Abstract
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.
Highlights
Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) and is responsible for about 2 million deaths annually [1]
In the search for the host molecular basis underlying this heterogeneity, we started by comparing the induction of cytokine production by bone marrowderived macrophages (BMDM) upon stimulation with a collection measured by immunoassay
Our analysis of cytokine production by infected cells was performed at 6 h post-infection, in order to focus on the events triggered by the innate immune recognition of Mtb strains, minimizing autocrine effects likely to occur at later times
Summary
Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB) and is responsible for about 2 million deaths annually [1]. The contribution of Mtb genetic variation to the heterogeneity of TB outcomes is gaining importance [4]. Much interest has been recently devoted to the study of the heterogeneity of responses associated with the East Asian (Bejing/W) (Bj) lineage of Mtb [8]. Several studies associate Mtb Bj strains with more severe forms of TB, TB outbreaks, drug resistance and less efficacious BCG vaccination [8,9,10]. Experimental infections with Mtb Bj strains show the induction of non-uniform immune responses [11,12,13,14,15], but the molecular bases underlying this variability remain largely unclear
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