Mycobacterium tuberculosis strains are differentially recognized by TLRs with an impact on the immune response

Tuberculosis associates with a wide spectrum of disease outcomes. The Beijing (Bj) lineage of Mycobacterium tuberculosis (Mtb) is suggested to be more virulent than other Mtb lineages and prone to elicit non-protective immune responses. However, highly heterogeneous immune responses were reported upon infection of innate immune cells with Bj strains or stimulation with their glycolipids. Using both in vitro and in vivo mouse models of infection, we here report that the molecular mechanism for this heterogeneity may be related to distinct TLR activations. Among this Mtb lineage, we found strains that preferentially activate TLR2, and others that also activate TLR4. Recognition of Mtb strains by TLR4 resulted in a distinct cytokine profile in vitro and in vivo, with specific production of type I IFN. We also uncover a novel protective role for TLR4 activation in vivo. Thus, our findings contribute to the knowledge of the molecular basis underlying how host innate immune cells handle different Mtb strains, in particular the intricate host-pathogen interaction with strains of the Mtb Bj lineage.This work has been funded by Fundacao para a Ciencia e Tecnologia, Portugal. Project grants: PTDC/SAU-MII/101977/2008 and PTDC/BIA-BCM/102776/2008. Personal grants: SFRH/BD/35981/2007 to JC; SFRH/BPD/3306/2007 to AC; SFRH/BPD/77399/2011 to LMT; SFRH/BI/33456/2008 to CS; and SFRH/BPD/33959/2009 to NSO. MS is a Ciencia 2007 fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript