Background Mycobacterium avium is the principal etiologic agent of non-tuberculous lymphadenitis in children. It is also a known pathogen for birds and other animals. Genetic typing of M. avium isolates has led to a proposal to expand the set of subspecies to include M. avium subsp. hominissuis. Isolates associated with disease in humans belong to this subspecies. Methodology/Principal Findings Peripheral blood mononuclear cells from six healthy blood donors were stimulated in vitro with ten isolates of M. avium avium and 11 isolates of M. avium hominissuis followed by multiplex bead array quantification of cytokines in supernatants. M. avium hominissuis isolates induced significantly more IL-10 and significantly less IL-12p70, TNF, IFN-γ and IL-17 when compared to M. avium avium isolates. All strains induced high levels of IL-17, but had very low levels of IL-12p70. Conclusion/Significance The strong association between M. avium subsp. hominissuis and disease in humans and the clear differences in the human immune response to M. avium subsp. hominissuis compared to M. avium subsp. avium isolates, as demonstrated in this study, suggest that genetic differences between M. avium isolates play an important role in the pathogenicity in humans.
References
[1]
Masson AM, Prissick FH (1956) Cervical lymphadenitis in children caused by chromogenic Mycobacteria. Can Med Assoc J 75: 798–803.
[2]
Kasperbauer SH, Daley CL (2008) Diagnosis and treatment of infections due to Mycobacterium avium complex. Semin Respir Crit Care Med 29: 569–576.
[3]
Wolinsky E (1995) Mycobacterial lymphadenitis in children: a prospective study of 105 nontuberculous cases with long-term follow-up. Clin Infect Dis 20: 954–963.
[4]
Evans MJ, Smith NM, Thornton CM, Youngson GG, Gray ES (1998) Atypical mycobacterial lymphadenitis in childhood–a clinicopathological study of 17 cases. J Clin Pathol 51: 925–927.
[5]
Falkinham JO 3rd (2002) Nontuberculous mycobacteria in the environment. Clin Chest Med 23: 529–551.
[6]
Mijs W, de Haas P, Rossau R, Van der Laan T, Rigouts L, et al. (2002) Molecular evidence to support a proposal to reserve the designation Mycobacterium avium subsp. avium for bird-type isolates and ‘M. avium subsp. hominissuis’ for the human/porcine type of M. avium. Int J Syst Evol Microbiol 52: 1505–1518.
[7]
Bruijnesteijn van Coppenraet LE, de Haas PE, Lindeboom JA, Kuijper EJ, van Soolingen D (2008) Lymphadenitis in children is caused by Mycobacterium avium hominissuis and not related to ‘bird tuberculosis’. Eur J Clin Microbiol Infect Dis 27: 293–299.
[8]
Thegerstrom J, Marklund BI, Hoffner S, Axelsson-Olsson D, Kauppinen J, et al. (2005) Mycobacterium avium with the bird type IS1245 RFLP profile is commonly found in wild and domestic animals, but rarely in humans. Scand J Infect Dis 37: 15–20.
[9]
Ottenhoff TH, Verreck FA, Lichtenauer-Kaligis EG, Hoeve MA, Sanal O, et al. (2002) Genetics, cytokines and human infectious disease: lessons from weakly pathogenic mycobacteria and salmonellae. Nat Genet 32: 97–105.
[10]
Haverkamp MH, van Dissel JT, Holland SM (2006) Human host genetic factors in nontuberculous mycobacterial infection: lessons from single gene disorders affecting innate and adaptive immunity and lessons from molecular defects in interferon-gamma-dependent signaling. Microbes Infect 8: 1157–1166.
[11]
Romani L, Puccetti P, Bistoni F (1997) Interleukin-12 in infectious diseases. Clin Microbiol Rev 10: 611–636.
[12]
Saunders BM, Zhan Y, Cheers C (1995) Endogenous interleukin-12 is involved in resistance of mice to Mycobacterium avium complex infection. Infect Immun 63: 4011–4015.
[13]
Matsuzaki G, Umemura M (2007) Interleukin-17 as an effector molecule of innate and acquired immunity against infections. Microbiol Immunol 51: 1139–1147.
[14]
Cooper AM, Khader SA (2008) The role of cytokines in the initiation, expansion, and control of cellular immunity to tuberculosis. Immunol Rev 226: 191–204.
[15]
Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180: 5771–5777.
[16]
Lind A, Larsson LO, Bentzon MW, Magnusson M, Olofson J, et al. (1991) Sensitivity to sensitins and tuberculin in Swedish children. I. A study of schoolchildren in an urban area. Tubercle 72: 29–36.
[17]
Fairchok MP, Rouse JH, Morris SL (1995) Age-dependent humoral responses of children to mycobacterial antigens. Clin Diagn Lab Immunol 2: 443–447.
[18]
Romanus V, Hallander HO, Wahlen P, Olinder-Nielsen AM, Magnusson PH, et al. (1995) Atypical mycobacteria in extrapulmonary disease among children. Incidence in Sweden from 1969 to 1990, related to changing BCG-vaccination coverage. Tuber Lung Dis 76: 300–310.
[19]
Hessle CC, Andersson B, Wold AE (2005) Gram-positive and Gram-negative bacteria elicit different patterns of pro-inflammatory cytokines in human monocytes. Cytokine 30: 311–318.
[20]
Danelishvilli L, Bermudez LE (2003) Role of type I cytokines in host defense against Mycobacterium avium infection. Curr Pharm Des 9: 61–65.
[21]
Scriba TJ, Kalsdorf B, Abrahams DA, Isaacs F, Hofmeister J, et al. (2008) Distinct, specific IL-17- and IL-22-producing CD4+ T cell subsets contribute to the human anti-mycobacterial immune response. J Immunol 180: 1962–1970.
[22]
Khader SA, Gopal R (2010) IL-17 in protective immunity to intracellular pathogens. Virulence 1: 423–427.
[23]
Torrado E, Cooper AM (2010) IL-17 and Th17 cells in tuberculosis. Cytokine Growth Factor Rev 21: 455–462.
[24]
Emile JF, Patey N, Altare F, Lamhamedi S, Jouanguy E, et al. (1997) Correlation of granuloma structure with clinical outcome defines two types of idiopathic disseminated BCG infection. J Pathol 181: 25–30.
[25]
Cruz A, Khader SA, Torrado E, Fraga A, Pearl JE, et al. (2006) Cutting edge: IFN-gamma regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection. J Immunol 177: 1416–1420.
[26]
Coury F, Annels N, Rivollier A, Olsson S, Santoro A, et al. (2008) Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fusion. Nat Med 14: 81–87.
[27]
Ordway D, Higgins DM, Sanchez-Campillo J, Spencer JS, Henao-Tamayo M, et al. (2007) XCL1 (lymphotactin) chemokine produced by activated CD8 T cells during the chronic stage of infection with Mycobacterium tuberculosis negatively affects production of IFN-gamma by CD4 T cells and participates in granuloma stability. J Leukoc Biol 82: 1221–1229.
[28]
Sweet L, Schorey JS (2006) Glycopeptidolipids from Mycobacterium avium promote macrophage activation in a TLR2- and MyD88-dependent manner. J Leukoc Biol 80: 415–423.
[29]
Ritacco V, Kremer K, van der Laan T, Pijnenburg JE, de Haas PE, et al. (1998) Use of IS901 and IS1245 in RFLP typing of Mycobacterium avium complex: relatedness among serovar reference strains, human and animal isolates. Int J Tuberc Lung Dis 2: 242–251.
[30]
Turenne CY, Wallace R Jr, Behr MA (2007) Mycobacterium avium in the postgenomic era. Clin Microbiol Rev 20: 205–229.