Toll-like Receptors are Regulated by an Autophagy Protein MAP1S & TLR-induced Innate Resistance against Flu
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Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs). The recognition leads to the activation of TLR signaling pathway, which initiates innate immune responses and facilitates the activation of adaptive immune responses. To control the immune response, the regulation of TLR activation is critical but is not well understood. Recent evidence has suggested that autophagy could regulate TLR signaling, but the underlying mechanism is not clear. Autophagy is a process of degrading intracellular components through lysosomal machinery to maintain homeostasis under stress conditions, and MAP1S is a recently characterized autophagy-related protein. We found that MAP1S deficiency in macrophages impaired cell membrane TLR activation and TLR mediated phagocytosis of bacteria. MAP1S interacts directly with MyD88 to regulate TLR signaling pathway. Furthermore, we demonstrate that, upon TLR activation, MyD88 is recruited to autophagy processing by co-localizing with LC3. Thus we reveal that an autophagy-related molecule MAP1S regulates TLR signaling. To take advantage of TLR-mediated innate immune responses to prevent infectious diseases, we set out to boost innate immunity against influenza. TLR9 agonist CpG-ODN in combination with TLR2 agonist Pam2CSK4 can induce innate resistance against lethal influenza A virus infection; however, the mechanisms are unclear. We found that in lung epithelial cell lines, pretreatment with CpG-ODN but not Pam2CSK4, inhibited influenza A virus infection. Surprisingly, CpG-ODN induced antiviral effect is TLR9-MyD88 independent. Also, other intracellular DNA sensors including STING, DDX58, and DNA-PKcs are not required for CpG-ODN induced antiviral effect. Intriguingly, we found that CpG-ODN induced antiviral activity occurred at the early stage of influenza A virus life cycle. Together, our findings demonstrate that CpG-ODN inhibit influenza A viral infection in lung epithelial cells in a TLR9-MyD88 independent manner. Thus, we identified an autophagy protein MAP1S to regulate TLR signaling pathway. We also found that boosting innate immunity with TLR agonists can prevent infectious diseases, and TLR9 ligand CpG-ODN can induce a robust antiviral activity in lung epithelial cells. Therefore, this strategy may eventually help develop a novel therapeutic agent against influenza.
Zhang, Yifan (2016). Toll-like Receptors are Regulated by an Autophagy Protein MAP1S & TLR-induced Innate Resistance against Flu. Doctoral dissertation, Texas A&M University. Available electronically from