Genetic determinants of virulence and drug resistance of Mycobacterium avium subsp. hominissuis — a causative agent of mycobacteriosis in humans

Cover Page

Cite item


Among the members of the large group of non-tuberculous mycobacteria (comprising more than 180 species), M. avium subsp. hominissuis (MAH) is the most significant causative agent of pulmonary infection in immunocompetent individuals as well as disseminated infection in immunocompromised hosts, e.g. human immunodeficiency virus (HIV)-positive patients. Due to increased incidence rate of mycobacteriosis, especially in HIV infection, much still need to be learnt about the MAH genetic control and virulence mechanisms. Deciphering the genome contents of the M. avium strain 104 (isolated from an AIDS patient with disseminated MAH disease) allowed to compare genome sequences of M. avium strains to gain insights into genomic diversity associated with variable hosts and environments. Comparative genome analysis of MAH strains isolated from patients with pulmonary and disseminated forms of mycobacteri-osis revealed differences in the structure of the genome, affecting the key virulence genes. This review provides current data on the genetic determinants of MAH virulence associated with the initial phase of infection. Several mycobacterial virulence-associated gene families, such as mce (mammalian cell entry), mmp (mycobacterial membrane proteins), pe/ppe and esx expressed by MAH during human infection are thought to be crucial for adhesion, entry, survival, and reproduction inside host macrophages. The genetic mechanisms of MAH survival in human macrophage cell culture as well as mice exposed to toxic effects of reactive oxygen, nitric oxide, bactericidal proteins (cathelicidin) are discussed. The MAH survival in the latency-like state is important for pathogen dissemination. Some genetic and phenotypic features of MAH (absence of a cord factor, presence of plasmids, potential to “switch” morphological types of colonies) are compared with M. tuberculosis. In addition, we summarized current state of MAH drug discovery, a role of MAH intrinsic multidrug resistance, genetic control, as well as mechanisms underlying formation of resistance to various groups of antibiotics in MAH strains.

About the authors

D. A. Starkova

St. Petersburg Pasteur Institute

Author for correspondence.

Starkova D.A., PhD, Researcher, Laboratory of Molecular Epidemiology and Evolutionary Genetics, St.PPI.

St. Petersburg

Russian Federation

O. V. Narvskaya

St. Petersburg Pasteur Institute; St. Petersburg Research Institute of Phthisiopulmonology


Narvskaya O.V., PhD, МD (Medicine), Professor, Leading Researcher, Laboratory of Molecular Epidemiology and Evolutionary Genetics, St.PPI; Scientific Advisor, St. Petersburg Research Institute of Phthisiopulmonology.

St. Petersburg

Russian Federation


  1. Вишневский Б.И., Маничева О.А., Щеголева Р.А., Оттен Т.Ф. Вирулентность потенциально патогенных нетуберкулезных микобактерий. Обзор // Медицинский альянс. 2015. № 4. С. 5—14.
  2. Оттен Т.Ф., Васильев А.В. Микобактериоз. СПб.: Медицинская пресса, 2005. 224 с.
  3. Babrak L., Danelishvili L., Rose S.J., Bermudez L.E. Microaggregate-associated protein involved in invasion of epithelial cells by Mycobacterium avium subsp. hominissuis. Virulence, 2015, vol. 6, no. 7, pp. 694—703. doi: 10.1080/21505594.2015.1072676
  4. Belanger A.E., Besra G.S., Ford M.E., Mikusova K., Belisle J.T., Brennan P.J., Inamine J.M. The embAB genes of Mycobacterium avium encode an arabinosyl transferase involved in cell wall arabinan biosynthesis that is the target for the antimycobacterial drug ethambutol. Proc. Natl. Acad. Sci. USA, 1996, vol. 93, no. 21, pp. 11919—11924. doi: 10.1073/pnas.93.21.11919
  5. Bermudez L.E., Danelishvili L., Babrack L., Pham T. Evidence for genes associated with the ability of Mycobacterium avium subsp. hominissuis to escape apoptotic macrophages. Front. Cell. Infect. Microbiol., 2015, vol. 5, no. 63. doi: 10.3389/fcimb.2015.00063
  6. Brown-Elliott B.A., Iakhiaeva E., Griffith D.E., Woods G.L., Stout J.E., Wolfe C.R., Turenne C.Y., Wallace R.J.Jr. In vitro activity of amikacin against isolates of Mycobacterium avium complex with proposed MIC breakpoints and finding of a 16S rRNA gene mutation in treated isolates. J. Clin. Microbiol, 2013, vol. 51, no. 10, pp. 3389—3394. doi: 10.1128/JCM.01612-13
  7. Cangelosi G.A., Do J.S., Freeman R., Bennett J.G., Semret M., Behr M.A. The two-component regulatory system mtrAB is required for morphotypic multidrug resistance in Mycobacterium avium. Antimicrob. Agents Chemother., 2006, vol. 50, no. 2, pp. 461-468. doi: 10.1128/AAC.50.2.461-468.2006
  8. Christianson S., Grierson W., Wolfe J., Sharma M.K. Rapid molecular detection of macrolide resistance in the Mycobacterium avium complex: are we there yet? J. Clin. Microbiol., 2013, vol. 51, no. 7, pp. 2425-2426. doi: 10.1128/JCM.00555-13
  9. Danelishvili L., Poort M.J., Bermudez L.E. Identification of Mycobacterium avium genes up-regulated in cultured macrophages and in mice. FEMSMicrobiol. Lett, 2004, vol. 239, no. 1, pp. 41-49. doi: 10.1016/j.femsle.2004.08.014
  10. Danelishvili L., Stang B., Bermudez L.E. Identification of Mycobacterium avium genes expressed during in vivo infection and the role of the oligopeptide transporter OppA in virulence. Microb. Pathog, 2014, vol. 76, pp. 67-76. doi: 10.1016/j.mic-path.2014.09.010
  11. Dumas E., Christina Boritsch E., Vandenbogaert M., Rodriguez de la Vega R.C., Thiberge J.M., Caro V., Gaillard J.L., Heym B., Girard-Misguich F., Brosch R., Sapriel G. Mycobacterial pan-genome analysis suggests important role of plasmids in the radiation of type VII secretion systems. Gen. Biol. Evol., 2016, vol. 8, no. 2, pp. 387-402. doi: 10.1093/gbe/evw001
  12. Early J., Fischer K. Bermudez L.E. Mycobacterium avium uses apoptotic macrophages as tools for spreading. Microb Pathog., 2011, vol. 50, no. 2, pp. 132-139. doi: 10.1016/j.micpath.2010.12.004
  13. Eckstein T.M., Inamine J.M., Lambert M.L., Belisle J.T. A genetic mechanism for deletion of the ser2 gene cluster and formation of rough morphological variants of Mycobacterium avium. J. Bacteriol., 2000, vol. 182, no. 21, pp. 6177-6182. doi: 10.1128/ jb.182.21.6177-6182.2000
  14. Falkinham 3rd J.O. Epidemiology of infection by nontuberculous mycobacteria. Clin. Microbiol. Rev., 1996, vol. 9, no. 2, pp. 177-215.
  15. Harriff M.J., Danelishvili L., Wu M., Wilder C., McNamara M., Kent M.L., Bermudez L.E. Mycobacterium avium genes MAV_5138 and MAV_3679 are transcriptional regulators that play a role in invasion of epithelial cells, in part by their regulation of CipA, a putative surface protein interacting with host cell signaling pathways. J. Bacteriol., 2009, vol. 191, no. 4, pp. 1132-1142. doi: 10.1128/JB.01359- 07
  16. Hayashi T., Rao S.P., Catanzaro A. Binding of the 68-kilodalton protein of Mycobacterium avium to alpha(v)beta3 on human monocyte-derived macrophages enhances complement receptor type 3 expression. Infect. Immun., 1997, vol. 65, no. 4, pp. 1211-1216.
  17. Honer zu Bentrup K., Swenson D.L., Miczak A., Russell D.G. Characterization of isocitrate lyase activity and expression in Mycobacterium avium and Mycobacterium tuberculosis. J. Bacteriol., 1999, vol. 181, no. 23, pp. 7161-7167.
  18. Hou J.Y., Graham J.E., Clark-Curtiss J.E. Mycobacterium avium genes expressed during growth in human macrophages detected by selective capture of transcribed sequences (SCOTS). Infect Immun., 2002, vol. 70, no. 7, pp. 3714-3726. doi: 10.1128/iai.70.7.3714-3726.2002
  19. Huh H.J., Kim S.Y., Jhun B.W., Shin S.J., Koh W.J. Recent advances in molecular diagnostics and understanding mechanisms of drug resistance in nontuberculous mycobacterial diseases. Infect. Genet. Evol., 2018, pii. S1567-1348(18)30784- 6. doi: 10.1016/j.meegid.2018.10.003
  20. Ignatov D., Kondratieva E., Azhikina T., Apt A. Mycobacterium avium-triggered diseases: pathogenomics. Cell Microbiol., 2012, vol. 14, no. 6,pp. 808-818. doi: 10.1111/j.1462-5822.2012.01776.x
  21. Iwamoto T., Arikawa K., Nakajima C., Nakanishi N., Nishiuchi Y., Yoshida S., Tamaru A., Tamura Y., Hoshino Y., Yoo H., Park Y.K., Saito H., Suzuki Y. Intra-subspecies sequence variability of the MACPPE12 gene in Mycobacterium avium subsp. hominissuis. Infect. Genet. Evol., 2014, vol. 21, pp. 479—483. doi: 10.1016/j.meegid.2013.08.010
  22. Jeffrey B., Rose S. J., Gilbert K., Lewis M., Bermudez L.E. Comparative analysis ofthe genomes of clinical isolates ofMycobacterium avium subsp. hominissuis regarding virulence related genes. J. Med. Microbiol., 2017, vol. 66, no. 7, pp. 1063—1075. doi: 10.1099/jmm.0.000507
  23. Khattak F.A., Kumar A., Kamal E., Kunisch R., Lewin A. Illegitimate recombination: an efficient method for random mutagenesis in Mycobacterium avium subsp. hominissuis. BMC Microbiol., 2012, vol. 12, no. 204. doi: 10.1186/1471-2180-12-204
  24. Kim S.Y., Jhun B.W., Moon S.M., Shin S.H., Jeon K., Kwon O.J., Yoo I.Y., Huh H.J., Ki C.S., Lee N.Y., Shin S.J., Daley C.L., Suh G.Y., Koh W.J. Mutations in gyrA and gyrB in moxifloxacin-resistant Mycobacterium avium complex and Mycobacterium abscessus complex clinical isolates. Antimicrob. Agents Chemother., 2018, vol. 62, no. 9: e00527—18. doi: 10.1128/AAC.00527-18
  25. Krzywinska E., Bhatnagar S., Sweet L., Chatterjee D., Schorey J.S. Mycobacterium avium 104 deleted of the methyltransferase D gene by allelic replacement lacks serotype-specific glycopeptidolipids and shows attenuated virulence in mice. Mol. Microbiol., 2005, vol. 56, no. 5, pp. 1262-1273. doi: 10.1111/j.1365-2958.2005.04608.x
  26. Lahiri A., Sanchini A., Semmler T., Schafer H., Lewin A. Identification and comparative analysis of a genomic island in Mycobacterium avium subsp. hominissuis. FEBSLett., 2014, vol. 588, no. 21, pp. 3906-3911. doi: 10.1016/j.febslet.2014.08.037.
  27. Li Y., Miltner E., Wu M., Petrofsky M., Bermudez L.E. A Mycobacterium avium PPE gene is associated with the ability of the bacterium to grow in macrophages and virulence in mice. Cell Microbiol., 2005, vol. 7, no. 4, pp. 539-548. doi: 10.1111/j.1462-5822.2004.00484.x
  28. Li Y. J., Danelishvili L., Wagner D., Petrofsky M., Bermudez L.E. Identification of virulence determinants of Mycobacterium avium that impact on the ability to resist host killing mechanisms. J. Med. Microbiol., 2010, vol. 59, pp 8-16. doi: 10.1099/jmm.0.012864-0
  29. Mackenzie N., Alexander D.C., Turenne C.Y., Behr M.A., de Buck J.M. Genomic comparison of PE and PPE genes in the Mycobacterium avium complex. J. Clin. Microbiol., 2009, vol. 47, no. 4, pp. 1002-1011. doi: 10.1128/JCM.01313-08
  30. McNamara M., Danelishvili L., Bermudez L.E. The Mycobacterium avium ESX-5 PPE protein, PPE25-MAV, interacts with an ESAT-6 family Protein, MAV_2921, and localizes to the bacterial surface. Microb Pathog., 2012, vol. 52, no. 4, pp. 227-238. doi: 10.1016/j.micpath.2012.01.004
  31. Moon S.M., Park H.Y., Kim S.Y., Jhun B.W., Lee H., Jeon K., Kim D.H., Huh H.J., Ki C.S., Lee N.Y., Kim H.K., Choi Y.S., Kim J., Lee S.H., Kim C.K., Shin S.J., Daley C.L., Koh W.J. Clinical characteristics, treatment outcomes, and resistance mutations associated with macrolide-resistant Mycobacterium avium Complex lung disease. Antimicrob. Agents Chemother., 2016, vol. 60, no. 11,pp. 6758-6765. doi: 10.1128/AAC.01240-16
  32. Moriyama M., Ogawa K., Nakagawa T., Nikai T., Uchiya K. Association between a pMAH135 and the progression of pulmonary disease caused by Mycobacterium avium. Kekkaku, 2016, vol. 91, no. 1, pp. 9-15.
  33. Morsczek C., Berger S., Plum G. The macrophage-induced gene (mig) of Mycobacterium avium encodes a medium chain acyl-coenzyme A synthetase. Biochim. Biophys. Acta., 2001, vol. 1521, no. 1-3, pp. 59- 65.
  34. Parte A.C. LPSN — List of Prokaryotic names with Standing in Nomenclature (, 20 years on. Intern. J. System. Evol. Microbiol, 2018, vol. 68, pp. 1825-1829. doi: 10.1099/ijsem.0.002786
  35. Petrofsky M., Bermudez L.E. CD4+ T cells but Not CD8+ or gammadelta+ lymphocytes are required for host protection against Mycobacterium avium infection and dissemination through the intestinal route. Infect. Immun., 2005, vol. 73, no. 5, pp. 26212627. doi: 10.1128/IAI.73.5.2621-2627.2005
  36. Philalay J.S. Palermo C.O., Hauge A.K., Rustad T.R., Cangelosi G.A. Genes required for intrinsic multidrug resistance in Mycobacterium avium. J. Antimicrob. Agents Chemother., 2004, vol. 48, no. 9, pp. 3412-3418. doi: 10.1128/AAC.48.9.3412-3418.2004
  37. Rindi L., Lari N., Garzelli C. Virulence of Mycobacterium avium Subsp. hominissuis Human Isolates in an in vitro Macrophage Infection Model. Int. J. Mycobacteriol., 2018, vol. 7, no. 1, pp. 48-52. doi: 10.4103/ijmy.ijmy_11_18
  38. Ritacco V., Kremer K., Laan T., Pijnenburg J.E., Haas P.E., Van Soolingen D. 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., 1998, vol. 2, no. 3, pp. 242-251.
  39. Rose S.J., Bermudez L.E. Mycobacterium avium biofilm attenuates mononuclear phagocyte function by triggering hyperstimulation and apoptosis during early infection. Infect. Immun., 2014, vol. 82, no. 1, pp. 405-412. doi: 10.1128/IAI.00820-13
  40. Sherman D.R., Sabo P.J., Hickey M.J., Arain T.M., Mahairas G.G., Yuan Y., Barry C.E. 3rd, Stover C.K. Disparate responses to oxidative stress in saprophytic and pathogenic mycobacteria. Proc. Natl. Acad. Sci. USA, 1995, vol. 92, no. 14, pp. 6625- 6629. doi: 10.1073/pnas.92.14.6625
  41. Uchiya K., Takahashi H., Nakagawa T., Yagi T., Moriyama M., Inagaki T., Ichikawa K., Nikai T., Ogawa K. Characterization of a Novel Plasmid, pMAH135, from Mycobacterium avium subsp. hominissuis. PLoS One, 2015, vol.10, no. 2: e0117797. doi: 10.1371/journal.pone.0117797
  42. Uchiya K., Takahashi H., Yagi T., Moriyama M., Inagaki T., Ichikawa K., Nakagawa T., Nikai T., Ogawa K. Comparative genome analysis of Mycobacterium avium revealed genetic diversity in strains that cause pulmonary and disseminated disease. PLoS One, 2013, vol. 8, no. 8: e71831. doi: 10.1371/journal.pone.0071831
  43. Uchiya K., Tomida S., Nakagawa T., Asahi S., Nikai T., Ogawa K. Comparative genome analyses of Mycobacterium avium reveal genomic features of its subspecies and strains that cause progression of pulmonary disease. Sci. Rep., 2017, vol. 7: 39750. doi: 10.1038/srep39750
  44. Wu M.L., Aziz D.B., Dartois V., Dick T. NTM drug discovery: status, gaps and the way forward. DrugDiscov. Today, 2018, vol. 23, no. 8,pp. 1502-1519. doi: 10.1016/j.drudis.2018.04.001
  45. Yakrus M.A., Good R.C. Geographic distribution, frequency, and specimen source of Mycobacterium avium complex serotypes isolated from patients with acquired immunodeficiency syndrome. J. Clin. Microbiol., 1990, vol. 28, no. 5, pp. 926-929.
  46. Yakrus M.A., Reeves M.W., Hunter S.B. Characterization of isolates of Mycobacterium avium serotypes 4 and 8 from patients with AIDS by multilocus enzyme electrophoresis. J. Clin. Microbiol., 1992, vol. 30, no. 6, pp. 1474—1478.
  47. Yamazaki Y., Danelishvili L., Wu M., MacNab M., Bermudez L.E. Mycobacterium avium genes associated with the ability to form a biofilm. Appl. Environ. Microbiol., 2006, vol. 72, no. 1,pp. 819—825. doi: 10.1128/AEM.72.1.819-825.2006
  48. Yoon J.H., Kim E.C., Kim J.S., Song E.Y., Yi J., Shin S. Possession of the macrophage-induced gene by isolates of the Mycobacterium avium complex is not associated with significant clinical disease. J. Med. Microbiol., 2009, vol. 58, no. 2, pp. 256—260. doi: 10.1099/jmm.0.001958-0

Supplementary files

There are no supplementary files to display.

Copyright (c) 2020 Starkova D.A., Narvskaya O.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies