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Infection and Immunity, July 2005, p. 4214-4221, Vol. 73, No. 7
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.7.4214-4221.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Identification of Mycobacterium avium Genes That Affect Invasion of the Intestinal Epithelium

Elizabeth Miltner,1 Koorosh Daroogheh,1 Parmod K. Mehta,2 Suat L. G. Cirillo,2 Jeffrey D. Cirillo,2 and Luiz E. Bermudez1,3*

Kuzell Institute for Arthritis & Infectious Diseases, California Pacific Medical Center Research Institute, San Francisco, California,1 Department of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln, Nebraska,2 Department of Biomedical Sciences, College of Veterinary Medicine, and Department of Microbiology, College of Sciences, Oregon State University, Corvallis, Oregon3

Received 17 December 2004/ Returned for modification 21 January 2005/ Accepted 17 February 2005

Invasion of intestinal mucosa of the host by Mycobacterium avium is a critical step in pathogenesis and likely involves several different bacterial proteins, lipids, glycoproteins, and/or glycolipids. Through the screening of an M. avium genomic library in Mycobacterium smegmatis, we have identified a number of M. avium genes that are associated with increased invasion of mucosal epithelial cells. In order to further investigate these genes, we cloned six of them into a plasmid downstream of a strong mycobacterial promoter (L5 mycobacterial phage promoter), resulting in constitutive expression. Bacteria were then evaluated for increased expression and examined for invasion of HT-29 intestinal epithelial cells. The genes identified encode proteins that are similar to (i) M. tuberculosis coenzyme A carboxylase, (ii) M. tuberculosis membrane proteins of unknown function, (iii) M. tuberculosis FadE20, (iv) a Mycobacterium paratuberculosis surface protein, and (v) M. tuberculosis cyclopropane fatty acyl-phopholipid synthase. The constitutive expression of these genes confers to M. avium the ability to invade HT-29 intestinal epithelial cells with a severalfold increase in efficiency compared to both the wild-type M. avium and M. avium containing the vector alone. Using the murine intestinal ligated loop model, it was observed that the constitutive expression of M. avium proteins has a modest impact on the ability to enter the intestinal mucosa when compared with the wild-type control, suggesting that under in vivo conditions these genes are expressed at higher levels. Evaluation of the expression of these invasion-related genes indicated that under conditions similar to the intestinal lumen environment, the genes identified are upregulated. These data suggest that invasion of the intestinal mucosa is an event that requires the participation of several bacterial factors and the expression of the genes that encode them is less observed under standard laboratory growth conditions.

* Corresponding author. Mailing address: Department of Biomedical Sciences, College of Veterinary Medicine, 106 Dryden Hall, Oregon State University, Corvallis, OR 97331-4804. Phone: (541) 737-6538. Fax: (541) 737-8035. E-mail: luiz.bermudez{at}oregonstate.edu.

Editor: V. J. DiRita

Infection and Immunity, July 2005, p. 4214-4221, Vol. 73, No. 7
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.7.4214-4221.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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