The temporal expression profile of Mycobacterium tuberculosis infection in mice

doi:10.1073/pnas.0306023101

The temporal expression profile of Mycobacterium tuberculosis infection in mice

^*Center for Biomedical Inventions, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8573; and ^‡Department of Internal Medicine, University of New Mexico Health Science Center, 915 Camino de Salud, Albuquerque, NM 87131

Edited by John J. Mekalanos, Harvard Medical School, Boston, MA, and approved January 8, 2004 (received for review September 18, 2003)

Abstract

Infection with Mycobacterium tuberculosis causes the illness tuberculosis with an annual mortality of ≈2 million. Understanding the nature of the host-pathogen interactions at different stages of tuberculosis is central to new strategies for developing chemotherapies and vaccines. Toward this end, we adapted microarray technology to analyze the change in gene expression profiles of M. tuberculosis during infection in mice. This protocol provides the transcription profile of genes expressed during the course of early tuberculosis in immune-competent (BALB/c) and severe combined immune-deficient (SCID) hosts in comparison with growth in medium. The microarray analysis revealed clusters of genes that changed their transcription levels exclusively in the lungs of BALB/c, SCID mice, or medium over time. We identified a set of genes (n = 67) activated only in BALB/c and not in SCID mice at 21 days after infection, a key point in the progression of tuberculosis. A subset of the lung-activated genes was previously identified as induced during mycobacterial survival in a macrophage cell line. Another group of in vivo-expressed genes may also define a previously unreported genomic island. In addition, our analysis suggests the similarity between mycobacterial transcriptional machinery during growth in SCID and in broth, which questions the validity of using the SCID model for assessing mycobacterial virulence. The in vivo expression-profiling technology presented should be applicable to any microbial model of infection.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: stephen.johnston{at}utsouthwestern.edu.
↵ † Present address: Department of Animal Health and Biomedical Sciences, University of Wisconsin, Madison, WI 53706.
↵ § Present address: Department of Microbiology and Immunology, University of Texas Health Center, Tyler, TX 75708-3154.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: Mtb, Mycobacterium tuberculosis; iVEGI, in vivo-expressed genomic island; ADGE, amplified differential gene expression; qPCR, quantitative PCR; SCID, severe combined immune-deficient; cfu, colony-forming unit.