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Open Access 01-06-2020 | Leprosy | Review

The immunology of other mycobacteria: M. ulcerans, M. leprae

Authors: Katharina Röltgen, Gerd Pluschke, John Stewart Spencer, Patrick Joseph Brennan, Charlotte Avanzi

Published in: Seminars in Immunopathology | Issue 3/2020

Abstract

Mycobacterial pathogens can be categorized into three broad groups: Mycobacterium tuberculosis complex causing tuberculosis, M. leprae and M. lepromatosis causing leprosy, and atypical mycobacteria, or non-tuberculous mycobacteria (NTM), responsible for a wide range of diseases. Among the NTMs, M. ulcerans is responsible for the neglected tropical skin disease Buruli ulcer (BU). Most pathogenic mycobacteria, including M. leprae, evade effector mechanisms of the humoral immune system by hiding and replicating inside host cells and are furthermore excellent modulators of host immune responses. In contrast, M. ulcerans replicates predominantly extracellularly, sheltered from host immune responses through the cytotoxic and immunosuppressive effects of mycolactone, a macrolide produced by the bacteria. In the year 2018, 208,613 new cases of leprosy and 2713 new cases of BU were reported to WHO, figures which are notoriously skewed by vast underreporting of these diseases.

As treatment with streptomycin has been shown to cause permanent ototoxicity and transient nephrotoxicity in BU patients, the WHO Technical Advisory Group on Buruli ulcer recommended in 2017 replacing streptomycin with oral clarithromycin for the treatment of BU in Africa.

It is currently not possible to distinguish between M. leprae and M. lepromatosis infection without molecular tools. Less than 20 cases of M. lepromatosis infection have been reported worldwide mostly in Mexico and the Caribbean region with a few sporadic cases in Asia, Europe, and North America. There have been not enough investigations regarding the differences in clinical outcomes and immunological responses between both pathogens. Therefore, the information reported in this review concerns M. leprae infections.

Ruf M-T, Steffen C, Bolz M, Schmid P, Pluschke G (2017) Infiltrating leukocytes surround early Buruli ulcer lesions, but are unable to reach the mycolactone producing mycobacteria. Virulence 8:1918–1926. https://doi.org/10.1080/21505594.2017.1370530 CrossRefPubMedPubMedCentral

Stinear TP, Seemann T, Pidot S, Frigui W, Reysset G, Garnier T, Meurice G, Simon D, Bouchier C, Ma L, Tichit M, Porter JL, Ryan J, Johnson PD, Davies JK, Jenkin GA, Small PL, Jones LM, Tekaia F, Laval F, Daffé M, Parkhill J, Cole ST (2007) Reductive evolution and niche adaptation inferred from the genome of Mycobacterium ulcerans, the causative agent of Buruli ulcer. Genome Res 17:192–200. https://doi.org/10.1101/gr.5942807 CrossRefPubMedPubMedCentral

Huber CA, Ruf M-T, Pluschke G, Käser M (2008) Independent loss of immunogenic proteins in Mycobacterium ulcerans suggests immune evasion. Clin Vaccine Immunol 15:598–606. https://doi.org/10.1128/CVI.00472-07 CrossRefPubMedPubMedCentral

Scollard DM, Adams LB, Gillis TP, Krahenbuhl JL, Truman RW, Williams DL (2006) The continuing challenges of leprosy. Clin Microbiol Rev 19:338–381. https://doi.org/10.1128/CMR.19.2.338-381.2006 CrossRefPubMedPubMedCentral

de Sousa JR, Sotto MN, Simões Quaresma JA (2017) Leprosy as a complex infection: breakdown of the Th1 and Th2 immune paradigm in the immunopathogenesis of the disease. Front Immunol 8. https://doi.org/10.3389/fimmu.2017.01635

Torrado E, Fraga AG, Castro AG, Stragier P, Meyers WM, Portaels F, Silva MT, Pedrosa J (2007) Evidence for an intramacrophage growth phase of Mycobacterium ulcerans. Infect Immun 75:977–987. https://doi.org/10.1128/IAI.00889-06 CrossRefPubMed

Röltgen K, Cruz I, Ndung’u JM, Pluschke G (2019) Laboratory diagnosis of Buruli ulcer: challenges and future perspectives. In: Pluschke G, Röltgen K (eds) Buruli ulcer: Mycobacterium ulcerans disease. Springer International Publishing, Cham, pp 183–202CrossRef

Kumar B, Uprety S, Dogra (2016) Clinical diagnosis of leprosy. In: The international textbook of leprosy, Scollard DM, Gillis TP

Nienhuis WA, Stienstra Y, Thompson WA et al (2010) Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomised controlled trial. Lancet 375:664–672. https://doi.org/10.1016/S0140-6736(09)61962-0

10.

Kar HK, Gupta R (2015) Treatment of leprosy. Clin Dermatol 33:55–65. https://doi.org/10.1016/j.clindermatol.2014.07.007 CrossRefPubMed

11.

Pluschke G, Röltgen K (2019) Buruli ulcer: Mycobacterium ulcerans disease. Springer International Publishing

12.

Doig KD, Holt KE, Fyfe JAM, Lavender CJ, Eddyani M, Portaels F, Yeboah-Manu D, Pluschke G, Seemann T, Stinear TP (2012) On the origin of Mycobacterium ulcerans, the causative agent of Buruli ulcer. BMC Genomics 13:258. https://doi.org/10.1186/1471-2164-13-258 CrossRefPubMedPubMedCentral

13.

George KM, Chatterjee D, Gunawardana G, Welty D, Hayman J, Lee R, Small PL (1999) Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence. Science 283:854–857. https://doi.org/10.1126/science.283.5403.854 CrossRefPubMed

14.

Röltgen K, Pluschke G (2015) Mycobacterium ulcerans disease (Buruli ulcer): potential reservoirs and vectors. Curr Clin Microbiol Rep 2:35–43. https://doi.org/10.1007/s40588-015-0013-3 CrossRef

15.

Käser M, Rondini S, Naegeli M, Stinear T, Portaels F, Certa U, Pluschke G (2007) Evolution of two distinct phylogenetic lineages of the emerging human pathogen Mycobacterium ulcerans. BMC Evol Biol 7:177. https://doi.org/10.1186/1471-2148-7-177 CrossRefPubMedPubMedCentral

16.

Mve-Obiang A, Lee RE, Portaels F, Small PLC (2003) Heterogeneity of mycolactones produced by clinical isolates of Mycobacterium ulcerans: implications for virulence. Infect Immun 71:774–783. https://doi.org/10.1128/iai.71.2.774-783.2003 CrossRefPubMedPubMedCentral

17.

Mve-Obiang A, Lee RE, Umstot ES et al (2005) A newly discovered mycobacterial pathogen isolated from laboratory colonies of Xenopus species with lethal infections produces a novel form of mycolactone, the Mycobacterium ulcerans macrolide toxin. Infect Immun 73:3307–3312. https://doi.org/10.1128/IAI.73.6.3307-3312.2005 CrossRefPubMedPubMedCentral

18.

Ranger BS, Mahrous EA, Mosi L, Adusumilli S, Lee RE, Colorni A, Rhodes M, Small PL (2006) Globally distributed mycobacterial fish pathogens produce a novel plasmid-encoded toxic macrolide, mycolactone F. Infect Immun 74:6037–6045. https://doi.org/10.1128/IAI.00970-06 CrossRefPubMedPubMedCentral

19.

Loftus MJ, Trubiano JA, Tay EL, Lavender CJ, Globan M, Fyfe JAM, Johnson PDR (2018) The incubation period of Buruli ulcer (Mycobacterium ulcerans infection) in Victoria, Australia - remains similar despite changing geographic distribution of disease. PLoS Negl Trop Dis 12:e0006323. https://doi.org/10.1371/journal.pntd.0006323 CrossRefPubMedPubMedCentral

20.

Hayman J, McQueen A (1985) The pathology of Mycobacterium ulcerans infection. Pathology (Phila) 17:594–600. https://doi.org/10.3109/00313028509084759 CrossRef

21.

Ruf M-T, Bolz M, Vogel M, Bayi PF, Bratschi MW, Sopho GE, Yeboah-Manu D, Um Boock A, Junghanss T, Pluschke G (2016) Spatial distribution of Mycobacterium ulcerans in Buruli ulcer lesions: implications for laboratory diagnosis. PLoS Negl Trop Dis 10:e0004767. https://doi.org/10.1371/journal.pntd.0004767 CrossRefPubMedPubMedCentral

22.

Guenin-Macé L, Ruf M-T, Pluschke G, Demangel C (2019) Mycolactone: more than just a cytotoxin. In: Pluschke G, Röltgen K (eds) Buruli ulcer: Mycobacterium ulcerans disease. Springer International Publishing, Cham, pp 117–134CrossRef

23.

George KM, Pascopella L, Welty DM, Small PL (2000) A Mycobacterium ulcerans toxin, mycolactone, causes apoptosis in guinea pig ulcers and tissue culture cells. Infect Immun 68:877–883. https://doi.org/10.1128/iai.68.2.877-883.2000 CrossRefPubMedPubMedCentral

24.

Coutanceau E, Marsollier L, Brosch R, Perret E, Goossens P, Tanguy M, Cole ST, Small PL, Demangel C (2005) Modulation of the host immune response by a transient intracellular stage of Mycobacterium ulcerans: the contribution of endogenous mycolactone toxin. Cell Microbiol 7:1187–1196. https://doi.org/10.1111/j.1462-5822.2005.00546.x CrossRefPubMed

25.

Adusumilli S, Mve-Obiang A, Sparer T et al (2005) Mycobacterium ulcerans toxic macrolide, mycolactone modulates the host immune response and cellular location of M. ulcerans in vitro and in vivo. Cell Microbiol 7:1295–1304. https://doi.org/10.1111/j.1462-5822.2005.00557.x CrossRefPubMed

26.

Bieri R, Scherr N, Ruf M-T et al (2017) The macrolide toxin mycolactone promotes Bim-dependent apoptosis in Buruli ulcer through inhibition of mTOR. ACS Chem Biol 12:1297–1307. https://doi.org/10.1021/acschembio.7b00053 CrossRefPubMed

27.

Guenin-Mace L, Baron L, Chany A-C, et al (2015) Shaping mycolactone for therapeutic use against inflammatory disorders. Sci Transl Med 7:289ra85-289ra85. https://doi.org/10.1126/scitranslmed.aab0458

28.

Hong H, Coutanceau E, Leclerc M et al (2008) Mycolactone diffuses from Mycobacterium ulcerans-infected tissues and targets mononuclear cells in peripheral blood and lymphoid organs. PLoS Negl Trop Dis 2:e325. https://doi.org/10.1371/journal.pntd.0000325 CrossRefPubMedPubMedCentral

29.

Volkman HE, Clay H, Beery D, Chang JC, Sherman DR, Ramakrishnan L (2004) Tuberculous granuloma formation is enhanced by a mycobacterium virulence determinant. PLoS Biol 2:e367. https://doi.org/10.1371/journal.pbio.0020367 CrossRefPubMedPubMedCentral

30.

Cole ST (2016) Inhibiting Mycobacterium tuberculosis within and without. Philos Trans R Soc B Biol Sci 371. https://doi.org/10.1098/rstb.2015.0506

31.

Marsollier L, Brodin P, Jackson M, Korduláková J, Tafelmeyer P, Carbonnelle E, Aubry J, Milon G, Legras P, André JP, Leroy C, Cottin J, Guillou ML, Reysset G, Cole ST (2007) Impact of Mycobacterium ulcerans biofilm on transmissibility to ecological niches and Buruli ulcer pathogenesis. PLoS Pathog 3:e62. https://doi.org/10.1371/journal.ppat.0030062 CrossRefPubMedPubMedCentral

32.

Gomez A, Mve-Obiang A, Vray B, Remacle J, Chemlal K, Meyers WM, Portaels F, Fonteyne PA (2000) Biochemical and genetic evidence for phospholipase C activity in Mycobacterium ulcerans. Infect Immun 68:2995–2997. https://doi.org/10.1128/iai.68.5.2995-2997.2000 CrossRefPubMedPubMedCentral

33.

Bolz M, Bénard A, Dreyer AM, Kerber S, Vettiger A, Oehlmann W, Singh M, Duthie MS, Pluschke G (2016) Vaccination with the surface proteins MUL_2232 and MUL_3720 of Mycobacterium ulcerans induces antibodies but fails to provide protection against Buruli ulcer. PLoS Negl Trop Dis 10:e0004431. https://doi.org/10.1371/journal.pntd.0004431 CrossRefPubMedPubMedCentral

34.

Bieri R, Bolz M, Ruf M-T, Pluschke G (2016) Interferon-γ is a crucial activator of early host immune defense against Mycobacterium ulcerans infection in mice. PLoS Negl Trop Dis 10:e0004450. https://doi.org/10.1371/journal.pntd.0004450 CrossRefPubMedPubMedCentral

35.

Röltgen K, Bratschi MW, Ross A, Aboagye SY, Ampah KA, Bolz M, Andreoli A, Pritchard J, Minyem JC, Noumen D, Koka E, Um Boock A, Yeboah-Manu D, Pluschke G (2014) Late onset of the serological response against the 18 kDa small heat shock protein of Mycobacterium ulcerans in children. PLoS Negl Trop Dis 8:e2904. https://doi.org/10.1371/journal.pntd.0002904 CrossRefPubMedPubMedCentral

36.

Dobos KM, Spotts EA, Marston BJ et al (2000) Serologic response to culture filtrate antigens of Mycobacterium ulcerans during Buruli ulcer disease. Emerg Infect Dis 6:158–164. https://doi.org/10.3201/eid0602.000208 CrossRefPubMedPubMedCentral

37.

Revill WD, Morrow RH, Pike MC, Ateng J (1973) A controlled trial of the treatment of Mycobacterium ulcerans infection with clofazimine. Lancet 2:873–877. https://doi.org/10.1016/s0140-6736(73)92005-9

38.

O’Brien DP, Murrie A, Meggyesy P et al (2019) Spontaneous healing of Mycobacterium ulcerans disease in Australian patients. PLoS Negl Trop Dis 13:e0007178. https://doi.org/10.1371/journal.pntd.0007178 CrossRefPubMedPubMedCentral

39.

Silva MT, Portaels F, Pedrosa J (2009) Pathogenetic mechanisms of the intracellular parasite Mycobacterium ulcerans leading to Buruli ulcer. Lancet Infect Dis 9:699–710. https://doi.org/10.1016/S1473-3099(09)70234-8 CrossRefPubMed

40.

Stanford JL, Revill WD, Gunthorpe WJ, Grange JM (1975) The production and preliminary investigation of Burulin, a new skin test reagent for Mycobacterium ulcerans infection. J Hyg (Lond) 74:7–16CrossRef

41.

Schütte D, Pluschke G (2009) Immunosuppression and treatment-associated inflammatory response in patients with Mycobacterium ulcerans infection (Buruli ulcer). Expert Opin Biol Ther 9:187–200. https://doi.org/10.1517/14712590802631854 CrossRefPubMed

42.

Baron L, Paatero AO, Morel J-D, Impens F, Guenin-Macé L, Saint-Auret S, Blanchard N, Dillmann R, Niang F, Pellegrini S, Taunton J, Paavilainen VO, Demangel C (2016) Mycolactone subverts immunity by selectively blocking the Sec61 translocon. J Exp Med 213:2885–2896. https://doi.org/10.1084/jem.20160662 CrossRefPubMedPubMedCentral

43.

Guenin-Macé L, Veyron-Churlet R, Thoulouze M-I, Romet-Lemonne G, Hong H, Leadlay PF, Danckaert A, Ruf MT, Mostowy S, Zurzolo C, Bousso P, Chrétien F, Carlier MF, Demangel C (2013) Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation. J Clin Invest 123:1501–1512. https://doi.org/10.1172/JCI66576 CrossRefPubMedPubMedCentral

44.

Eddyani M, Lavender C, de Rijk WB et al (2014) Multicenter external quality assessment program for PCR detection of Mycobacterium ulcerans in clinical and environmental specimens. PLoS One 9:e89407. https://doi.org/10.1371/journal.pone.0089407 CrossRefPubMedPubMedCentral

45.

Initiative WHOGBU (2004) Provisional guidance on the role of specific antibiotics in the management of Mycobacterium ulcerans disease (Buruli ulcer)

46.

Teelken MA, Stienstra Y, Ellen DE, Quarshie E, Klutse E, van der Graaf W, van der Werf T (2003) Buruli ulcer: differences in treatment outcome between two centres in Ghana. Acta Trop 88:51–56. https://doi.org/10.1016/S0001-706X(03)00170-0 CrossRefPubMed

47.

Nienhuis WA, Stienstra Y, Abass KM et al (2012) Paradoxical responses after start of antimicrobial treatment in Mycobacterium ulcerans infection. Clin Infect Dis 54:519–526. https://doi.org/10.1093/cid/cir856

48.

Bell LCK, Breen R, Miller RF, Noursadeghi M, Lipman M (2015) Paradoxical reactions and immune reconstitution inflammatory syndrome in tuberculosis. Int J Infect Dis 32:39–45. https://doi.org/10.1016/j.ijid.2014.12.030 CrossRefPubMed

49.

Schütte D, Um-Boock A, Mensah-Quainoo E et al (2007) Development of highly organized lymphoid structures in Buruli ulcer lesions after treatment with rifampicin and streptomycin. PLoS Negl Trop Dis 1:e2. https://doi.org/10.1371/journal.pntd.0000002 CrossRefPubMedPubMedCentral

50.

Friedman ND, McDonald AH, Robson ME, O’Brien DP (2012) Corticosteroid use for paradoxical reactions during antibiotic treatment for Mycobacterium ulcerans. PLoS Negl Trop Dis 6:e1767. https://doi.org/10.1371/journal.pntd.0001767 CrossRefPubMedPubMedCentral

51.

O’Brien DP, Callan P, Friedman ND et al (2019) Mycobacterium ulcerans disease management in Australian patients: the re-emergence of surgery as an important treatment modality. ANZ J Surg 89:653–658. https://doi.org/10.1111/ans.14829 CrossRefPubMed

52.

Bratschi MW, Bolz M, Minyem JC et al (2013) Geographic distribution, age pattern and sites of lesions in a cohort of Buruli ulcer patients from the Mapé Basin of Cameroon. PLoS Negl Trop Dis 7:e2252. https://doi.org/10.1371/journal.pntd.0002252 CrossRefPubMedPubMedCentral

53.

Capela C, Sopoh GE, Houezo JG et al (2015) Clinical epidemiology of Buruli ulcer from Benin (2005-2013): effect of time-delay to diagnosis on clinical forms and severe phenotypes. PLoS Negl Trop Dis 9:e0004005. https://doi.org/10.1371/journal.pntd.0004005 CrossRefPubMedPubMedCentral

54.

N’krumah RTAS, Koné B, Cissé G et al (2017) Characteristics and epidemiological profile of Buruli ulcer in the district of Tiassalé, south Côte d’Ivoire. Acta Trop 175:138–144. https://doi.org/10.1016/j.actatropica.2016.12.023 CrossRefPubMed

55.

Boyd SC, Athan E, Friedman ND, Hughes A, Walton A, Callan P, McDonald A, O'Brien DP (2012) Epidemiology, clinical features and diagnosis of Mycobacterium ulcerans in an Australian population. Med J Aust 196:341–344. https://doi.org/10.5694/mja12.10087 CrossRefPubMed

56.

(1971) Epidemiology of Mycobacterium ulcerans infection (Buruli ulcer) at Kinyara, Uganda. Trans R Soc Trop Med Hyg 65:763–775. https://doi.org/10.1016/0035-9203(71)90090-3

57.

Klein SL, Flanagan KL (2016) Sex differences in immune responses. Nat Rev Immunol 16:626–638. https://doi.org/10.1038/nri.2016.90 CrossRefPubMed

58.

Johnson RC, Nackers F, Glynn JR et al (2008) Association of HIV infection and Mycobacterium ulcerans disease in Benin. AIDS 22:901–903. https://doi.org/10.1097/QAD.0b013e3282f7690a

59.

Christinet V, Comte E, Ciaffi L et al (2014) Impact of human immunodeficiency virus on the severity of Buruli ulcer disease: results of a retrospective study in Cameroon. Open Forum Infect Dis 1. https://doi.org/10.1093/ofid/ofu021

60.

Tuffour J, Owusu-Mireku E, Ruf M-T, Aboagye S, Kpeli G, Akuoku V, Pereko J, Paintsil A, Bonney K, Ampofo W, Pluschke G, Yeboah-Manu D (2015) Challenges associated with management of Buruli ulcer/human immunodeficiency virus coinfection in a treatment center in Ghana: a case series study. Am J Trop Med Hyg 93:216–223. https://doi.org/10.4269/ajtmh.14-0571 CrossRefPubMedPubMedCentral

61.

Stienstra Y, van der Werf TS, van der Graaf WTA, Secor WE, Kihlstrom SL, Dobos KM, Asamoa K, Quarshi E, Etuaful SN, Klutse EY, King CH (2004) Buruli ulcer and schistosomiasis: no association found. Am J Trop Med Hyg 71:318–321CrossRef

62.

Stienstra Y, van der Werf TS, Oosterom E et al (2006) Susceptibility to Buruli ulcer is associated with the SLC11A1 (NRAMP1) D543N polymorphism. Genes Immun 7:185–189. https://doi.org/10.1038/sj.gene.6364281 CrossRefPubMed

63.

Bibert S, Bratschi MW, Aboagye SY et al (2017) Susceptibility to Mycobacterium ulcerans disease (Buruli ulcer) is associated with IFNG and iNOS gene polymorphisms. Front Microbiol 8:1903. https://doi.org/10.3389/fmicb.2017.01903 CrossRefPubMedPubMedCentral

64.

Manzanillo PS, Ayres JS, Watson RO et al (2013) PARKIN ubiquitin ligase mediates resistance to intracellular pathogens. Nature 501:512–516. https://doi.org/10.1038/nature12566 CrossRefPubMedPubMedCentral

65.

Capela C, Dossou AD, Silva-Gomes R, Sopoh GE, Makoutode M, Menino JF, Fraga AG, Cunha C, Carvalho A, Rodrigues F, Pedrosa J (2016) Genetic variation in autophagy-related genes influences the risk and phenotype of Buruli ulcer. PLoS Negl Trop Dis 10:e0004671. https://doi.org/10.1371/journal.pntd.0004671 CrossRefPubMedPubMedCentral

66.

Nackers F, Dramaix M, Johnson RC, Zinsou C, Robert A, de Biurrun Bakedano E, Glynn JR, Portaels F, Tonglet R (2006) BCG vaccine effectiveness against Buruli ulcer: a case-control study in Benin. Am J Trop Med Hyg 75:768–774CrossRef

67.

Phillips RO, Phanzu DM, Beissner M, Badziklou K, Luzolo EK, Sarfo FS, Halatoko WA, Amoako Y, Frimpong M, Kabiru AM, Piten E, Maman I, Bidjada B, Koba A, Awoussi KS, Kobara B, Nitschke J, Wiedemann FX, Kere AB, Adjei O, Löscher T, Fleischer B, Bretzel G, Herbinger KH (2015) Effectiveness of routine BCG vaccination on Buruli ulcer disease: a case-control study in the Democratic Republic of Congo, Ghana and Togo. PLoS Negl Trop Dis 9:e3457. https://doi.org/10.1371/journal.pntd.0003457 CrossRefPubMedPubMedCentral

68.

Portaels F, Aguiar J, Debacker M, Steunou C, Zinsou C, Guédénon A, Meyers WM (2002) Prophylactic effect of mycobacterium bovis BCG vaccination against osteomyelitis in children with Mycobacterium ulcerans disease (Buruli ulcer). Clin Diagn Lab Immunol 9:1389–1391. https://doi.org/10.1128/cdli.9.6.1389-1391.2002 CrossRefPubMedPubMedCentral

69.

Portaels F, Aguiar J, Debacker M, Guédénon A, Steunou C, Zinsou C, Meyers WM (2004) Mycobacterium bovis BCG vaccination as prophylaxis against Mycobacterium ulcerans osteomyelitis in Buruli ulcer disease. Infect Immun 72:62–65. https://doi.org/10.1128/iai.72.1.62-65.2004 CrossRefPubMedPubMedCentral

70.

Smith PG, Revill WD, Lukwago E, Rykushin YP (1976) The protective effect of BCG against Mycobacterium ulcerans disease: a controlled trial in an endemic area of Uganda. Trans R Soc Trop Med Hyg 70:449–457. https://doi.org/10.1016/0035-9203(76)90128-0 CrossRefPubMed

71.

(1969) BCG vaccination against mycobacterium ulcerans infection (Buruli ulcer). First results of a trial in Uganda. Lancet 1:111–115

72.

Fraga AG, Martins TG, Torrado E, Huygen K, Portaels F, Silva MT, Castro AG, Pedrosa J (2012) Cellular immunity confers transient protection in experimental Buruli ulcer following BCG or mycolactone-negative Mycobacterium ulcerans vaccination. PLoS One 7:e33406. https://doi.org/10.1371/journal.pone.0033406 CrossRefPubMedPubMedCentral

73.

Tanghe A, Adnet P-Y, Gartner T, Huygen K (2007) A booster vaccination with Mycobacterium bovis BCG does not increase the protective effect of the vaccine against experimental Mycobacterium ulcerans infection in mice. Infect Immun 75:2642–2644. https://doi.org/10.1128/IAI.01622-06 CrossRefPubMedPubMedCentral

74.

Hart BE, Hale LP, Lee S (2015) Recombinant BCG expressing Mycobacterium ulcerans Ag85A imparts enhanced protection against experimental Buruli ulcer. PLoS Negl Trop Dis 9:e0004046. https://doi.org/10.1371/journal.pntd.0004046 CrossRefPubMedPubMedCentral

75.

Hart BE, Lee S (2016) Overexpression of a Mycobacterium ulcerans Ag85B-EsxH fusion protein in recombinant BCG improves experimental Buruli ulcer vaccine efficacy. PLoS Negl Trop Dis 10:e0005229. https://doi.org/10.1371/journal.pntd.0005229 CrossRefPubMedPubMedCentral

76.

Hart BE, Hale LP, Lee S (2016) Immunogenicity and protection conferred by a recombinant Mycobacterium marinum vaccine against Buruli ulcer. Trials Vaccinol 5:88–91. https://doi.org/10.1016/j.trivac.2016.04.001 CrossRef

77.

Watanabe M, Nakamura H, Nabekura R, Shinoda N, Suzuki E, Saito H (2015) Protective effect of a dewaxed whole-cell vaccine against Mycobacterium ulcerans infection in mice. Vaccine 33:2232–2239. https://doi.org/10.1016/j.vaccine.2015.03.046 CrossRefPubMed

78.

Tanghe A, Dangy J-P, Pluschke G, Huygen K (2008) Improved protective efficacy of a species-specific DNA vaccine encoding mycolyl-transferase Ag85A from Mycobacterium ulcerans by homologous protein boosting. PLoS Negl Trop Dis 2:e199. https://doi.org/10.1371/journal.pntd.0000199 CrossRefPubMedPubMedCentral

79.

Coutanceau E, Legras P, Marsollier L, Reysset G, Cole ST, Demangel C (2006) Immunogenicity of Mycobacterium ulcerans Hsp65 and protective efficacy of a Mycobacterium leprae Hsp65-based DNA vaccine against Buruli ulcer. Microbes Infect 8:2075–2081. https://doi.org/10.1016/j.micinf.2006.03.009 CrossRefPubMed

80.

Roupie V, Pidot SJ, Einarsdottir T et al (2014) Analysis of the vaccine potential of plasmid DNA encoding nine mycolactone polyketide synthase domains in Mycobacterium ulcerans infected mice. PLoS Negl Trop Dis 8:e2604. https://doi.org/10.1371/journal.pntd.0002604 CrossRefPubMedPubMedCentral

81.

Dangy J-P, Scherr N, Gersbach P et al (2016) Antibody-mediated neutralization of the exotoxin mycolactone, the main virulence factor produced by Mycobacterium ulcerans. PLoS Negl Trop Dis 10:e0004808. https://doi.org/10.1371/journal.pntd.0004808 CrossRefPubMedPubMedCentral

82.

Singh P, Benjak A, Schuenemann VJ et al (2015) Insight into the evolution and origin of leprosy bacilli from the genome sequence of Mycobacterium lepromatosis. Proc Natl Acad Sci U S A 112(14):4459–4464. https://doi.org/10.1073/pnas.1421504112 CrossRefPubMedPubMedCentral

83.

Mazini PS, Alves HV, Reis PG et al (2016) Gene association with leprosy: a review of published data. Front Immunol 6:658. https://doi.org/10.3389/fimmu.2015.00658 CrossRefPubMedPubMedCentral

84.

Fonseca AB, Simon M, Cazzaniga RA et al (2017) The influence of innate and adaptative immune responses on the differential clinical outcomes of leprosy. Infect Dis Poverty 6(1):5. https://doi.org/10.1186/s40249-016-0229-3 CrossRefPubMedPubMedCentral

85.

Walker SL, Lockwood DNJ (2008) Leprosy type 1 (reversal) reactions and their management. Lepr Rev 79:372–386PubMed

86.

Teles RMB, Lu J, Tió-Coma M, Goulart IMB, Banu S, Hagge D, Bobosha K, Ottenhoff THM, Pellegrini M, Geluk A, Modlin RL (2019) Identification of a systemic interferon-γ inducible antimicrobial gene signature in leprosy patients undergoing reversal reaction. PLoS Negl Trop Dis 13:e0007764. https://doi.org/10.1371/journal.pntd.0007764 CrossRefPubMedPubMedCentral

87.

Polycarpou A, Walker SL, Lockwood DNJ (2017) A systematic review of immunological studies of erythema nodosum leprosum. Front Immunol 8. https://doi.org/10.3389/fimmu.2017.00233

88.

Kamath S, Vaccaro SA, Rea TH, Ochoa MT (2014) Recognizing and managing the immunologic reactions in leprosy. J Am Acad Dermatol 71:795–803. https://doi.org/10.1016/j.jaad.2014.03.034 CrossRefPubMed

89.

Pinheiro RO, Schmitz V, Silva BJA et al (2018) Innate immune responses in leprosy. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.00518

90.

Sehgal VN, Srivastava G, Sharma VK (1987) Contemplative immune mechanism of Lucio phenomenon and its global status. J Dermatol 14:580–585. https://doi.org/10.1111/j.1346-8138.1987.tb03630.x CrossRefPubMed

91.

Scollard DM (2016) Pathogenesis and pathology of leprosy. In: The international textbook of leprosy, Scollard DM, Gillis TP

92.

Montoya D, Cruz D, Teles RMB et al (2009) Divergence of macrophage phagocytic and antimicrobial programs in leprosy. Cell Host Microbe 6:343–353. https://doi.org/10.1016/j.chom.2009.09.002 CrossRefPubMedPubMedCentral

93.

Brennan PJ, Spencer JS (2016) The physiology of Mycobacterium leprae. In: International Textbook of Leprosy

94.

Hunter SW, Brennan PJ (1983) Further specific extracellular phenolic glycolipid antigens and a related diacylphthiocerol from Mycobacterium leprae. J Biol Chem 258:7556–7562PubMed

95.

Rambukkana A (2001) Molecular basis for the peripheral nerve predilection of Mycobacterium leprae. Curr Opin Microbiol 4:21–27CrossRef

96.

Madigan CA, Cambier CJ, Kelly-Scumpia KM et al (2017) A macrophage response to Mycobacterium leprae phenolic glycolipid initiates nerve damage in leprosy. Cell 170:973–985.e10. https://doi.org/10.1016/j.cell.2017.07.030 CrossRefPubMedPubMedCentral

97.

Torrelles JB, Khoo K-H, Sieling PA et al (2004) Truncated structural variants of lipoarabinomannan in Mycobacterium leprae and an ethambutol-resistant strain of Mycobacterium tuberculosis. J Biol Chem 279:41227–41239. https://doi.org/10.1074/jbc.M405180200 CrossRefPubMed

98.

Turner J, Torrelles JB (2018) Mannose-capped lipoarabinomannan in Mycobacterium tuberculosis pathogenesis. Pathog Dis:76. https://doi.org/10.1093/femspd/fty026

99.

Nahas AA, de Silva LMI, Goulart IMB, Goulart LR (2018) Anti-lipoarabinomannan-specific salivary IgA as prognostic marker for leprosy reactions in patients and cellular immunity in contacts. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.01205

100.

Bahia El Idrissi N, Das PK, Fluiter K et al (2015) M. leprae components induce nerve damage by complement activation: identification of lipoarabinomannan as the dominant complement activator. Acta Neuropathol (Berl) 129:653–667. https://doi.org/10.1007/s00401-015-1404-5 CrossRef

101.

Moraes MO, Batista-Silva LR, Olmo R (2016) Innate immunity. In: Int. Textb. Lepr. https://internationaltextbookofleprosy.org/chapter/innate-immunity. Accessed 16 Aug 2018

102.

Kim EW, Teles RMB, Haile S, Liu PT, Modlin RL (2018) Vitamin D status contributes to the antimicrobial activity of macrophages against Mycobacterium leprae. PLoS Negl Trop Dis 12:e0006608. https://doi.org/10.1371/journal.pntd.0006608 CrossRefPubMedPubMedCentral

103.

Toledo Pinto TG, Batista-Silva LR, Medeiros RCA et al (2018) Type I interferons, autophagy and host metabolism in leprosy. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.00806

104.

Weiss DI, Ma F, Merleev AA, Maverakis E, Gilliet M, Balin SJ, Bryson BD, Ochoa MT, Pellegrini M, Bloom BR, Modlin RL (2019) IL-1β induces the rapid secretion of the antimicrobial protein IL-26 from Th17 cells. J Immunol 203:911–921. https://doi.org/10.4049/jimmunol.1900318 CrossRefPubMed

105.

Bleharski JR, Li H, Meinken C, Graeber TG, Ochoa MT, Yamamura M, Burdick A, Sarno EN, Wagner M, Röllinghoff M, Rea TH, Colonna M, Stenger S, Bloom BR, Eisenberg D, Modlin RL (2003) Use of genetic profiling in leprosy to discriminate clinical forms of the disease. Science 301:1527–1530. https://doi.org/10.1126/science.1087785 CrossRefPubMed

106.

Burshtyn DN, Morcos C (2016) The expanding spectrum of ligands for leukocyte Ig-like receptors. J Immunol 196:947–955. https://doi.org/10.4049/jimmunol.1501937 CrossRefPubMed

107.

Silva BJ de Andrade, Barbosa M de Mayara Garcia, Andrade PR, et al (2017) Innate immune responses in leprosy. PLoS Pathog 13:. https://doi.org/10.1371/journal.ppat.1006103

108.

Cruz D, Watson AD, Miller CS et al (2008) Host-derived oxidized phospholipids and HDL regulate innate immunity in human leprosy. J Clin Invest 118:2917–2928. https://doi.org/10.1172/JCI34189 CrossRefPubMedPubMedCentral

109.

Geluk A (2018) Correlates of immune exacerbations in leprosy. Semin Immunol 39:111–118. https://doi.org/10.1016/j.smim.2018.06.003 CrossRefPubMed

110.

Sadhu S, Mitra DK (2018) Emerging concepts of adaptive immunity in leprosy. Front Immunol 9. https://doi.org/10.3389/fimmu.2018.00604

111.

Lima HR, Gasparoto TH, de Souza Malaspina TS et al (2017) Immune checkpoints in leprosy: immunotherapy as a feasible approach to control disease progression. Front Immunol 8. https://doi.org/10.3389/fimmu.2017.01724

112.

Sampaio EP, Caneshi JR, Nery JA, Duppre NC, Pereira GM, Vieira LM, Moreira AL, Kaplan G, Sarno EN (1995) Cellular immune response to Mycobacterium leprae infection in human immunodeficiency virus-infected individuals. Infect Immun 63:1848–1854CrossRef

113.

Scollard DM (2000) Endothelial cells and the pathogenesis of lepromatous neuritis: insights from the armadillo model. Microbes Infect 2:1835–1843. https://doi.org/10.1016/S1286-4579(00)01335-6 CrossRefPubMed

114.

Fava VM, Schurr E (2016) The complexity of the host genetic contribution to the human response to Mycobacterium leprae. In: International Textbook of Leprosy

115.

Ukwaja KN (2015) Interactions between leprosy and human immunodeficiency virus: more questions than answers. J Neurosci Rural Pract 6:135–136. https://doi.org/10.4103/0976-3147.150291 CrossRefPubMedPubMedCentral

116.

Fitness J, Tosh K, Hill AVS (2002) Genetics of susceptibility to leprosy. Genes Immun 3:441–453. https://doi.org/10.1038/sj.gene.6363926 CrossRefPubMed

117.

Fava VM, Xu YZ, Lettre G, van Thuc N, Orlova M, Thai VH, Tao S, Croteau N, Eldeeb MA, MacDougall E, Cambri G, Lahiri R, Adams L, Fon EA, Trempe JF, Cobat A, Alcaïs A, Abel L, Schurr E (2019) Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson’s disease. Proc Natl Acad Sci 116:15616–15624. https://doi.org/10.1073/pnas.1901805116 CrossRefPubMed

118.

Brites D, Gagneux S (2015) Co-evolution of Mycobacterium tuberculosis and Homo sapiens. Immunol Rev 264:6–24. https://doi.org/10.1111/imr.12264 CrossRefPubMedPubMedCentral

119.

Benjak A, Avanzi C, Singh P, Loiseau C, Girma S, Busso P, Fontes ANB, Miyamoto Y, Namisato M, Bobosha K, Salgado CG, da Silva MB, Bouth RC, Frade MAC, Filho FB, Barreto JG, Nery JAC, Bührer-Sékula S, Lupien A, al-Samie AR, al-Qubati Y, Alkubati AS, Bretzel G, Vera-Cabrera L, Sakho F, Johnson CR, Kodio M, Fomba A, Sow SO, Gado M, Konaté O, Stefani MMA, Penna GO, Suffys PN, Sarno EN, Moraes MO, Rosa PS, Baptista IMFD, Spencer JS, Aseffa A, Matsuoka M, Kai M, Cole ST (2018) Phylogenomics and antimicrobial resistance of the leprosy bacillus Mycobacterium leprae. Nat Commun 9:352. https://doi.org/10.1038/s41467-017-02576-z CrossRefPubMedPubMedCentral

120.

Sharma R, Singh P, Pena M et al (2018) Differential growth of Mycobacterium leprae strains (SNP genotypes) in armadillos. Infect Genet Evol 62:20–26. https://doi.org/10.1016/j.meegid.2018.04.017 CrossRefPubMed

121.

Sociedade Brasileira de Hansenologia (SBH) Sociedade Brasileira de Hansenologia divulga manifesto contra mudança no tratamento de pacientes de hanseníase no Brasil. In: SBH Soc. Bras. Hansen. http://www.sbhansenologia.org.br/noticia/sociedade-brasileira-de-hansenologia-divulga-manifesto-contra-mudanca-no-tratamento-de-pacientes-de-hanseniase-no-brasil. Accessed 21 Oct 2019

122.

Reed SG, Duthie MS (2016) Vaccine for prevention of leprosy. In: The international textbook of leprosy, Scollard DM, Gillis TP

123.

Convit J, Sampson C, Zúñiga M et al (1992) Immunoprophylactic trial with combined Mycobacterium leprae/BCG vaccine against leprosy: preliminary results. Lancet 339:446–450. https://doi.org/10.1016/0140-6736(92)91056-E CrossRefPubMed

124.

Kumar A, Parkash O, Girdhar BK (2014) Analysis of antigens of Mycobacterium leprae by interaction to sera IgG, IgM, and IgA response to improve diagnosis of leprosy. Biomed Res Int 2014:. https://doi.org/10.1155/2014/283278

125.

Duthie MS, Sampaio LH, Oliveira RM et al (2013) Development and pre-clinical assessment of a 73kD chimeric fusion protein as a defined sub-unit vaccine for leprosy. Vaccine 31:813–819. https://doi.org/10.1016/j.vaccine.2012.11.073 CrossRefPubMed

126.

Duthie MS, Pena MT, Ebenezer GJ, Gillis TP, Sharma R, Cunningham K, Polydefkis M, Maeda Y, Makino M, Truman RW, Reed SG (2018) LepVax, a defined subunit vaccine that provides effective pre-exposure and post-exposure prophylaxis of M. leprae infection. Npj Vaccines 3:1–9. https://doi.org/10.1038/s41541-018-0050-z CrossRef

127.

Barbieri RR, Manta FSN, Moreira SJM et al (2019) Quantitative polymerase chain reaction in paucibacillary leprosy diagnosis: a follow-up study. PLoS Negl Trop Dis 13:e0007147. https://doi.org/10.1371/journal.pntd.0007147 CrossRefPubMedPubMedCentral

128.

Bührer-Sékula S (2008) PGL-I leprosy serology. Rev Soc Bras Med Trop 41:3–5. https://doi.org/10.1590/S0037-86822008000700002 CrossRefPubMed

129.

Bernardes Filho F, de Paula NA, Leite MN et al (2017) Evidence of hidden leprosy in a supposedly low endemic area of Brazil. Mem Inst Oswaldo Cruz 112:822–828. https://doi.org/10.1590/0074-02760170173 CrossRef

130.

de Moura RS, Calado KL, Oliveira MLW, Bührer-Sékula S (2008) Leprosy serology using PGL-I: a systematic review. Rev Soc Bras Med Trop 41:11–18. https://doi.org/10.1590/S0037-86822008000700004 CrossRefPubMed

131.

Duthie MS, Hay MN, Morales CZ, Carter L, Mohamath R, Ito L, Oyafuso LK, Manini MI, Balagon MV, Tan EV, Saunderson PR, Reed SG, Carter D (2010) Rational design and evaluation of a multiepitope chimeric fusion protein with the potential for leprosy diagnosis. Clin Vaccine Immunol 17:298–303. https://doi.org/10.1128/CVI.00400-09

132.

Serrano-Coll H, Muñoz M, Camilo Beltrán J, Duthie MS, Cardona-Castro N (2017) Anti-natural octyl disaccharide-leprosy IDRI diagnostic (NDO-LID) antibodies as indicators of leprosy reactions and neuritis. Trans R Soc Trop Med Hyg 111:125–131. https://doi.org/10.1093/trstmh/trx026 CrossRefPubMed

133.

van Hooij A, Geluk A (2016) Immunodiagnostics for leprosy. In: International textbook of leprosy

134.

Geluk A, Duthie MS, Spencer JS (2011) Postgenomic Mycobacterium leprae antigens for cellular and serological diagnosis of M. leprae exposure, infection and leprosy disease. Lepr Rev 82:402–421PubMed

135.

Corstjens PLAM, van Hooij A, Tjon Kon Fat EM, Alam K, Vrolijk LB, Dlamini S, da Silva MB, Spencer JS, Salgado CG, Richardus JH, van Hees C, Geluk A (2019) Fingerstick test quantifying humoral and cellular biomarkers indicative for M. leprae infection. Clin Biochem 66:76–82. https://doi.org/10.1016/j.clinbiochem.2019.01.007 CrossRefPubMed

136.

Cole ST, Eiglmeier K, Parkhill J et al (2001) Massive gene decay in the leprosy bacillus. Nature 409:1007–1011. https://doi.org/10.1038/35059006 CrossRefPubMed

137.

Stinear TP, Seemann T, Harrison PF et al (2008) Insights from the complete genome sequence of Mycobacterium marinum on the evolution of Mycobacterium tuberculosis. Genome Res 18:729–741. https://doi.org/10.1101/gr.075069.107 CrossRefPubMedPubMedCentral

138.

Han XY, Seo Y-H, Sizer KC, Shoberle T, May GS, Spencer JS, Li W, Nair RG. 2008. A new Mycobacterium species causing diffuse lepromatous leprosy. Am J Clin Path 130: 856-864

139.

Moet FJ, Pahan D, Oskam L, Richardus JH, COLEP Study Group (2008) Effectiveness of single dose rifampicin in preventing leprosy in close contacts of patients with newly diagnosed leprosy: cluster randomised controlled trial. BMJ 336:761–764. https://doi.org/10.1136/bmj.39500.885752.BE CrossRefPubMedPubMedCentral

140.

Tiwari A, Dandel S, Djupuri R et al (2018) Population-wide administration of single dose rifampicin for leprosy prevention in isolated communities: a three year follow-up feasibility study in Indonesia. BMC Infect Dis 18:324. https://doi.org/10.1186/s12879-018-3233-3 CrossRefPubMedPubMedCentral

141.

Zhai W, Wu F, Zhang Y et al (2019) The immune escape mechanisms of Mycobacterium tuberculosis. Int J Mol Sci 20. https://doi.org/10.3390/ijms20020340

142.

Bruchfeld J, Correia-Neves M, Källenius G (2015) Tuberculosis and HIV coinfection. Cold Spring Harb Perspect Med 5. https://doi.org/10.1101/cshperspect.a017871

143.

Moliva JI, Turner J, Torrelles JB (2017) Immune responses to Bacillus Calmette–Guérin vaccination: why do they fail to protect against Mycobacterium tuberculosis? Front Immunol 8. https://doi.org/10.3389/fimmu.2017.00407

144.

Colditz GA, Brewer TF, Berkey CS et al (1994) Efficacy of BCG vaccine in the prevention of tuberculosis: meta-analysis of the published literature. JAMA 271:698–702. https://doi.org/10.1001/jama.1994.03510330076038 CrossRefPubMed

145.

Merle CSC, Cunha SS, Rodrigues LC (2010) BCG vaccination and leprosy protection: review of current evidence and status of BCG in leprosy control. Expert Rev Vaccines 9:209–222. https://doi.org/10.1586/erv.09.161 CrossRefPubMed

146.

Trunz BB, Fine P, Dye C (2006) Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 367:1173–1180. https://doi.org/10.1016/S0140-6736(06)68507-3

147.

Netea MG, Quintin J, van der Meer JWM (2011) Trained immunity: a memory for innate host defense. Cell Host Microbe 9:355–361. https://doi.org/10.1016/j.chom.2011.04.006 CrossRefPubMed

148.

Covián C, Fernández-Fierro A, Retamal-Díaz A et al (2019) BCG-induced cross-protection and development of trained immunity: implication for vaccine design. Front Immunol:10. https://doi.org/10.3389/fimmu.2019.02806

149.

Koeken VACM, Verrall AJ, Netea MG et al (2019) Trained innate immunity and resistance to Mycobacterium tuberculosis infection. Clin Microbiol Infect 25:1468–1472. https://doi.org/10.1016/j.cmi.2019.02.015 CrossRefPubMed

150.

Avanzi C, Cole ST (2018) Genomics: a Swiss army knife to fight leprosy. Thesis, Ecole Polytechnique Federale de Lausanne

Title: The immunology of other mycobacteria: M. ulcerans, M. leprae
Authors: Katharina Röltgen
Gerd Pluschke
John Stewart Spencer
Patrick Joseph Brennan
Charlotte Avanzi
Publication date: 01-06-2020
Publisher: Springer Berlin Heidelberg
Keyword: Leprosy
Published in: Seminars in Immunopathology / Issue 3/2020
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI: https://doi.org/10.1007/s00281-020-00790-4

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