Potassium ion channel K_ir2.1 negatively regulates protective responses to Mycobacterium bovis BCG

Tuberculosis caused by the pathogen Mycobacterium tuberculosis leads to increased mortality and morbidity worldwide. The prevalence of highly drug-resistant strains has reinforced the need for greater understanding of host-pathogen interactions at the cellular and molecular levels. Our previous work demonstrated critical roles of calcium ion channels in regulating protective responses to mycobacteria. In this report, we deciphered the roles of inwardly rectifying K+ ion channel K(ir)2.1 in epithelial cells. Data showed that infection of epithelial cells (and macrophages) increases the surface expression of K(ir)2.1. This increased expression of K(ir)2.1 results in higher intracellular mycobacterial survival, as either inhibiting or knocking down K(ir)2.1 results in mounting of a higher oxidative burst leading to a significant attenuation of mycobacterial survival. Further, inhibiting K(ir)2.1 also led to increased expression of T cell costimulatory molecules accompanied with increased activation of MAP kinases and transcription factors nuclear factor kappa B and phosphorylated CREB. Furthermore, inhibiting K(ir)2.1 induced increased autophagy and apoptosis that could also contribute to decreased bacterial survival. Interestingly, an increased association of heat shock protein 70 kDa with K(ir)2.1 was observed. These results showed that mycobacteria modulate the expression and function of K(ir)2.1 in epithelial cells to its advantage.