APOE Protects Against Severe Infection with Mycobacterium tuberculosis by Restraining Production of Neutrophil Extracellular Traps (scRNA-Seq)
Mice lacking apolipoprotein E (APOE, Apoe-/- mice) are highly susceptible to infection with Mycobacterium tuberculosis (Mtb) but the underlying immune dysregulation has been unclear. We found that Mtb infected Apoe-/- mice have significantly elevated levels of neutrophils in their lungs compared to controls and demonstrated that depleting neutrophils, depleting pDCs, blocking type1 interferon signaling, and blocking LTB4 receptor signaling all improved the outcome of Mtb-infected Apoe-/- mice. Neutrophils can undergo a specialized form of cell death termed NETosis in which activation of the enzyme PAD4 leads to extrusion of neutrophil extracellular traps (NETs). NETs have been associated with severe tuberculosis in other mouse models and in humans but a role of NETs in the pathology has not been directly established. We demonstrate that blocking PAD4 activation leads to a decrease in NETs in the lungs and, strikingly, completely reverses the hypersusceptiblity of Apoe-/- mice. Overall design: To examine the role of Apoe in the responses of pulmonary immune cells to infection with Mtb in vivo, we fed B6, Apoe-/-, and Ldlr-/- mice a normal or high cholesterol diet, infected them with ~50 CFU of Mtb H37Rv via aerosol, and isolated CD45+, IV- cells from the lung prior to infection (day 0) or at 14 days following infection. This population was analyzed by single-cell RNA-seq using the 10X Genomics platform.