PIM ₆ Induces Tolerance and Confers Protection against Mycobacterium tuberculosis in Primary Macrophages

Glycolipids are major components of the mycobacterial cell envelope and play critical roles in host-pathogen interactions. Here we investigate the capacity of the mycobacterial glycolipid phosphatidyl-myo-inositol hexamannosides (PIM ₆ ) to modulate innate responsiveness in naive primary human monocytes and monocyte-derived macrophages (MDMs). Monocytes and MDMs prestimulated with PIM6, followed by 5 days of rest, secreted attenuated levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 10 (IL-10) following LPS challenge. PIM ₆ pretreatment significantly altered pattern recognition receptor expression through the experimental time course and programmed a tolerized phenotype in myeloid cells independent of TLR2 activity. In an infection challenge with H37Rv Mycobacterium tuberculosis (M.tb), MDMs pretreated with PIM ₆ secreted decreased levels of TNF-α and IL-10 and exhibited early increased bacterial control. Together, these data reveal PIM ₆ as a complex immunomodulator that tolerizes myeloid cells to subsequent stimuli and exerts direct effects on the control of M.tb infection.