| Summary: | 碩士 === 國立臺灣大學 === 微生物學研究所 === 107 === Siglecs (sialic acid-binding immunoglobulin-like lectins) are receptors recognizing sialic acids. Siglec-5 and Siglec-14, expressing on monocytes, macrophages and neutrophils, can transduce inhibitory and activating signals through ITIM and ITAM, respectively, upon ligand engagement. In addition, SIGLEC5/14 polymorphism has been discovered in human population and the presence of SIGLEC14 WT allele has been linked to exaggerated host antimicrobial and inflammatory responses upon infection. We and others have demonstrated that Siglec-14 promotes proinflammatory responses of macrophages and neutrophils upon bacterial infection. However, the role of SIGLEC5/14 polymorphism in host proinflammatory and antiviral responses upon viral infection is largely unknown. Influenza A virus (IAV) infection often associates with exacerbated host inflammation (cytokine storm) and eventually leads to lung tissue destruction. Sendai virus (SeV), structurally similar to IAV, is a wildly used model to study host antiviral responses since SeV infection constantly mounts a robust host interferon (IFN) response. Thus, we applied both IAV and SeV to infect THP-1 cells expressing either Siglec-5 or Siglec-14 to explore the role of SIGLEC5/14 polymorphism in antiviral innate immune responses. We found that H5N1 or SeV infection stimulates more TNF-a and IL-1b production in S14/THP-1 cells (THP-1 cells expressing Siglec-14) compared with that produced in infected S5/THP-1 cells (THP-1 cells expressing Siglec-5). In addition, H5N1 infection caused enhanced p38 and AKT phosphorylation in S14/THP-1 cells. Our data suggest that Siglec-14 may promote proinflammatory responses through activating p38 and AKT signaling pathway upon viral infection. In contrast, reduced production of IFN-b mRNA was observed in S14/THP-1 cells infected with IAV or SeV. Neither the released IFN protein nor the activated TBK1 and IRF3 can be detected in our experimental system, we will therefore optimize experimental conditions to further clarify the role of Siglec-14 in regulating host IFN responses. Comparable IAV replication was observed in S5/THP-1 and S14/THP-1 cells, indicating that reduced IFN responses in the S14/THP-1 cells upon IAV infection were not directly affected by restricted virus entry and virion production by Siglec-14. Engagement of ITIM-bearing Siglecs have been shown to trigger cell death in various cell types, we next examined whether Sigelc-5 and Siglec-14 can modulate cell survival upon IAV infection. Our data showed that IAV-infected S14/THP-1 cells survive better than infected S5/THP-1 cells, although the detail mechanism is still unknown. Finally, we demonstrated that IAV can directly interact with Siglec-5 and Siglec-14, indicating that IAV may engage Siglec-5 or Siglec-14 expressing on the monocytes to modulate their antiviral innate immune responses.
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