Around 5 million people worldwide are affected annually by the influenza A virus (IAV), with infection resulting in severe morbidity and sometimes death. Although effective IAV vaccines exist, annual influenza epidemics occur due to its ability to quickly evolve new strains. Therefore, IAV remains a serious public health threat as evidenced by the recent pandemics involving swine H1N1 and avian H7N9. Thus, there is a vital need to develop more effective vaccines against influenza. Normally, vaccines function by priming the immune system to recognize a pathogen so that the body can more easily identify and eliminate it upon a second encounter. This protective immunity relies on receptors in the innate immune system such as the pattern recognition receptors (PRRs) Toll-like receptors (TLRs) and retinoic acid inducible gene I (RIG-I). In contrast, Nod-like receptors (NLRs) sense cellular damage as a result of infection and ...view middle of the document...
Studies show that vaccination with attenuated influenza does not provide the same cross-protection against subsequent infection with variant strains that is induced by natural influenza infections. This may due to the fact that inactivated vaccines do not activate inflammasomes. Our long-term goal is to develop a more effective vaccine by mimicking the process of natural infection that bridges the innate and adaptive immune responses. The objective of this proposal is to further understand the role of IL-1 in replacing PRRs in promoting adaptive immune responses to IAV. The underlying hypothesis of this project is that using IL-1 as an adjuvant for the IAV vaccine adjuvant will provide a more effective vaccine by resulting in a more complete immune priming. Further study of IL-1/IL-1R signaling in this context will move the field closer to understanding the potential of IL-1 as a vaccine adjuvant.
Aim 1: Determine why PAMP recognition is not enough to activate DCs and prime CD8 T cells after infection with IAV.
DCs that recognize IAV through PRRs are necessar¬ily infected by the virus, preventing them from functioning properly as antigen-presenting cells. DC activation and antigen-presenting capability will be compared between cells that are IAV-infected or IAV-free. Also, the level of infection of DCs that do not have PRRs specific for IAV will be examined.
Aim 2: Examine whether the TLR homology of IL-1R results in the exclusion of other inflammatory cytokines (i.e. IL-18) from functioning similarly.
IL-1R and TLRs share some homology due to being part of the same receptor family. Therefore they have overlapping gene activation profiles. A gene expression array will be performed on genes known to be activated by either receptor to determine overlap. Also, the TLR-homology domain of IL-1R will be mutated to determine if it is necessary for promoting adaptive immune response to IAV. Likewise, a chimeric version of the receptor for another inflammatory cytokine, like IL-18R, will be created with the IL-1R TLR homology domain to determine if it gains the same function as IL-1R.