Dectin-1 (CLEC-7A) and Mincle (CLEC-4E) suppress protective responses of macrophages during mycobacterial infection.

Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), is responsible for extreme mortality and morbidity across the globe. The bacteria have evolved multiple strategies for their successful prevalence. The emergence of multidrug-resistant TB (MDR-TB) has established the importance of eliciting host-pathogen interactions at cellular and molecular levels. Various pattern recognition receptors play determinant roles when encountering M. tb infection. Here, we investigated the regulation of key defense responses from Dectin-1 and Mincle during mycobacterial infection in THP-1-derived macrophages, the long-term hosts for mycobacteria. Our data indicate that infection of THP-1 macrophages with either M. bovis Bacillus Calmette-Guérin (BCG) or M. tb H37Rv increases the surface expression of Dectin-1 and Mincle. This increase translated directly to increased intracellular bacterial survival within macrophages. Likewise, M. bovis BCG infection of human peripheral blood mononuclear cell-derived macrophages also led to an increased expression of Dectin-1 and Mincle. Stimulation of Dectin-1 or Mincle along with BCG infection induces suppressor responses such as an attenuated oxidative burst and mitochondrial membrane potential intactness. In addition, decreased apoptosis and autophagy induction was also observed following stimulation of Dectin-1 and Mincle. Conversely, RNA interference-mediated knockdown of Dectin-1 or Mincle reversed the previous responses, resulting in higher oxidative burst, mitochondrial membrane potential disruption, increased mitochondrial reactive oxygen species production, and increased apoptosis. This results in a significant decrease in intracellular mycobacterial survival. These results point toward a well-orchestrated strategy of fine-tuning the host's defense machinery of Dectin-1 and Mincle adopted by mycobacteria to suppress protective responses mounted against it and prepare the macrophages for prolonged persistent infection.