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Patrick J Brennan - One of the best experts on this subject based on the ideXlab platform.

  • the role of mycobacterium leprae Phenolic Glycolipid i pgl i in serodiagnosis and in the pathogenesis of leprosy
    Leprosy Review, 2011
    Co-Authors: John S Spencer, Patrick J Brennan
    Abstract:

    Summary PGL-I (Phenolic Glycolipid I) emerged in the early 1980s on the one hand as part of intensive efforts to define the typing antigens of ah ost of Mycobacterium spp. and also from characterisation of the lipids of skin biopsies from highly bacillary positive lepromatous leprosy patients. PGL-I, despite its extreme lipophilicity due to its inherent phthiocerol dimycocerosyl component, is highly antigenic evoking high titre IgM antibodies in lepromatous leprosy patients, attributable largely to the unique 3,6-di- O -methyl- b -D-glucosyl entity at the non-reducing terminus of its trisaccharide. PGL-I itself or in the form of semisynthetic neoglycoproteins containing the synthetic terminal disaccharide or the whole trisaccharide chemically conjugated to such as bovine or human serum albumin, has found its greatest utility in the serological diagnosis, confirmation and management of lepromatous leprosy. PGL-I has also been implicated in the tropism of M. leprae for Schwann cells, through specific binding to laminin, and to play an important role in downregulation of the inflammatory immune response and inhibition of dendritic cell maturation and activation, thereby facilitating the persistence of M. leprae/leprosy.

  • Production and characterization of peptide mimotopes of Phenolic Glycolipid-I of Mycobacterium leprae.
    Fems Immunology and Medical Microbiology, 2004
    Co-Authors: Ju Ho Youn, Patrick J Brennan, Han-jeong Myung, Abraham Liav, Delphi Chatterjee, In-hong Choi, Jeon-soo Shin
    Abstract:

    Phenolic Glycolipid-I (PGL-I), a Mycobacterium leprae-specific antigen, has been widely used for the serodiagnosis of leprosy and has been implicated in the pathogenesis of leprosy. In an effort to produce an alternate antigen of PGL-I, the mimotope peptides of PGL-I, W(T/R)LGPY(V/M), were obtained using a monoclonal antibody, III603.8, specific to PGL-I by a phage library. The biotin-labeled predominant mimotope peptide of PGLP1, WTLGPYV, bound to III603.8 in a dose-dependent manner in an immunoassay. However, PGLP1 did not bind to anti-PGL-I antibodies in the serum samples from leprosy patients that were reactive to PGL-I. Although the mimotope peptide of WTLGPYV was not effective as an alternate antigen of PGL-I for the serodiagnosis of leprosy, but it would be of interest to know how the mimotope peptides mimic the role of PGL-I antigen in the pathogenesis of M. leprae infection.

  • detection of Phenolic Glycolipid i of mycobacterium leprae in sera from leprosy patients before and after start of multidrug therapy
    Clinical and Vaccine Immunology, 2001
    Co-Authors: Sang Nae Cho, R. V. Cellona, T. T. Fajardo, G. P. Walsh, Joo-deuk Kim, L G Villahermosa, Marivic F Balagon, R M Abalos, Esterlina V Tan, Patrick J Brennan
    Abstract:

    A total of 100 untreated new leprosy patients were recruited prospectively and examined for the presence of Phenolic Glycolipid I (PGL-I) antigen in their serum specimens by dot enzyme-linked immunosorbent assay (ELISA) using rabbit anti-PGL-I antiserum. The presence of circulating PGL-I antigen was closely related to the bacterial indices (BI) of the patients. The PGL-I antigen was detectable in 27 (93.1%) of 29 patients with a BI of 4.0 or above and in 15 (68.2%) of 22 patients with a BI of 3.0 to 3.9. However, none of the 37 patients with a BI of less than 1.9 had detectable PGL-I antigen by the methods used in this study. The level of PGL-I in serum declined rapidly by about 90% 1 month after the start of multidrug therapy. This study showed clearly that anti-PGL-I IgM antibodies and circulating PGL-I antigen levels reflect the bacterial loads in untreated leprosy patients. The serological parameters based on the PGL-I antigen may therefore be useful in the assessment of leprosy patients at the time of diagnosis and possibly in monitoring patients following chemotherapy.

  • role of the cell wall Phenolic Glycolipid 1 in the peripheral nerve predilection of mycobacterium leprae
    Cell, 2000
    Co-Authors: George Zanazzi, Rupert Timpl, Jan F Talts, James L Salzer, Patrick J Brennan, Anura Rambukkana
    Abstract:

    The cell wall of pathogenic mycobacteria is abundant with complex Glycolipids whose roles in disease pathogenesis are mostly unknown. Here, we provide evidence for the involvement of the specific trisaccharide unit of the Phenolic Glycolipid-1 (PGL-1) of Mycobacterium leprae in determining the bacterial predilection to the peripheral nerve. PGL-1 binds specifically to the native laminin-2 in the basal lamina of Schwann cell-axon units. This binding is mediated by the alpha(2LG1, alpha2LG4, and alpha2LG5 modules present in the naturally cleaved fragments of the peripheral nerve laminin alpha2 chain, and is inhibited by the synthetic terminal trisaccharide of PGL-1. PGL-1 is involved in the M. leprae invasion of Schwann cells through the basal lamina in a laminin-2-dependent pathway. The results indicate a novel role of a bacterial Glycolipid in determining the nerve predilection of a human pathogen.

  • Structural elucidation and antigenicity of a novel Phenolic Glycolipid antigen from Mycobacterium haemophilum.
    Biochemistry, 1991
    Co-Authors: Gurdyal S. Besra, David E. Minnikin, Françoise Portaels, Malin Ridell, Michael R. Mcneil, Patrick J Brennan
    Abstract:

    The structure of a novel antigenic Glycolipid that distinguishes the opportunistic pathogen Mycobacterium haemophilum from all other mycobacteria was established by a series of degradation reactions leading to products that were analyzed by gas/liquid chromatography-mass spectrometry. The complete structure of the oligosaccharide unit was determined as 2,3-di-O-CH3-alpha-L-Rhap(1----2)3-O-CH3-alpha-L-Rhap(1----4 )-2,3-di-O-CH3-alpha-L-Rhap(1----. The lipid portion of the Phenolic Glycolipid was composed of two component phenolphthiocerols differing by two methylene groups, as determined by analysis of their per-O-trideuteriomethylated derivatives. The diol unit of the phenolphthiocerols has a threo relative configuration. The absolute stereochemistry of the asymmetric centers of the phenolphthiocerols is uncertain, but the centers are probably 3R, 4S, 9R, and 11R as found for phthiocerol A from Mycobacterium tuberculosis. The hydroxyl functions of the branched glycolic chain are esterified to a complex mixture of multi-methyl branched mycocerosic acids, C27, C30, C32, C34, and C37 with molecular weights (as methyl esters) of 424, 466, 494, 522, and 564, respectively. The stereochemistry of the methyl branches of the mycocerosates have R absolute configuration. The Glycolipid is highly antigenic and appears to be specific for M. haemophilum. There are intriguing similarities between the product from M. haemophilum and the well-known Phenolic Glycolipid I of Mycobacterium leprae, a matter that is discussed.

Sang Nae Cho - One of the best experts on this subject based on the ideXlab platform.

  • Comparison of two rapid tests for anti-Phenolic Glycolipid-I serology in Brazil and Nepal
    Memórias do Instituto Oswaldo Cruz, 2012
    Co-Authors: Mariane Martins De Araújo Stefani, Adriano Badotti Grassi, Lucas H. Sampaio, Ana Lucia Maroclo Sousa, Maurício Barcelos Costa, Pauline Scheelbeek, Kapil D. Neupane, Deanna A. Hagge, Murdo Macdonald, Sang Nae Cho
    Abstract:

    The diagnosis of leprosy continues to be based on clinical symptoms and early diagnosis and treatment are critical to preventing disability and transmission. Sensitive and specific laboratory tests are not available for diagnosing leprosy. Despite the limited applicability of anti-Phenolic Glycolipid-I (PGL-I) serology for diagnosis, it has been suggested as an additional tool to classify leprosy patients (LPs) for treatment purposes. Two formats of rapid tests to detect anti-PGL-I antibodies [ML immunochromatography assay (ICA) and ML Flow] were compared in different groups, multibacillary patients, paucibacillary patients, household contacts and healthy controls in Brazil and Nepal. High ML Flow intra-test concordance was observed and low to moderate agreement between the results of ML ICA and ML Flow tests on the serum of LPs was observed. LPs were "seroclassified" according to the results of these tests and the seroclassification was compared to other currently used classification systems: the World Health Organization operational classification, the bacilloscopic index and the Ridley-Jopling classification. When analysing the usefulness of these tests in the operational classification of PB and MB leprosy for treatment and follow-up purposes, the ML Flow test was the best point-of-care test for subjects in Nepal and despite the need for sample dilution, the ML ICA test yielded better performance among Brazilian subjects. Our results identified possible ways to improve the performance of both tests.

  • detection of Phenolic Glycolipid i of mycobacterium leprae in sera from leprosy patients before and after start of multidrug therapy
    Clinical and Vaccine Immunology, 2001
    Co-Authors: Sang Nae Cho, R. V. Cellona, T. T. Fajardo, G. P. Walsh, Joo-deuk Kim, L G Villahermosa, Marivic F Balagon, R M Abalos, Esterlina V Tan, Patrick J Brennan
    Abstract:

    A total of 100 untreated new leprosy patients were recruited prospectively and examined for the presence of Phenolic Glycolipid I (PGL-I) antigen in their serum specimens by dot enzyme-linked immunosorbent assay (ELISA) using rabbit anti-PGL-I antiserum. The presence of circulating PGL-I antigen was closely related to the bacterial indices (BI) of the patients. The PGL-I antigen was detectable in 27 (93.1%) of 29 patients with a BI of 4.0 or above and in 15 (68.2%) of 22 patients with a BI of 3.0 to 3.9. However, none of the 37 patients with a BI of less than 1.9 had detectable PGL-I antigen by the methods used in this study. The level of PGL-I in serum declined rapidly by about 90% 1 month after the start of multidrug therapy. This study showed clearly that anti-PGL-I IgM antibodies and circulating PGL-I antigen levels reflect the bacterial loads in untreated leprosy patients. The serological parameters based on the PGL-I antigen may therefore be useful in the assessment of leprosy patients at the time of diagnosis and possibly in monitoring patients following chemotherapy.

  • Prevalance of IgM antibodies to Phenolic Glycolipid I among household contacts and controls in Korea and the Philippines
    Leprosy review, 1992
    Co-Authors: Sang Nae Cho, Seong-hwa Kim, R. V. Cellona, Gertrude P. Chan, T. T. Fajardo, G. P. Walsh, Joo-deuk Kim
    Abstract:

    Phenolic Glycolipid I (PGL-I) is a Mycobacterium leprae-specific antigen and the antibodies to the antigen may suggest an M. leprae infection. To compare the M. leprae transmission among the populations, we compared the prevalence of anti-PGL-I IgM antibodies among household contacts and controls between Korea and the Philippines. In Korea (prevalence of leprosy--0.04: 1000), the prevalence of anti-PGL-I antibodies were 4.8% among controls and 8.0% among contacts, respectively. On the other hand, the seroprevalence rate was 10.8% among controls and 13.4% among contacts in the Philippines (prevalence of leprosy--0.70: 1000). Interestingly, a marked difference was noted in the prevalance of anti-PGL-I antibodies among children between the countries; 10-14% among children under 10 years old and 15-18% among those aged between 10 and 19 in the Philippines compared to 0% and 2.9-6.4% in Korea, respectively. This study, therefore suggests that a high prevalance of anti-PGL-I IgM antibodies among children may indicate an active transmission of M. leprae, resulting in a higher incidence of leprosy in the population.

  • Production of monoclonal antibody to a Phenolic Glycolipid of Mycobacterium tuberculosis and its use in detection of the antigen in clinical isolates.
    Journal of clinical microbiology, 1992
    Co-Authors: Sang Nae Cho, J S Shin, M Daffe, Yunsop Chong, Sung Kyu Kim, Joo-deuk Kim
    Abstract:

    A monoclonal antibody (MAbIII604) specific to Phenolic Glycolipid Tb (PGL-Tb), a Mycobacterium tuberculosis-specific antigen, was produced and used in the detection of the antigen. MAbIII604 reacted with the PGL-Tb antigen but not with other Phenolic Glycolipids from Mycobacterium leprae, M. bovis, and M. kansasii, thus indicating the specificity of the monoclonal antibody to PGL-Tb. A dot enzyme-linked immunosorbent assay with MAbIII604 was employed to detect the PGL-Tb antigen in lipids purified from M. tuberculosis clinical isolates. Of 50 isolates, 32 (64.0%) showed clear evidence of the PGL-Tb antigen by the dot enzyme-linked immunosorbent assay, but there were marked variations in the intensities and sizes of spots. This suggests differences in PGL-Tb antigen production among M. tuberculosis strains even when they are grown in the same culture media and conditions. This was most evident from the fact that in only eight (16.0%) of the isolates examined was the PGL-Tb antigen detectable by thin-layer chromatography, which is much less sensitive for the detection of Glycolipid antigens. This study shows that monoclonal antibodies specific to PGL-Tb are useful in detecting the antigen in lipid extracts and that there is a marked variation in the PGL-Tb production among M. tuberculosis clinical isolates.

  • detection of Phenolic Glycolipid i antigen and antibody in sera from new and relapsed lepromatous patients treated with various drug regimens
    International Journal of Leprosy and Other Mycobacterial Diseases, 1991
    Co-Authors: Sang Nae Cho, R. V. Cellona, T. T. Fajardo, G. P. Walsh, Joo-deuk Kim, R M Abalos, E Dela C Cruz, P. J. Brennan
    Abstract:

    Since Phenolic Glycolipid-I (PGL-I) is an unequivocal marker of Mycobacterium leprae, the antigen has been a good candidate for the serodiagnosis and monitoring the effectiveness of leprosy chemotherapy. As an effort to define the kinetics of the PGL-I antigen and its antibodies in leprosy patients, this study was initiated to examine the serum specimens obtained serially from lepromatous patients under chemotherapy trials. PGL-I was detectable in 64 (94.1%) of 68 new lepromatous (bacterial index, BI = 3.2 to 5.8) and in 26 (78.8%) of 33 relapsed lepromatous patients (BI = 3.0 to 5.3). Meanwhile, virtually all of the new and relapsed patients were strongly seropositive to PGL-I. PGL-I was not detectable in any of the patients about 18 months after chemotherapy was initiated; however, anti-PGL-I reactivity declined by 50% at 2 years and by about 70% at 5 years after chemotherapy regardless of the drug regimens under study. Considering the rapid disappearance of the PGL-I antigen and steady decrease in anti-PGL-I IgM antibodies following chemotherapy, the PGL-I-based serology may be useful for monitoring the effectiveness of treatment, at both the early and late stages, in leprosy patients whose initial sera contain a significant level of PGL-I antigen or antibodies.

Paul R. Klatser - One of the best experts on this subject based on the ideXlab platform.

  • A SIMPLE DIPSTICK ASSAY FOR THE DETECTION OF ANTIBODIES TO Phenolic Glycolipid-I OF MYCOBACTERIUM LEPRAE
    The American journal of tropical medicine and hygiene, 1998
    Co-Authors: S S Bührer, Henk L. Smits, George C. Gussenhoven, C. W. Van Ingen, Paul R. Klatser
    Abstract:

    Among the many reported applications of the detection of antibodies to Phenolic Glycolipid-I (PGL-I) of Mycobacterium leprae, in particular, the use of seroprevalence as an indicator of the magnitude of the leprosy problem may turn out to be very useful in leprosy control programs. An operational function of serology within the leprosy control services requires a simple test system. We have developed a simple dipstick assay for the detection of antibodies to PGL-I and compared its performance with that of an ELISA. A high degree of agreement (97.2%) was observed between the ELISA and the dipstick assay when tested on 435 sera; the agreement beyond chance (Kappa value) was 0.92. No significant difference was found between the dipstick assay and the ELISA when seropositivity rates obtained in groups of leprosy patients, household contacts, and controls were compared. The interpretation of the dipstick results as positive or negative was unequivocal, as illustrated by the high agreement between different persons reading the test (Kappa values > 0.88). Storage of the only reagents required, the dipsticks and the stabilized detection reagent, up to three weeks under tropical conditions of high temperatures, high humidity, and exposure to light, did not influence the results of the assay. The dipstick assay described here is an easy-to-perform method for the detection of IgM antibodies to PGL-I of M. leprae; it does not require any special equipment and the highly stable reagents make the test robust and suitable for use in tropical countries. An internal control validates the performance of the assay. This dipstick assay may be the method of choice for epidemiologic mapping of leprosy.

Mamadou Daffe - One of the best experts on this subject based on the ideXlab platform.

  • characterization of three glycosyltransferases involved in the biosynthesis of the Phenolic Glycolipid antigens from the mycobacterium tuberculosis complex
    Journal of Biological Chemistry, 2004
    Co-Authors: Esther Perez, Mamadou Daffe, Patricia Constant, Anne Lemassu, Francoise Laval, Christophe Guilhot
    Abstract:

    Mycobacterium tuberculosis and Mycobacterium leprae, the two main mycobacterial pathogens in humans, produce highly specific long chain beta-diols, the dimycocerosates of phthiocerol, and structurally related Phenolic Glycolipid (PGL) antigens, which are important virulence factors. In addition, M. tuberculosis also secretes glycosylated p-hydroxybenzoic acid methyl esters (p-HBAD) that contain the same carbohydrate moiety as the species-specific PGL of M. tuberculosis (PGL-tb). The genes involved in the biosynthesis of these compounds in M. tuberculosis are grouped on a 70-kilobase chromosomal fragment containing three genes encoding putative glycosyltransferases: Rv2957, Rv2958c, and Rv2962c. To determine the functions of these genes, three recombinant M. tuberculosis strains, in which these genes were individually inactivated, were constructed and biochemically characterized. Our results demonstrated that (i) the biosynthesis of PGL-tb and p-HBAD involves common enzymatic steps, (ii) the Rv2957, Rv2958c, and Rv2962c genes are involved in the formation of the glycosyl moiety of the two classes of molecules, and (iii) the product of Rv2962c catalyzes the transfer of a rhamnosyl residue onto p-hydroxybenzoic acid ethyl ester or phenolphthiocerol dimycocerosates, whereas the products of Rv2958c and Rv2957 add a second rhamnosyl unit and a fucosyl residue to form the species-specific triglycosyl appendage of PGL-tb and p-HBAD. The recombinant strains produced provide the tools to study the role of the carbohydrate domain of PGL-tb and p-HBAD in M. tuberculosis pathogenesis.

  • Chemical Synthesis and Seroreactivity of a Neoantigen Containing the Oligosaccharide Hapten of the Mycobacterium tuberculosis-Specific Phenolic Glycolipid
    The Journal of infectious diseases, 1991
    Co-Authors: Mamadou Daffe, Sang Nae Cho, Delphi Chatterjee, Patrick J Brennan
    Abstract:

    The report of a major triglycosyl phenol phthiocerol (Phenolic) Glycolipid in some strains of Mycobacterium tuberculosis that resembles the Phenolic Glycolipid I of Mycobacterium leprae raised the prospects of a specific serodiagnostic tool for human tuberculosis. The terminal diglycosyl unit of the M. tuberculosis product was synthesized and converted to a corresponding neoglycoprotein, the O-(2,3,4-tri-O-methyl-alpha-L-fucopyranosyl)-(1----3)-O-alpha-L- rhamnopyranosyl)-(1----9)-oxynonanoyl-bovine serum albumin, and applied, in ELISA, to sera from individuals with tuberculosis. Although the correlation coefficient between the synthetic product and the native Glycolipid was excellent, the seroreactivity rate of tuberculous sera was disappointing; only 24 of 119 sera from tuberculosis patients showed evidence of anti-Glycolipid antibodies. In isolates of M. tuberculosis from tuberculosis patients the Glycolipid was present in only 1 of 11. A partially deglycosylated version was present in two other isolates; however, most isolates lacked the Glycolipid. Accordingly, while the results, unlike those of others, do not portend a future for this form of serodiagnosis in the management of tuberculosis, they offer intriguing hints as to the basis of the variable immunogenicity and pathogenicity of strains of M. tuberculosis.

S S Bührer - One of the best experts on this subject based on the ideXlab platform.

  • A SIMPLE DIPSTICK ASSAY FOR THE DETECTION OF ANTIBODIES TO Phenolic Glycolipid-I OF MYCOBACTERIUM LEPRAE
    The American journal of tropical medicine and hygiene, 1998
    Co-Authors: S S Bührer, Henk L. Smits, George C. Gussenhoven, C. W. Van Ingen, Paul R. Klatser
    Abstract:

    Among the many reported applications of the detection of antibodies to Phenolic Glycolipid-I (PGL-I) of Mycobacterium leprae, in particular, the use of seroprevalence as an indicator of the magnitude of the leprosy problem may turn out to be very useful in leprosy control programs. An operational function of serology within the leprosy control services requires a simple test system. We have developed a simple dipstick assay for the detection of antibodies to PGL-I and compared its performance with that of an ELISA. A high degree of agreement (97.2%) was observed between the ELISA and the dipstick assay when tested on 435 sera; the agreement beyond chance (Kappa value) was 0.92. No significant difference was found between the dipstick assay and the ELISA when seropositivity rates obtained in groups of leprosy patients, household contacts, and controls were compared. The interpretation of the dipstick results as positive or negative was unequivocal, as illustrated by the high agreement between different persons reading the test (Kappa values > 0.88). Storage of the only reagents required, the dipsticks and the stabilized detection reagent, up to three weeks under tropical conditions of high temperatures, high humidity, and exposure to light, did not influence the results of the assay. The dipstick assay described here is an easy-to-perform method for the detection of IgM antibodies to PGL-I of M. leprae; it does not require any special equipment and the highly stable reagents make the test robust and suitable for use in tropical countries. An internal control validates the performance of the assay. This dipstick assay may be the method of choice for epidemiologic mapping of leprosy.