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Title: Innate recognition of viruses by plasmacytoid dendritic cells
Author: Seeds, Rosalind E.
ISNI:       0000 0001 3392 3547
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2008
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Plasmacytoid dendritic cells (pDCs) are thought to be specialized for early viral recognition and secrete large amounts of the anti-viral cytokines type I interferon (lFNa/f3). This thesis studied viral recognition by pDCs and aimed to identify novel viral sensing receptors for viral glycoproteins. Murine pDCs were found to express the predominantly myeloid restricted lectins (mannose receptor, SIGNRI, Dectin-I and Dectin-2); a scavenger receptor, immunomodulatory receptor-ligand pairs (CD200R, CD200, SIRPa and CD47) and myeloid differentiation antigens (F4/80 and 7/4). This extends the known phenotype of pDCs and identified candidate receptors for further study. A protocol based on flow cytometric intracellular staining was developed to measure IFNa/f3 production by pDCs. This, together with an IFNa ELISA and IFN bioassay, was used to investigate viral recognition by pDCs. HI and H5 subtypes of influenza virus haemagglutinin (HA) and gp 120 from human immunodeficiency virus (HIVICN54) stimulated IFN production by splenocytes (containing pDCs). Mannan inhibited inactivated influenza virus (A/Guangdong/25/93), HA and gpl20 stimulated IFN production which implied a role for a mannose specific receptor in viral sensing, however, no requirement for mannose receptor or SIGNRI was observed. IFN induction by inactivated influenza virus, HA and gpl20 was also dependent on MyD88, but influenza virus recognition was not dependent on Toll-like receptor (TLR)2 or TLR4, raising the possibility of glycoprotein recognition through another TLR. The ability of CD200 to modulate IFNa induction was also tested. Consistent with the known inhibitory functions of CD200 through CD200R, CD200 knock-out macrophages produced more IFNa in response to the MyD88-independent stimulus polyinosinic-polycytidylic acid. In contrast, the blocking anti-CD200 monoclonal antibody OX90 inhibited MyD88-dependent IFNa production by spleen cells stimulated with influenza virus and CpG ODN suggesting that C0200 could promote IFNa production. C0200 may therefore differentially regulate IFNa induction pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available