AbstractSialic acids (Sia) are abundantly found on the surface of mammalian cells, where they serve as a marker for “self” and mediate key cellular processes. Yet, Sia expression can be hijacked by certain “non-self” pathogens for immune evasion. Understanding the role of Sia receptors, and how they regulate responses to self or “non-self” will therefore help gain clarity on host-pathogen interactions. One such Sia receptor is sialoadhesin (Sn, Siglec-1, CD169), a major macrophage receptor that preferentially recognizes terminal Sia in specific linkages to underlying sugars. Studies on the functions of Sn have demonstrated a role in mediating cell-cell interactions with the innate and adaptive immune systems, and the binding and uptake of sialylated pathogens. Alveolar macrophages (AM) express Sn constitutively, and while it has been shown that Sn on these cells can mediate the uptake of a sialylated respiratory virus to initiate infection, it remains unclear if Sn will be able to recognize a pathogen devoid of terminal Sia, but triggers its upregulation through a type I IFN response. The aim of this thesis is therefore, to address Sn’s regulation of immunity towards influenza A virus (IAV), a respiratory virus devoid of terminal Sia due to its surface viral neuraminidase. Additionally, infection by IAV triggers a well-defined innate and adaptive immune response that can be modulated by Sn through cell-cell interactions. A combination of in vivo and in vitro systems was adopted, using wildtype, Sn-deficient (Sn-/-), and Sn-binding mutant (SnW2QR97A) mice. In this thesis, I have established and validated a mouse model of IAV infection, where Sn ameliorated disease severity, contributing to host protection. Sn was also shown to attenuate inflammatory responses without affecting control of viral burden, as Sn-/- mice expressed higher levels of proinflammatory cytokines, with a higher viral burden in the lungs. In addition, I have also demonstrated that Sn contributed to greater numbers of IAV-specific CTLs in the lungs of infected WT mice. These IAV-specific CTLs were shown to express higher levels of cell surface TCRs compared to Sn-/- mice, suggesting that IAV-specific CTLs in the lungs of WT mice may be functionally regulated. Yet, viral clearance in WT mice was unaffected. Lastly, PD-1 and PD-L1 expression was observed to be more upregulated in the lungs of WT mice compared to Sn-/- mice following infection, which may represent a way of fine-tuning the activity of T cells to achieve viral clearance while controlling immunopathology. In conclusion, I have demonstrated that Sn regulates both the innate and adaptive immunity for clearance of IAV infection, contributing to host protection.
|Date of Award||2020|
|Supervisor||Paul Crocker (Supervisor)|
- Influenza A virus
Investigating the role of Sialoadhesin in Influenza A virus infection
Ong, R. (Author). 2020
Student thesis: Doctoral Thesis › Doctor of Philosophy