids

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Arnaud Kengmo Tchoupa ◽  
Andreas Peschel
Keyword(s):  
Fatty Acids ◽  
Staphylococcus Aureus ◽  
Immune Responses ◽  
Membrane Vesicle ◽  
Membrane Vesicles ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Content Type ◽  
Healthy Humans ◽  
Toll Like Receptor 2

ABSTRACT Staphylococcus aureus is a major pathogen, which colonizes one in three otherwise healthy humans. This significant spread of S. aureus is largely due to its ability to circumvent innate immune responses, including antimicrobial fatty acids (AFAs) on the skin and in nasal secretions. In response to AFAs, S. aureus swiftly induces resistance mechanisms, which have yet to be completely elucidated. Here, we identify membrane vesicle (MV) release as a resistance strategy used by S. aureus to sequester host-specific AFAs. MVs protect S. aureus against a wide array of AFAs. Strikingly, beside MV production, S. aureus modulates MV composition upon exposure to AFAs. MVs purified from bacteria grown in the presence of linoleic acid display a distinct protein content and are enriched in lipoproteins, which strongly activate Toll-like receptor 2 (TLR2). Cumulatively, our findings reveal the protective capacities of MVs against AFAs, which are counteracted by an increased TLR2-mediated innate immune response. IMPORTANCE The nares of one in three humans are colonized by Staphylococcus aureus. In these environments, and arguably on all mucosal surfaces, bacteria encounter fatty acids with antimicrobial properties. Our study uncovers that S. aureus releases membrane vesicles (MVs) that act as decoys to protect the bacterium against antimicrobial fatty acids (AFAs). The AFA-neutralizing effects of MVs were neither strain specific nor restricted to one particular AFA. Hence, MVs may represent “public goods” playing an overlooked role in shaping bacterial communities in AFA-rich environments such as the skin and nose. Intriguingly, in addition to MV biogenesis, S. aureus modulates MV composition in response to exposure to AFAs, including an increased release of lipoproteins. These MVs strongly stimulate the innate immunity via Toll-like receptor 2 (TLR2). TLR2-mediated inflammation, which helps to fight infections, may exacerbate inflammatory disorders like atopic dermatitis. Our study highlights intricate immune responses preventing infections from colonizing bacteria.

scholarly journals Toll-Like Receptor 2-Dependent Extracellular Signal-Regulated Kinase Signaling in Mycobacterium tuberculosis-Infected Macrophages Drives Anti-Inflammatory Responses and Inhibits Th1 Polarization of Responding T Cells

2015 ◽  
Vol 83 (6) ◽  
pp. 2242-2254 ◽  
Author(s):  
Edward T. Richardson ◽  
Supriya Shukla ◽  
David R. Sweet ◽  
Pamela A. Wearsch ◽  
Philip N. Tsichlis ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Erk Signaling ◽  
Toll Like Receptor ◽  
Content Type ◽  
Extracellular Signal ◽  
Toll Like Receptor 2 ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Th1 Polarization

Mycobacterium tuberculosissurvives within macrophages and employs immune evasion mechanisms to persist in the host. Protective T helper type 1 (Th1) responses are induced, and the immune response in most individuals is sufficient to restrictM. tuberculosisto latent infection, but most infections are not completely resolved. As T cells and macrophages respond, a balance is established between protective Th1-associated and other proinflammatory cytokines, such as interleukin-12 (IL-12), interferon gamma (IFN-γ), and tumor necrosis factor alpha, and anti-inflammatory cytokines, such as IL-10. The mechanisms by whichM. tuberculosismodulates host responses to promote its survival remain unclear. In these studies, we demonstrate thatM. tuberculosisinduction of IL-10, suppression of IL-12, and inhibition of class II major histocompatibility complex (MHC-II) molecules in infected macrophages are all driven by Toll-like receptor 2 (TLR2)-dependent activation of the extracellular signal-regulated kinases (ERK). Elimination of ERK signaling downstream of TLR2 by pharmacologic inhibition with U0126 or genetic deletion ofTpl2blocks IL-10 secretion and enhances IL-12 p70 secretion. We demonstrate thatM. tuberculosisregulation of these pathways in macrophages affects T cell responses to infected macrophages. Thus, genetic blockade of the ERK pathway inTpl2−/−macrophages enhances Th1 polarization and IFN-γ production by antigen-specific CD4+T cells responding toM. tuberculosisinfection. These data indicate thatM. tuberculosisand its potent TLR2 ligands activate ERK signaling in macrophages to promote anti-inflammatory macrophage responses and blunt Th1 responses against the pathogen.

scholarly journals Toll-Like Receptor 2 Agonist Pam3CSK4 Alleviates the Pathology of Leptospirosis in Hamster

2016 ◽  
Vol 84 (12) ◽  
pp. 3350-3357 ◽  
Author(s):  
Wenlong Zhang ◽  
Naisheng Zhang ◽  
Xufeng Xie ◽  
Jian Guo ◽  
Xuemin Jin ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Interleukin 10 ◽  
Peritoneal Macrophages ◽  
High Ratio ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Target Organs ◽  
Toll Like Receptor 2

Leptospirosis, caused by pathogenic spirochetes, is a zoonotic disease of global importance. The detailed pathogenesis of leptospirosis is still unclear, which limits the ideal treatment of leptospirosis. In this study, we analyzed the expression of Toll-like receptor 2 (TLR2) and TLR4 in target organs of both resistant mice and susceptible hamsters after Leptospira interrogans serovar Autumnalis infection. TLR2 but not TLR4 transcripts in mouse organs contrasted with delayed induction and overexpression in hamster organs. Coinjection of leptospires and the TLR2 agonist Pam3CSK4 into hamsters improved their survival rate, alleviated tissue injury, and decreased the abundance of leptospires in target organs. The production of interleukin-10 (IL-10) from tissues was enhanced in hamsters of the group coinjected with leptospires and Pam3CSK4 compared with the leptospira-injected group. Similarly, IL-10 levels in TLR2-deficient mice were lower than those in wild-type mice. A high ratio of IL-10/tumor necrosis factor alpha (TNF-α) levels was found in both infected wild-type mice and hamsters coinjected with leptospires and Pam3CSK4. Moreover, TLR2-dependent IL-10 expression was detected in peritoneal macrophages after leptospira infection. Our data demonstrate that coinjection of leptospires and Pam3CSK4 alleviates the pathology of leptospirosis in hamsters; this effect may result from the enhanced expression of TLR2-dependent IL-10.

scholarly journals NOD2 Stimulation by Staphylococcus aureus-Derived Peptidoglycan Is Boosted by Toll-Like Receptor 2 Costimulation with Lipoproteins in Dendritic Cells

2014 ◽  
Vol 82 (11) ◽  
pp. 4681-4688 ◽  
Author(s):  
Holger Schäffler ◽  
Dogan Doruk Demircioglu ◽  
Daniel Kühner ◽  
Sarah Menz ◽  
Annika Bender ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Dendritic Cells ◽  
Immune System ◽  
Cytokine Secretion ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Murine Bone Marrow ◽  
J774 Cells ◽  
Toll Like Receptor 2

ABSTRACTMutations in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) play an important role in the pathogenesis of Crohn's disease. NOD2 is an intracellular pattern recognition receptor (PRR) that senses bacterial peptidoglycan (PGN) structures, e.g., muramyl dipeptide (MDP). Here we focused on the effect of more-cross-linked, polymeric PGN fragments (PGNpol) in the activation of the innate immune system. In this study, the effect of combined NOD2 and Toll-like receptor 2 (TLR2) stimulation was examined compared to single stimulation of the NOD2 receptor alone. PGNpol species derived from a lipoprotein-containingStaphylococcus aureusstrain (SA113) and a lipoprotein-deficient strain (SA113 Δlgt) were isolated. While PGNpol constitutes a combined NOD2 and TLR2 ligand, lipoprotein-deficient PGNpolΔlgtleads to activation of the immune system only via the NOD2 receptor. Murine bone marrow-derived dendritic cells (BMDCs), J774 cells, and Mono Mac 6 (MM6) cells were stimulated with these ligands. Cytokines (interleukin-6 [IL-6], IL-12p40, and tumor necrosis factor alpha [TNF-α]) as well as DC activation and maturation parameters were measured. Stimulation with PGNpolΔlgtdid not lead to enhanced cytokine secretion or DC activation and maturation. However, stimulation with PGNpol led to strong cytokine secretion and subsequent DC maturation. These results were confirmed in MM6 and J774 cells. We showed that the NOD2-mediated activation of DCs with PGNpol was dependent on TLR2 costimulation. Therefore, signaling via both receptors leads to a more potent activation of the immune system than that with stimulation via each receptor alone.

scholarly journals Roles of Toll-Like Receptor 2 (TLR2), TLR4, and MyD88 during Pulmonary Coxiella burnetii Infection

2016 ◽  
Vol 84 (4) ◽  
pp. 940-949 ◽  
Author(s):  
Andrew G. Ramstead ◽  
Amanda Robison ◽  
Anne Blackwell ◽  
Maria Jerome ◽  
Brett Freedman ◽  
...  
Keyword(s):  
Immune Responses ◽  
Coxiella Burnetii ◽  
Bacterial Growth ◽  
Pulmonary Infection ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Content Type ◽  
Link Type ◽  
Peripheral Infection ◽  
Toll Like Receptor 2

Coxiella burnetii, the causative agent of Q fever, is an obligate intracellular, primarily pulmonary, bacterial pathogen. Although much is known about adaptive immune responses against this bacterium, our understanding of innate immune responses againstC. burnetiiis not well defined, particularly within the target tissue for infection, the lung. Previous studies examined the roles of the innate immune system receptors Toll-like receptor 2 (TLR2) and TLR4 in peripheral infection models and described minimal phenotypes in specific gene deletion animals compared to those of their wild-type controls (S. Meghari et al., Ann N Y Acad Sci 1063:161–166, 2005,http://dx.doi.org/10.1196/annals.1355.025; A. Honstettre et al., J Immunol 172:3695–3703, 2004,http://dx.doi.org/10.4049/jimmunol.172.6.3695) . Here, we assessed the roles for TLR2, TLR4, and MyD88 in pulmonaryC. burnetiiinfection and compared responses to those that occurred in TLR2- and TLR4-deficient animals following peripheral infection. As observed previously, neither TLR2 nor TLR4 was needed for limiting bacterial growth after peripheral infection. In contrast, TLR2 and, to a lesser extent, TLR4 limited growth (or dissemination) of the bacterium in the lung and spleen after pulmonary infection. TLR2, TLR4, and MyD88 were not required for the general inflammatory response in the lungs after pulmonary infection. However, MyD88 signaling was important for infection-induced morbidity. Finally, TLR2 expression on hematopoietic cells was most important for limiting bacterial growth in the lung. These results expand on our knowledge of the roles for TLR2 and TLR4 inC. burnetiiinfection and suggest various roles for these receptors that are dictated by the site of infection.

scholarly journals Essential Engagement of Toll-Like Receptor 2 in Initiation of Early Protective Th1 Response against Rough Variants of Mycobacterium abscessus

2015 ◽  
Vol 83 (4) ◽  
pp. 1556-1567 ◽  
Author(s):  
Jong-Seok Kim ◽  
Min-Jung Kang ◽  
Woo Sik Kim ◽  
Seung Jung Han ◽  
Hong Min Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Protective Immunity ◽  
Mycobacterium Abscessus ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Term Survival ◽  
Content Type ◽  
Specific Manner ◽  
Toll Like Receptor 2

AlthoughMycobacterium abscessus(M. abscessus) is becoming more prevalent in patients without overt immunodeficiency, little is known about the factors that contribute to disease susceptibility. This study was undertaken to investigate how Toll-like receptor 2 (TLR2) functionally contributes to the generation of protective immunity againstM. abscessusin a morphotype-specific manner. We found thatTlr2−/−mice were extremely susceptible to an intravenous (i.v.) model of infection byM. abscessusrough variants, displaying uncontrolled infection in the lungs and a significantly lower survival rate than with wild-type (WT) mice. This uncontrolled infection resulted from failures in the following processes: (i) production of the crucial cytokines gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin 12p70 (IL-12p70); (ii) early infiltration of neutrophils, monocytes, and dendritic cells (DCs) in the lungs ofTlr2−/−mice; (iii) rapid influx of CD4+and CD8+T cells; and (iv) the expansion of memory/effector T cells. Notably, systemic administration ofM. abscessusculture filtrate-treated syngeneic DCs from WT mice greatly strengthened immune primingin vivo, resulting in a dramatic reduction in bacterial growth and improved long-term survival inTlr2−/−mice, with a recovery of protective immunity. Our findings demonstrate that TLR2 is an essential contributor to instructive and effector immunity duringM. abscessusinfection in a morphotype-specific manner.

scholarly journals Sonic hedgehog-Dependent Induction of MicroRNA 31 and MicroRNA 150 Regulates Mycobacterium bovis BCG-Driven Toll-Like Receptor 2 Signaling

2012 ◽  
Vol 33 (3) ◽  
pp. 543-556 ◽  
Author(s):  
Devram Sampat Ghorpade ◽  
Sahana Holla ◽  
Srini V. Kaveri ◽  
Jagadeesh Bayry ◽  
Shripad A. Patil ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Adaptor Protein ◽  
Toll Like Receptor ◽  
Shh Signaling ◽  
Content Type ◽  
Tnf Α ◽  
Toll Like Receptor 2 ◽  
Hh Signaling ◽  
Tlr2 Signaling

ABSTRACTHedgehog (HH) signaling is a significant regulator of cell fate decisions during embryogenesis, development, and perpetuation of various disease conditions. Testing whether pathogen-specific HH signaling promotes unique innate recognition of intracellular bacteria, we demonstrate that among diverse Gram-positive or Gram-negative microbes,Mycobacterium bovisBCG, a vaccine strain, elicits a robust activation of Sonic HH (SHH) signaling in macrophages. Interestingly, sustained tumor necrosis factor alpha (TNF-α) secretion by macrophages was essential for robust SHH activation, as TNF-α−/−macrophages exhibited compromised ability to activate SHH signaling. Neutralization of TNF-α or blockade of TNF-α receptor signaling significantly reduced the infection-induced SHH signaling activation bothin vitroandin vivo. Intriguingly, activated SHH signaling downregulatedM. bovisBCG-mediated Toll-like receptor 2 (TLR2) signaling events to regulate a battery of genes associated with divergent functions of M1/M2 macrophages. Genome-wide expression profiling as well as conventional gain-of-function or loss-of-function analysis showed that SHH signaling-responsive microRNA 31 (miR-31) and miR-150 target MyD88, an adaptor protein of TLR2 signaling, thus leading to suppression of TLR2 responses. SHH signaling signatures could be detectedin vivoin tuberculosis patients andM. bovisBCG-challenged mice. Collectively, these investigations identify SHH signaling to be what we believe is one of the significant regulators of host-pathogen interactions.

scholarly journals Impact of Toll-Like Receptor 2 Deficiency on Immune Responses to Mycobacterial Antigens

2011 ◽  
Vol 79 (11) ◽  
pp. 4649-4656 ◽  
Author(s):  
Muhammad J. Rahman ◽  
Olga D. Chuquimia ◽  
Dagbjort H. Petursdottir ◽  
Natalia Periolo ◽  
Mahavir Singh ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cellular Responses ◽  
Mouse Strains ◽  
Mycobacterial Antigen ◽  
Toll Like Receptor ◽  
Partial Explanation ◽  
Content Type ◽  
Tlr2 Ligand ◽  
Toll Like Receptor 2

ABSTRACTIn the present study, we addressed the question of whether Toll-like receptor 2 (TLR2)-mediated innate immunity can contribute to the development of acquired immune responses. We immunized TLR2−/−and wild-type (WT) mice three times subcutaneously with the mycobacterial antigen (Ag19kDa) (a TLR2 ligand) or Ag85A (not a TLR2 ligand). One week after the last immunization, sera and spleens were collected. To evaluate cellular responses, we measured gamma interferon (IFN-γ) afterin vitrorestimulation of spleen cells with antigen alone or antigen-pulsed bone marrow-derived macrophages (BMMAg) or pulmonary macrophages (PuMAg). Antibody responses were comparable in the two mouse strains, but we observed differences in the cellular responses. Recall responses to Ag85A were similar in the two strains, but responses to Ag19kDa given alone or presented by BMM or PuM were lower in TLR2−/−than in WT mice. The largest differences in cellular responses were observed when Ag19kDa was presented by PuM. To understand this, we analyzed phenotypic and functional differences between BMM and PuM upon stimulation with various ligands. Generally, PuM had a lower response to the TLR2 ligand Pam3Cys-Ser-(Lys)4trihydrochloride and to anti-CD40 than BMM, as measured by cytokine secretion and upregulation of costimulatory molecules. This might provide a partial explanation for the lower capacity of PuM when pulsed with Ag19kDa, also a TLR2 ligand. Altogether, our results revealed weaknesses in the T cell and antigen-presenting cell (APC) compartments of the Ag19kDa-immunized TLR2−/−mice but indicated that specific immune responses could be generated in the absence of TLR2 regardless of the characteristics of the antigen used.

scholarly journals Cytadherence of Mycoplasma pneumoniae Induces Inflammatory Responses through Autophagy and Toll-Like Receptor 4

2014 ◽  
Vol 82 (7) ◽  
pp. 3076-3086 ◽  
Author(s):  
Takashi Shimizu ◽  
Yui Kimura ◽  
Yutaka Kida ◽  
Koichi Kuwano ◽  
Masato Tachibana ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mycoplasma Pneumoniae ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Hypothetical Protein ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Content Type ◽  
Toll Like Receptor 2

ABSTRACTMycoplasma pneumoniaecauses pneumonia, tracheobronchitis, pharyngitis, and asthma in humans. The pathogenesis ofM. pneumoniaeinfection is attributed to excessive immune responses. We previously demonstrated thatM. pneumoniaelipoproteins induced inflammatory responses through Toll-like receptor 2 (TLR2). In the present study, we demonstrated thatM. pneumoniaeinduced strong inflammatory responses in macrophages derived from TLR2 knockout (KO) mice. Cytokine production in TLR2 KO macrophages was increased compared with that in the macrophages of wild-type (WT) mice. Heat-killed, antibiotic-treated, and overgrownM. pneumoniaefailed to induce inflammatory responses in TLR2 KO macrophages. 3-Methyladenine and chloroquine, inhibitors of autophagy, decreased the induction of inflammatory responses in TLR2 KO macrophages. These inflammatory responses were also inhibited in macrophages treated with the TLR4 inhibitor VIPER and those obtained from TLR2 and TLR4 (TLR2/4) double-KO mice. Two mutants that lacked the ability to induce inflammatory responses in TLR2 KO macrophages were obtained by transposon mutagenesis. The transposons were inserted inatpCencoding an ATP synthase F0F1 ε subunit andF10_orf750encoding hypothetical protein MPN333. These mutants showed deficiencies in cytadherence. These results suggest that cytadherence ofM. pneumoniaeinduces inflammatory responses through TLR4 and autophagy.

scholarly journals Subinhibitory Doses of Aminoglycoside Antibiotics Induce Changes in the Phenotype of Mycobacterium abscessus

2015 ◽  
Vol 59 (10) ◽  
pp. 6161-6169 ◽  
Author(s):  
Sheng-Hui Tsai ◽  
Hsin-Chih Lai ◽  
Shiau-Ting Hu
Keyword(s):  
Mycobacterium Abscessus ◽  
Aminoglycoside Antibiotics ◽  
Toll Like Receptor ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Tnf Α ◽  
Bacterial Morphology ◽  
Toll Like Receptor 2 ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACTSubinhibitory doses of antibiotics have been shown to cause changes in bacterial morphology, adherence ability, and resistance to antibiotics. In this study, the effects of subinhibitory doses of aminoglycoside antibiotics onMycobacterium abscessuswere investigated. The treatment ofM. abscessuscells with subinhibitory doses of amikacin was found to change their colony from a smooth to a rough morphotype and increase their ability to adhere to a polyvinylchloride plate, aggregate in culture, and resist phagocytosis and killing by macrophages.M. abscessuscells treated with a subinhibitory dose of amikacin also became more potent in Toll-like receptor 2 (TLR-2) stimulation, leading to increased tumor necrosis factor alpha (TNF-α) production by macrophages. The MAB_3508c gene was shown to play a role in mediating these phenotypic changes, as its expression inM. abscessuscells was increased when they were treated with a subinhibitory dose of amikacin. In addition, overexpression of MAB_3508c inM. abscessuscells caused changes similar to those induced by subinhibitory doses of amikacin, including a switch from smooth to rough colony morphology, increased ability to aggregate in liquid culture, decreased motility, and increased resistance to killing by macrophages. These findings suggest the importance of using sufficient doses of antibiotics for the treatment ofM. abscessusinfections.

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