Mycobacterial Genetics / Research / Host/Pathogen Interactions

Host/Pathogen Interactions

Role of DC-SIGN during TB

We have previously shown that DC-SIGN (CD209) is the major M. tuberculosis receptor on human monocyte-derived dendritic cells (Tailleux L. et al. J. Exp. Med. 2003) (See Figure below). In order to explore the possible role of DC-SIGN in M. tuberculosis infection in vivo, we have analysed DC-SIGN expression in broncho-alveolar lavage (BAL) cells from patients with TB or with other non-mycobacterial lung pathologies. We have shown that in patients with TB, up to 70% of alveolar Mφ express DC-SIGN (Tailleux et al. PLoS Med. 2005). By contrast, the lectin is barely detected in alveolar Mφ from all other individuals. Ex vivo binding and inhibition of binding experiments further revealed that DC-SIGN-expressing alveolar Mφ constitute preferential target cells for M. tuberculosis. Altogether, DC-SIGN induction in alveolar Mφ may have important consequences on lung colonization by the tubercle bacillus, and on pulmonary inflammatory and immune responses in the infected host.

Figure. DC-SIGN is transiently present onto the M. tuberculosis phagosome (From Tailleux et al. J. Exp. Med. 2003)

In a collaborative study between our team, the team of Lluis Quintana-Murci (Institut Pasteur) and the team of Eileen Hoal (Stellenbosch University, South Africa), we have performed a case control study was conducted in a cohort of 711 individuals, including 351 TB patients and 360 healthy controls living in the Cape Town area. We observed an association between two CD209 promoter variants (-871G and -336A) and decreased risk of developing tuberculosis (Barreiro et al. PLoS Med 2006).

Altogether our results provide strong evidence for an important role of DC-SIGN during TB in humans.

Transcriptional profiles of macrophages and dendritic cells upon M. tuberculosis infection

The outcome of host cell and mycobacterial interactions most likely depends on differential molecular events, a snapshot of which may be measured in the changing transcriptional profiles of Mφ and DC. In collaboration with Paola Ricciardi-Castagnoli’s, Neil Stoker’s and Philip Butcher’s teams, we have used microarray technology to decipher simultaneously transcriptional changes in M. tuberculosis, and in Mφ and DC throughout infection. Our results identify a core set of genes that respond similarly in Mφ and DC upon M. tuberculosis infection, as well as cell-type specific gene expression patterns (see figure below); on the microbial side, mycobacteria exhibit both a common response to Mφ and DC infection, as well as differential responses to the two cell types. In particular, we could identify a clear mycobacterial stress response signature in DC, which is in line with previous findings on the low replication rate of bacilli inside these cells. In contrast the mycobacterial transcriptome in Mφ reflects that of intracellularly replicating bacteria. Transcriptome analysis indicates that the bacilli perceive the DC phagosome as a more constraining environment than the Mφ phagosome, with a greater induction of stress responsive genes during DC infection. Over-expression of mycobacterial ribosomal genes in Mφ as compared to in DC for instance, is an indicator of active protein synthesis and likely of bacterial division. This is in accordance with our previous results showing mycobacterial growth inside human-derived Mφ and mycobacterial stasis inside human DC.

Figure. Transcriptional profiling of dendritic cells (DC) and macrophages (MP) infected by M. tuberculosis, at different times post infection (p.i.) Example of genes involved in phagocyte oxidase assembly and resistance to oxidative stress.