Introduction
Tuberculosis (TB) is the most devestating infectious disease of bacterial origin today, affecting two billion people or one-third of the world's population, with nine million new cases of active disease annually, resulting in two million deaths, mostly in developing countries. Of particular concern is the fact that multidrug-resistant (MDR) TB is emerging as an increasingly major cause of morbidity and mortality.
Most of the infected people (90 percent) have asymptomatic or latent TB infection. The other 10 percent can progress to active TB disease which, if left untreated, will kill up to 50 percent of its victims. Classical twin studies and recent linkage analyses in African populations have revealed a potential involvement of host genetic factors in susceptibility or resistance to M. tuberculosis infection. In order to define the candidate genes involved and test their causal implication, we have made use of a mouse model of tuberculosis, because mouse strains also differ substantially in their susceptibility to infection.  Gene expression profiles of cells and lungs from two highly susceptible and two resistant mouse strains were analysed after infection with M. tuberculosis using Affymetrix# GeneChip U74A Array microarray gene chips.

Results/Project Status
Both, in vitro and in vivo approaches showed a higher number of regulated genes in susceptible than in resistant mouse strains, particularly at later time points of infection (1, 2; Fig. 1). Further data mining suggested a potential contribution of neutrophil granulocytes and/or their products in susceptibility to tuberculosis in mice. Further experiments defining the deleterious role of this important cell type in TB progression are currently being conducted in our Biosafety Level III facility (Fig. 2). In addition, a number of knockout mouse strains, deficient for putative susceptibility genes (such as the Vitamin D receptor or the chemokine CCL4)  have been infected with M. tuberculosis, but few or no differences in pathology, survival and colony forming units in lung, liver and spleen were detected. In contrast, in the absence of the IL-27 receptor subunit WSX-1, decreased bacterial loads in the lung, but increased mortality were
 observed following aerosol TB challenge of mice (3).

Outlook
Selected KO mouse strains are being infected to determine the functional relevance of individual genes defined by macrophage and ex vivo gene expression analyses as being associated with resistance/susceptibility to TB. Additional experimental manipulation of the infection model by neutralization and depletion studies in vivo will allow us to assign the exact causative role of the identified candidate genes in the pathogenesis of TB.

Lit. : 1. Keller C et al. Resistance and susceptibility to tuberculosis analysed at the transcriptome level: lessons from mouse macrophages.Tuberculosis (Edinb). 2004;84(3-4):144-58. 2. Blumenthal A et al. Common and unique gene expression signatures of human macrophages in response to four strains of Mycobacterium avium that differ in their growth and persistence characteristics.Infect Immun. 2005 Jun;73(6):3330-41.  3. Hölscher C et al. The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tuberculosis. J Immunol. 2005 174:3534-44.