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Identification of virulence determinants of Mycobacterium avium which impact the ability to resist host killing mechanisms

¹ Oregon State University;

² University of Freiburg, Germany;

³ California Pacific Medical Center

⁴ E-mail: luiz.bermudez{at}oregonstate.edu

Received May 14, 2009
Accepted September 7, 2009

230 Summary31 Mycobacterium avium is an opportunistic pathogen associated with pulmonary disease in non-32 AIDS patients and disseminated infection in patients with AIDS. The chief route of infection is33 by colonizing and invading mucosa of gastrointestinal tract, but infection through the respiratory34 route also occurs. After crossing the mucosa, M. avium infects and replicates within tissue35 macrophages.36 To identify M. avium genes required for survival in vivo, a library of signature-tagged37 transposon mutants was constructed and screened for clones attenuated in mice. Thirty-two38 clones were found attenuated for their virulence, from which eleven have been sequenced and39 tested further. All the mutants studied grew in vitro similarly to the wild-type MAC104. Ten40 mutants were tested individually in mice, confirming the attenuated phenotype. MAV_2450, a41 polydetide synthase homologue to Mycobacterium tuberculosis pks12, was identified. STM542 and STM10 genes (encoding for two hypothetical proteins MAV_4292 and MAV_4012) were43 associated with susceptibility to oxidative products. Mutants MAV_2450, MAV_4292,44 MAV_0385 and MAV_4264 live in macrophage vacuole with acidic pH (below 6.9). Mutants45 MAV_4292, MAV_0385 and MAV_4264 were susceptible to NO in vitro. The study of46 individual mutants can potentially lead to new knowledge about M. avium pathogenic47 mechanisms.