Epithelial TLR9 upregulation by respiratory viruses impairs pulmonary antibacterial immunity

Abstract While much is known about signaling downstream of the dsDNA sensor TLR9, regulation its expression underexplored and has significant consequences for innate immune responses to pathogens. Mice lacking TLR9 surprisingly fare better upon coinfection with influenza Staphylococcus aureus, other groups have shown protection from S. aureus alone as well. These TLR9KO mice display lower inflammatory cytokine production, reduced cellular infiltration into airspaces, increased survival. macrophages taken influenza-infected bacterial phagocytosis killing, inhibition on wild-type murine ex vivo decreased their ability phagocytize kill aureus. Bone marrow chimera experiments revealed that lack in non-hematopoietic cells was responsible super-infection seen whole-body mice. To assess which structural cell types were important this protection, we bred epithelial- endothelial-specific mice, a role epithelial but not endothelium. Interestingly, also found infection caused upregulation cells. Moreover, two respiratory viruses increase expression, did treatment antiviral mediator interferon beta (IFNB). IFNB long been regulate susceptibility during influenza, these results suggest it does so part by upregulating TLR9. Together, data show upregulation, likely driven IFNB, pathogenesis viral/bacterial coinfection. Funding research made possible Michigan Postdoctoral Pioneer Program at University Medical School, NIH grants NHLBI T32HL007517 (Helen Rich) R35HL144481 (Beth Moore).