Structure-function relationships of Toll-like receptors, key mediators of antiviral innate immunity, in Human Papillomavirus 16 infection and cervical cancer

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Toll-like receptors (TLRs) are a family of cell surface receptors required for innate activation and subsequent adaptive immunity in response to invasion by bacteria, viruses, and other microbes. TLRs detect a multitude of conserved molecular structures such as bacterial lipopolysaccharide (TLR4), lipoproteins (TLR2); bacterial DNA (TLR9); viral RNA (TLR3 and 7), viral proteins (TLRs 2 and 4) but the molecular principles of ligand recognition, receptor activation and intracellular signalling remain largely unknown. Human Papillomavirus (HPV) 16 is the primary etiological agent for cervical cancer and the second biggest cause of female cancer mortality worldwide. There is evidence that components of the innate immune response are crucial in controlling viral infection. TLRs are among the primary candidates for HPV immune recognition. Consequently, TLRs have an enormous potential in the fight against HPV16-infection and the prevention of cervical cancer. This project attempts to address key aspects of TLR biology from a structure-function perspective. Using available (from protein crystal structures) and deducible (by comparative modelling) structural information, a functional assay based on mutagenesis is employed to identify amino acids of importance for signalling. Subsequently, the effects of mutagenesis will be investigated in more detail using biochemical and biophysical methods. Additionally, the role of TLRs in HPV16 immunity will be investigated. Correlations between TLR single nucleotide polymorphisms (SNPs) and persistent HPV16 infection/cervical cancer will be analyzed by introducing SNP information into the established mutagenesis-based functional screen. Furthermore, TLR expression and the influence of receptor stimulation on the progression of viral infection will be studied in an HPV model of infection.