HSP70 as immune potentiator for vaccines in infection and conditions of immune imbalance. (360G-Wellcome-085733_B_08_Z)

HSP are immuno-potentiators but also can display immuno-modulatory properties. Microbial HSP70 triggers the innate immune system and elicits antimicrobial immunity as a carrier when complexed with heterologous peptides. On the other hand, HSP70 can stimulate regulatory T-cell responses producing disease-suppressive immuno-modulatory effects in inflammatory diseases. We will analyse molecular and cellular mechanisms responsible for the anti-microbial and immune-modulatory activity of HSP70 by analyzing the immune response initiating events at the level of HSP70 and innate receptor CCR5 interactions. We have shown that mycobacterial (and not mammalian) HSP70 induces signalling through human but not mouse CCR5. To further analyse the role of CCR5 we will identify regions within mycobacterial HSP70 responsible for binding human CCR5 and make the appropriate mutations so as to 'mycobacterialise' human HSP70 and 'humanize' mycobacterial HSP70. This will allow us to use human CCR5 Tg mice to analyse CCR5 in the interactions with these HSP70 molecules complexed with defined T cell epitopes. We will analyse the quality and functionality of the resulting cellular immune responses in mouse infection models (listeria and influenza). In addition we will study the immunoregulatory responses triggered by HSP70 in absence of CCR5 interaction in a natural allergic disease condition: canine atopic dermatitis.