TLR9 Knockout in Non-Hematopoietic Cells Protects Mice From Influenza/MRSA Super-infection

Abstract

Abstract Millions of people worldwide are infected with influenza each year, with tens of thousands of deaths yearly in the United States alone. A significant contributor to mortality from influenza is bacterial super-infection from nasal colonizers including S. aureus. Paradoxically, mice lacking the bacterial DNA sensor TLR9 have reduced morbidity and mortality from MRSA super-infection during influenza, concurrent with reduced proinflammatory cytokines in BAL. Surprisingly, macrophages from influenza-infected TLR9−/− mice display increased MRSA phagocytosis and killing compared to macrophages from WT mice. However, bone marrow chimeras reveal that loss of TLR9 on structural (non-hematopoietic) cells is sufficient to reduce bacterial burden to the level of whole-body TLR9−/− mice, while loss of TLR9 in hematopoietic cells does not reduce bacterial burden. Thus, we hypothesize that reduced bacterial recognition by structural cells due to lack of TLR9, mediated by a lower proinflammatory cytokine response, protects animals from influenza/MRSA super-infection. Interestingly, TLR9 may also impact the immune response to influenza through recognizing host mitochondrial DNA. Our data show that influenza induces tlr9 in a wide range of structural and immune cells. Others have shown that influenza induces ER stress, and that influenza infection causes the release of mtDNA into the cytoplasm of lung structural cells. Moreover, others have shown that mtDNA upregulates tlr9 in human lung epithelium. Together, these data suggest that influenza increases mtDNA release inside lung structural cells, which stimulates tlr9 expression in intact lung epithelium, priming the lung for an overexuberant response to bacterial infection.