Survival tactics of Mycobacterium avium subspecies paratuberculosis


  • Deepak Kumar Verma Department of Biotechnology, Faculty of Natural and Computational Sciences, University of Gondar, P.O. Box-196, Gondar, Ethiopia.


Mycobacterium avium subspecies paratuberculosis, Survival mechanism, Host pathogen interaction, Macrophage, Environment


Pathogenic mycobacteria have evolved the mechanisms to subvert host immune response in the favor of longtime persistence and proliferation in the intercellular environment of the host, with resulting in functional dysregulation and disease in the host. Among the genus mycobacteria, Mycobacterium avium subspecies paratuberculosis is a robust pathogen, have a remarkable capacity to persist in the host and adverse environmental conditions (pasteurization temperature, high pH) and recently, emerged as a major concern of public health significance. Mycobacterium avium subspecies paratuberculosis is the causative agent of Johne’s disease in animals and also has been incriminated as the causative agent of Crohn’s disease in human beings. Therefore, understanding the factors that contribute to the longevity of this pathogen is essential to restrict the clinical outcomes of infection and design the control strategies. The present review summarizes our understanding of factors that contribute to the survival of MAP within the host and different environmental sources.


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Adékambi, T., Ben Salah, S., Khlif, M., Raoult, D. & Drancourt, M. (2006). Survival of environmental mycobacteria in Acanthamoeba polyphaga. Appl. Environ. Microbiol., 72(9): 5974–5981.

Aderem, A. (2003). Phagocytosis and the inflammatory response. J. Infect. Dis., 187 Suppl 2: S340–S345.

Aho, A.D., McNulty, A.M. & Coussens, P.M. (2003). Enhanced Expression of Interleukin-1α and Tumor Necrosis Factor Receptor-Associated Protein 1 in Ileal Tissues of Cattle Infected with Mycobacterium avium subsp. paratuberculosis. Infect. Immun., 71(11): 6479–6486.

Akaki, T., Tomioka, H., Shimizu, T., Dekio, S. & Sato, K. (2000). Comparative roles of free fatty acids with reactive nitrogen intermediates and reactive oxygen intermediates in expression of the anti-microbial activity of macrophages against Mycobacterium tuberculosis. Clin. Exp. Immunol., 121(2): 302-310.

Armstrong, J.A. & Hart, P.D. (1975). Phagosome-lysosome interactions in cultured macrophages infected with virulent tubercle bacilli. Reversal of the usual nonfusion pattern and observations on bacterial survival. J. Exp. Med., 142(1): 1–16.

Balcewicz-Sablinska, M.K., Keane, J., Kornfeld, H. & Remold, H.G. (1998). Pathogenic Mycobacterium tuberculosis Evades Apoptosis of Host Macrophages by Release of TNF-R2, Resulting in Inactivation of TNF-α. J. Immunol., 161(5): 2636–2641.

Behr, M.A. & Kapur, V. (2008). The evidence for Mycobacterium paratuberculosis in Crohn's disease. Curr. Opin. Gastroenterol., 24(1): 17–21.

Behr, M.A. & Schurr, E. (2006). Mycobacteria in Crohn's disease: a persistent hypothesis. Inflamm. Bowel. Dis., 12(10): 1000–1004.

Ben Salah, I. & Drancourt, M. (2010). Surviving within the amoebal exocyst: the Mycobacterium avium complex paradigm. BMC Microbiol., 10: 99.

Bendixen, P.H., Bloch, B. & Jorgensen, J.B. (1981). Lack of intracellular degradation of Mycobacterium paratuberculosis by bovine macrophages infected in vitro and in vivo: light microscopic and electron microscopic observations. Am. J. Vet. Res., 42(1): 109–113.

Berghaus, R.D., Farver, T.B., Anderson, R.J., Jaravata, C.C. & Gardner, I.A. (2006). Environmental sampling for detection of Mycobacterium avium ssp. paratuberculosis on large California dairies. J. Dairy Sci., 89(3): 963–970.

Bolster, C.H., Haznedaroglu, B.Z. & Walker, S.L. (2009). Diversity in cell properties and transport behavior among 12 different environmental Escherichia coli isolates. J. Environ. Qual., 38(2): 465–472.

Buza, J.J., Hikono, H., Mori, Y., Nagata, R., Hirayama, S., Aodon-geril, Bari, A.M., Shu, Y., Tsuji, N.M. & Momotani, E. (2004). Neutralization of interleukin-10 significantly enhances gamma interferon expression in peripheral blood by stimulation with Johnin purified protein derivative and by infection with Mycobacterium avium subsp. paratuberculosis in experimentally infected cattle with paratuberculosis. Infect. Immun., 72(4): 2425–2428.

Byrd, S.R., Gelber, R. & Bermudez, L.E. (1993). Roles of Soluble Fibronectin and β1 Integrin Receptors in the Binding of Mycobacterium leprae to NaSal Epithelial Cells. Clin. Immunol. Immunopathol., 69(3): 266–271.

Chamberlin, W.M. & Naser, S.A. (2006). Integrating theories of the etiology of Crohn's disease. On the etiology of Crohn's disease: questioning the hypotheses. Med. Sci. Monit., 12(2): RA27–RA33.

Chan, J., Fan, X.D., Hunter, S.W., Brennan, P.J. & Bloom, B.R. (1991). Lipoarabinomannan, a possible virulence factor involved in persistence of Mycobacterium tuberculosis within macrophages. Infect. Immun., 59(5): 1755–1761.

Chiang, S.K., Sommer, S., Aho, A.D., Kiupel, M., Colvin, C., Tooker, B. & Coussens, P.M. (2007). Relationship between Mycobacterium avium subspecies paratuberculosis, IL-1α, and TRAF1 in primary bovine monocyte-derived macrophages. Vet. Immunol. Immunopathol., 116(3): 131–144.

Chilima, B.Z., Clark, I.M., Floyd, S., Fine, P.E. & Hirsch, P.R. (2006). Distribution of environmental mycobacteria in Karonga District, northern Malawi. Appl. Environ. Microbiol., 72(4): 2343–2350.

Chiodini, R.J., Van Kruiningen, H.J., Thayer, W.R., Merkal, R.S. & Coutu, J.A. (1984). Possible role of mycobacteria in inflammatory bowel disease. I. An unclassified Mycobacterium species isolated from patients with Crohn's disease. Dig. Dis. Sci., 29(12): 1073–1079.

Cirillo, J.D., Weisbrod, T.R., Banerjee, A., Bloom, B.R. & Jacobs, W.R. (1997). Genetic determination of the meso-diaminopimelate biosynthetic pathway of mycobacteria. J. Bacteriol., 179(8): 2792.

Clark, M.A., Hirst, B.H. & Jepson, M.A. (1998). M-Cell Surface β1 Integrin Expression and Invasin-Mediated Targeting of Yersinia pseudotuberculosis to Mouse Peyer’s Patch M Cells. Infect. Immun., 66(3): 1237–1243.

Collins, D.M., Gabric, D.M. & De Lisle, G.W. (1989). Identification of a repetitive DNA sequence specific to Mycobacterium paratuberculosis. FEMS Microbiol. Lett., 60(2): 175–178.

Collins, M.T., Spahr, U. & Murphy, P.M. (2001). Ecological characteristics of M. paratuberculosis. In: Bulletin of the International Dairy Federation, no. 362/2001. International Dairy Federation, Brussels, Belgium. p. 32-40.

Da Silva, R.P., Hall, B.F., Joiner, K.A. & Sacks, D.L. (1989). CR1, the C3b receptor, mediates binding of infective Leishmania major metacyclic promastigotes to human macrophages. J. Immunol., 143(2): 617–622.

Dhand, N.K., Toribio, J.A. & Whittington, R.J. (2009). Adsorption of Mycobacterium avium subsp. paratuberculosis to Soil Particles. Appl. Environ. Microbiol., 75(17): 5581–5585.

Dick, T., Manjunatha, U., Kappes, B. & Gengenbacher, M. (2010). Vitamin B6 biosynthesis is essential for survival and virulence of Mycobacterium tuberculosis. Mol. Microbiol., 78(4): 980–988.

Dow, C.T. & Ellingson, J.L. (2010). Detection of Mycobacterium avium ss. Paratuberculosis in Blau Syndrome Tissues. Autoimmune Dis., 2010: 127692.

Epstein, A.K., Pokroy, B., Seminara, A. & Aizenberg, J. (2011). Bacterial biofilm shows persistent resistance to liquid wetting and gas penetration. Proc. Natl. Acad. Sci. USA, 108(3): 995–1000.

Faille, C., Jullien, C., Fontaine, F., Bellon-Fontaine, M.N., Slomianny, C. & Benezech, T. (2002). Adhesion of Bacillus spores and Escherichia coli cells to inert surfaces: role of surface hydrophobicity. Can. J. Microbiol., 48(8): 728–738.

Gatfield, J. & Pieters, J. (2003). Molecular mechanisms of host-pathogen interaction: entry and survival of mycobacteria in macrophages. Adv. Immunol., 81: 45–96.

Gilbert, P. & McBain, A.J. (2001). Biofilms: Their impact on health and their recalcitrance toward biocides. Am. J. Infect. Control, 29(4): 252–255.

Grant, I.R., Ball, H.J. & Rowe, M.T. (2002). Incidence of Mycobacterium paratuberculosis in bulk raw and commercially pasteurized cows' milk from approved dairy processing establishments in the United Kingdom. Appl. Environ. Microbiol., 68(5): 2428–2435.

Greenstein, R.J. (2003). Is Crohn's disease caused by a mycobacterium? Comparisons with leprosy, tuberculosis, and Johne's disease. Lancet Infect. Dis., 3(8): 507–514.

Grewal, S.K., Rajeev, S., Sreevatsan, S. & Michel, F.C., Jr (2006). Persistence of Mycobacterium avium subsp. paratuberculosis and other zoonotic pathogens during simulated composting, manure packing, and liquid storage of dairy manure. Appl. Environ. Microbiol., 72(1): 565–574.

Hermon-Taylor, J. (2001). Protagonist. Mycobacterium avium subspecies paratuberculosis is a cause of Crohn's disease. Gut, 49(6): 755–756.

Hermon-Taylor, J. (2009). Mycobacterium avium subspecies paratuberculosis, Crohn's disease and the Doomsday scenario. Gut Pathog., 1(1): 15.

Hermon-Taylor, J., Bull, T.J., Sheridan, J.M., Cheng, J., Stellakis, M.L. & Sumar, N. (2000). Causation of Crohn's disease by Mycobacterium avium subspecies paratuberculosis. Can. J. Gastroenterol., 14(6): 521–539.

Ishibashi, Y. & Arai, T. (1990). Roles of the complement receptor type 1 (CR1) and type 3 (CR3) on phagocytosis and subsequent phagosome-lysosome fusion in Salmonella-infected murine macrophages. FEMS Microbiol. Immunol., 2(2): 89–96.

Jorgensen, J.B. (1977). Survival of Mycobacterium paratuberculosis in slurry. Nord. Vet. Med., 29(6): 267–270.

Kamala, T., Paramasivan, C.N., Herbert, D., Venkatesan, P. & Prabhakar, R. (1994). Isolation and Identification of Environmental Mycobacteria in the Mycobacterium bovis BCG Trial Area of South India. Appl. Environ. Microbiol., 60(6): 2180–2183.

Kang, P.B., Azad, A.K., Torrelles, J.B., Kaufman, T.M., Beharka, A., Tibesar, E., DesJardin, L.E. & Schlesinger, L.S. (2005). The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis. J. Exp. Med., 202(7): 987–999.

Kawaji, S., Gumber, S. & Whittington, R.J. (2012). Evaluation of the immunogenicity of Mycobacterium avium subsp. paratuberculosis (MAP) stress-associated recombinant proteins. Vet. Microbiol., 155(2): 298–309.

Keane, J., Balcewicz-Sablinska, M.K., Remold, H.G., Chupp, G.L., Meek, B.B., Fenton, M.J. & Kornfeld, H. (1997). Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis. Infect. Immun., 65(1): 298–304.

Khalifeh, M.S. & Stabel, J.R. (2004). Effects of Gamma Interferon, Interleukin-10, and Transforming Growth Factor β on the Survival of Mycobacterium avium subsp. paratuberculosis in Monocyte-Derived Macrophages from Naturally Infected Cattle. Infect. Immun., 72(4): 1974–1982.

Koets, A., Santema, W., Mertens, H., Oostenrijk, D., Keestra, M., Overdijk, M., Labouriau, R., Franken, P., Frijters, A., Nielen, M. & Rutten, V. (2010). Susceptibility to paratuberculosis infection in cattle is associated with single nucleotide polymorphisms in Toll-like receptor 2 which modulate immune responses against Mycobacterium avium subspecies paratuberculosis. Prev. Vet. Med., 93(4): 305–315.

Koul, A., Herget, T., Klebl, B. & Ullrich, A. (2004). Interplay between mycobacteria and host signalling pathways. Nat. Rev. Microbiol., 2(3): 189–202.

Krensky, A.M. (2000). Granulysin: a novel antimicrobial peptide of cytolytic T lymphocytes and natural killer cells. Biochem. Pharmacol., 59(4): 317–320.

Kuroda, K., Brown, E.J., Telle, W.B., Russell, D.G. & Ratliff, T.L. (1993). Characterization of the internalization of bacillus Calmette-Guerin by human bladder tumor cells. J. Clin. Invest., 91(1): 69–76.

Kusner, D.J. (2005). Mechanisms of mycobacterial persistence in tuberculosis. Clin. Immunol., 114(3): 239–247.

Lahiri, R. & Krahenbuhl, J.L. (2008). The role of free-living pathogenic amoeba in the transmission of leprosy: a proof of principle. Lepr. Rev., 79(4): 401–409.

Lowe, A.M., Yansouni, C.P. & Behr, M.A. (2008). Causality and gastrointestinal infections: Koch, Hill, and Crohn's. Lancet Infect. Dis., 8(11): 720–726.

Meena, L.S. & Rajni (2010). Survival mechanisms of pathogenic Mycobacterium tuberculosis H37Rv. FEBS J., 277(11): 2416–2427.

Megyeri, K., Buzás, K., Miczák, A., Buzás, E., Kovács, L., Seprényi, G., Falus, A. & Mándi, Y. (2006). The role of histamine in the intracellular survival of Mycobacterium bovis BCG. Microbes Infect., 8(4): 1035–1044.

Momotani, E., Whipple, D.L., Thiermann, A.B. & Cheville, N.F. (1988). Role of M cells and macrophages in the entrance of Mycobacterium paratuberculosis into domes of ileal Peyer's patches in calves. Vet. Pathol., 25(2): 131–137.

Olsen, J.E., Jørgensen, J.B. & Nansen, P. (1985). On the reduction of Mycobacterium paratuberculosis in bovine slurry subjected to batch mesophilic or thermophilic anaerobic digestion. Agric. Wastes, 13(4): 273–280.

Pickup, R.W., Rhodes, G., Arnott, S., Sidi-Boumedine, K., Bull, T.J., Weightman, A., Hurley, M. & Hermon-Taylor, J. (2005). Mycobacterium avium subsp. paratuberculosis in the catchment area and water of the River Taff in South Wales, United Kingdom, and its potential relationship to clustering of Crohn's disease cases in the city of Cardiff. Appl. Environ. Microbiol., 71(4): 2130–2139.

Pierce, E.S. (2009). Where are all the Mycobacterium avium subspecies paratuberculosis in patients with Crohn's disease? PLoS Pathog., 5(3): e1000234.

Raizman, E.A., Wells, S.J., Godden, S.M., Bey, R.F., Oakes, M.J., Bentley, D.C. & Olsen, K.E. (2004). The distribution of Mycobacterium avium ssp. paratuberculosis in the environment surrounding Minnesota dairy farms. J. Dairy Sci., 87(9): 2959–2966.

Reid, J.D. & Chiodini, R.J. (1993). Serologic reactivity against Mycobacterium paratuberculosis antigens in patients with sarcoidosis. Sarcoidosis, 10(1): 32–35.

Rumsey, J., Valentine, J.F. & Naser, S.A. (2006). Inhibition of phagosome maturation and survival of Mycobacterium avium subspecies paratuberculosis in polymorphonuclear leukocytes from Crohn's disease patients. Med. Sci. Monit., 12(4): BR130–BR139.

Saito, H. & Tomioka, H. (1988). Susceptibilities of transparent, opaque, and rough colonial variants of Mycobacterium avium complex to various fatty acids. Antimicrob. Agents Chemother., 32(3): 400–402.

Schorey, J.S., Li, Q., McCourt, D.W., Bong-Mastek, M., Clark-Curtiss, J.E., Ratliff, T.L. & Brown, E.J. (1995). A Mycobacterium leprae gene encoding a fibronectin binding protein is used for efficient invasion of epithelial cells and Schwann cells. Infect. Immun., 63(7): 2652–2657.

Secott, T.E., Lin, T.L. & Wu, C.C. (2004). Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein facilitates M-cell targeting and invasion through a fibronectin bridge with host integrins. Infect. Immun., 72(7): 3724–3732.

Shankar, H., Singh, S.V., Singh, P.K., Singh, A.V., Sohal, J.S. & Greenstein, R.J. (2010). Presence, characterization, and genotype profiles of Mycobacterium avium subspecies paratuberculosis from unpasteurized individual and pooled milk, commercial pasteurized milk, and milk products in India by culture, PCR, and PCR-REA methods. Int. J. Infect. Dis., 14(2): e121–e126.

Shi, S. & Ehrt, S. (2006). Dihydrolipoamide acyltransferase is critical for Mycobacterium tuberculosis pathogenesis. Infect. Immun., 74(1): 56–63.

Souza, C.D., Evanson, O.A., Sreevatsan, S. & Weiss, D.J. (2007). Cell membrane receptors on bovine mononuclear phagocytes involved in phagocytosis of Mycobacterium avium subsp paratuberculosis. Am. J. Vet. Res., 68(9): 975–980.

Souza, C.D., Evanson, O.A. & Weiss, D.J. (2006). Regulation by Jun N-terminal kinase/stress activated protein kinase of cytokine expression in Mycobacterium avium subsp paratuberculosis-infected bovine monocytes. Am. J. Vet. Res., 67(10): 1760–1765.

Strahl, E.D., Gillaspy, G.E. & Falkinham, J.O., 3rd (2001). Fluorescent acid-fast microscopy for measuring phagocytosis of Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium scrofulaceum by Tetrahymena pyriformis and their intracellular growth. Appl. Environ. Microbiol., 67(10): 4432–4439.

Sturgill-Koszycki, S., Schaible, U.E. & Russell, D.G. (1996). Mycobacterium-containing phagosomes are accessible to early endosomes and reflect a transitional state in normal phagosome biogenesis. EMBO J., 15(24): 6960–6968.

Sung, N. & Collins, M.T. (2000). Effect of Three Factors in Cheese Production (pH, Salt, and Heat) on Mycobacterium avium subsp. paratuberculosis Viability. Appl. Environ. Microbiol., 66(4): 1334–1339.

Sweeney, R.W. (1996). Transmission of paratuberculosis. Vet. Clin. North Am. Food Anim. Pract., 12(2): 305–312.

Sweeney, R.W., Whitlock, R.H., Hamir, A.N., Rosenberger, A.E. & Herr, S.A. (1992). Isolation of Mycobacterium paratuberculosis after oral inoculation in uninfected cattle. Am. J. Vet. Res., 53(8): 1312–1314.

Szalai, G., Krishnamurthy, R. & Hajnóczky, G. (1999). Apoptosis driven by IP3-linked mitochondrial calcium signals. EMBO J., 18(22): 6349–6361.

Tamura, A., Yamasaki, M., Okutani, A., Igimi, S., Saitoh, N., Ekawa, T., Ohta, H., Katayama, Y. & Amano, F. (2009). Dry-resistance of Salmonella enterica subsp. enterica serovar Enteritidis is regulated by both SEp22, a novel pathogenicity-related factor of Salmonella, and nutrients. Microbes Environ., 24(2): 121–127.

Tatchou-Nyamsi-König, J.A., Dague, E., Mullet, M., Duval, J.F.L., Gaboriaud, F. & Block, J.C. (2008). Adhesion of Campylobacter jejuni and Mycobacterium avium onto polyethylene terephtalate (PET) used for bottled waters. Water Res., 42(19): 4751–4760.

Tessema, M.Z., Koets, A.P., Rutten, V.P. & Gruys, E. (2001). How does Mycobacterium avium subsp. paratuberculosis resist intracellular degradation? Vet. Q., 23(4): 153–162.

Tomioka, H., Sano, C., Sato, K., Ogasawara, K., Akaki, T., Sano, K., Cai, S.S. & Shimizu, T. (2005). Combined effects of ATP on the therapeutic efficacy of antimicrobial drug regimens against Mycobacterium avium complex infection in mice and roles of cytosolic phospholipase A2-dependent mechanisms in the ATP-mediated potentiation of antimycobacterial host resistance. J. Immunol., 175(10): 6741–6749.

Vergne, I., Chua, J., Lee, H.H., Lucas, M., Belisle, J. & Deretic, V. (2005). Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA, 102(11): 4033–4038.

Weiss, D.J., Evanson, O.A., Deng, M. & Abrahamsen, M.S. (2004). Gene expression and antimicrobial activity of bovine macrophages in response to Mycobacterium avium subsp. paratuberculosis. Vet. Pathol., 41(4): 326–337.

Weiss, D.J., Evanson, O.A., McClenahan, D.J., Abrahamsen, M.S. & Walcheck, B.K. (2001). Regulation of expression of major histocompatibility antigens by bovine macrophages infected with Mycobacterium avium subsp. paratuberculosis or Mycobacterium avium subsp. avium. Infect. Immun., 69(2): 1002–1008.

Weiss, D.J., Evanson, O.A., Moritz, A., Deng, M.Q. & Abrahamsen, M.S. (2002). Differential responses of bovine macrophages to Mycobacterium avium subsp. paratuberculosis and Mycobacterium avium subsp. avium. Infect. Immun, 70(10): 5556–5561.

Weiss, D.J., Souza, C.D., Evanson, O.A., Sanders, M. & Rutherford, M. (2008). Bovine monocyte TLR2 receptors differentially regulate the intracellular fate of Mycobacterium avium subsp. paratuberculosis and Mycobacterium avium subsp. avium. J. Leukoc. Biol., 83(1): 48–55.

Whan, L., Grant, I.R. & Rowe, M.T. (2006). Interaction between Mycobacterium avium subsp. paratuberculosis and environmental protozoa. BMC Microbiol., 6(1): 63.

Whitlock, R.H. & Buergelt, C. (1996). Preclinical and clinical manifestations of paratuberculosis (including pathology). Vet. Clin. North Am. Food Anim. Pract., 12(2): 345–356.

Whittington, R.J., Marsh, I.B. & Reddacliff, L.A. (2005). Survival of Mycobacterium avium subsp. paratuberculosis in dam water and sediment. Appl. Environ. Microbiol., 71(9): 5304–5308.

Whittington, R.J., Marshall, D.J., Nicholls, P.J., Marsh, I.B. & Reddacliff, L.A. (2004). Survival and dormancy of Mycobacterium avium subsp. paratuberculosis in the environment. Appl. Environ. Microbiol., 70(5): 2989–3004.

Woo, S.R., Heintz, J.A., Albrecht, R., Barletta, R.G. & Czuprynski, C.J. (2007). Life and death in bovine monocytes: the fate of Mycobacterium avium subsp. paratuberculosis. Microb. Pathog., 43(2-3): 106–113.

Yamazaki, Y., Danelishvili, L., Wu, M., Macnab, M. & Bermudez, L.E. (2006). Mycobacterium avium genes associated with the ability to form a biofilm. Appl. Environ. Microbiol., 72(1): 819–825.

Young, J.S., Gormley, E. & Wellington, E.M. (2005). Molecular detection of Mycobacterium bovis and Mycobacterium bovis BCG (Pasteur) in soil. Appl. Environ. Microbiol., 71(4): 1946–1952.




How to Cite

Verma, D. K. (2013). Survival tactics of Mycobacterium avium subspecies paratuberculosis. Journal of Advanced Laboratory Research in Biology, 4(4), 141–149. Retrieved from