Selection activation of Pattern Recognition Receptors to enhance host protective immunity against infection (360G-Wellcome-099788_Z_12_A)

The emergence of antibiotic resistance, coupled with the lack of an efficient vaccine means Salmonella infections are still a huge problem the developing world; development of a suitable vaccine would be a significant contribution to disease control. This project aims to identify a modified strain of Salmonella enterica serovar Typhimurium (STm) which utilises host PRRs TLR4 and NLRC4 to initiate a strong Th1 immune response. TLR4 is activated by the binding of the Lipid A component of LPS, initiating asignaling cascade via the Myd88 and TRIF/Tram pathways. It is thought a dephosphorylated form ofLipid A, MPLA, signals exclusively by the TRIF/Tram pathway, reducing the potential foroveractivation of TLR4; engineering a strain to express MPLA would mean it remains immunogenic while reducing harmful side effects. NLRC4 is activated by the binding of bacterial flagellin and components of T3SS. Activation is thought to suppress the Th1 immune response; by mutating components of flagellin to prevent recognition by NLRC4, a maximum Th1 response will be achieved.By coupling activation of TLR4 via the TRIF pathway, and reducing activation of NLRC4, this will induce a strong Th1 immune response while having low toxicity, producing a highly promising vaccine candidate.