A foil to itself: TLR2 signaling protects and damages host tissue during Mycobacterium tuberculosis infection (MPF1P.773)

Abstract

Abstract TLR2 polymorphisms have been associated with increased susceptibility to tuberculosis (TB). We have demonstrated that TLR2 is critical for host resistance against Mtb infection and limits immunopathology in the lung. Recent publications illustrating a role for epithelial cells in host immunity against Mtb led us to investigate TLR2’s role in hematopoietic (H) cells and nonhematopoietic (NH) cells in host defense against Mtb. We generated radiation bone marrow chimeric mice, which lack TLR2 either in the H, NH, or both compartments, and infected these mice with Erdman Mtb. Our results show that TLR2 signaling on the H component is crucial for control of chronic murine Mtb infection. Loss of TLR2 in the H component resulted in increased bacterial burden, decreased accumulation of regulatory T cells, and disruption of granuloma architecture. In contrast, loss of TLR2 on the NH compartment resulted in decreased inflammation and dissemination of Mtb to extrapulmonary sites. These data illustrate a novel role for TLR2 and a paradox within TLR2 signaling: TLR2 signaling on H cells is protective to the host both by controlling infection and regulating inflammation while on NH cells it promotes inflammation induced immunopathology. This balanced response is essential to maintaining host control of TB and could lead to the development of cell-specific TLR2 inhibitors.