Peptide Aggregation Induced Immunogenic Rupture (PAIIR)

Abstract

Immunogenic cell death (ICD) arises when cells are under stress, and their membranes are damaged. They release damage‐associated molecular patterns (DAMPs) that stimulate and drive the type and magnitude of the immune response. In the presence of an antigen, DAMPs ride the longevity and efficacy of antigen‐specific immunity. Yet, no tool can induce the controlled ICD with predictable results. A peptide‐based tool, [II], is designed that aggregates in the cell and causes cell membrane damage, generates ICD and DAMPs release on various cell types, and hence can act as an adjuvant. An influenza vaccine is prepared by combining [II] with influenza hemagglutinin (HA) subunit antigens. The results show that [II] induced significantly higher HA‐specific immunoglobulin G1 (IgG1) and IgG2a antibodies than HA‐only immunized mice, while the peptide itself did not elicit antibodies. This paper demonstrates the first peptide‐aggregation induced immunogenic rupture (PAIIR) approach as a vaccine adjuvant. PAIIR is a promising adjuvant with a high potential to promote universal protection upon influenza HA vaccination.

Controllable membrane damage by tunable peptide aggregation with albumin

“…0.2 w% albumin) as shown before. 18 During 3 h of treatment, [II] in 0 w% (without albumin) did not cause any membrane damage (Figure 3B), as…”

“…0.2w% albumin) as shown before. 12 During 3h of treatment, [II] in 0 w% (without albumin) did not cause any membrane damage (Figure 3B), as [II] fibrils do not interact with the lipid membrane (Figure 1B). Addition of [II] with 0.2 w% albumin showed increasing membrane damage over time which is quantified by the release of lactate dehydrogenase (LDH), a cytoplasmic enzyme released upon membrane damage.…”

“…On the cell membrane, aggregation of [II] peptides causes immunogenic rupture (PAIIR), which starts immunogenic cell death (ICD) and results in the release of damage-associated molecular patterns (DAMPs), which act as an immunostimulatory agent. 18 PAIIR induces secondary pyroptosis, a programmed ICD, and a common feature of amyloid-inducing cell death as in Alzheimer's and Parkinson's diseases. 19,20 PAIIR is a simplified peptide-based tool designed to mimic the function instead of the sequence of a protein; thus, there is no natural ortholog of [II].…”

Controllable membrane damage by tunable peptide aggregation with albumin

“…40,41 We previously showed that [II] aggregation-induced cell death is ICD through the release of DAMPs in multiple cell lines. 12 Given that eIF2α phosphorylation results in calreticulin surface localization, we identified the localization of calreticulin within the cells incubated with [II]. Cal-reticulin was observed only intracellularly in control cells and cells treated with 0.5mM [II] in 0% albumin.…”

“…On the cell membrane, [II] peptide-aggregation induces immunogenic rupture (PAIIR) that initiates immunogenic cell death (ICD) and associated release of damage associated molecular patterns (DAMPs) as an immunostimulatory tool. 12 PAIIR induces secondary pyroptosis, a programmed ICD and a common feature of amyloid inducing cell death as in Alzheimer’s and Parkinson’s diseases. 13,14 PAIIR is a simplified peptide-based tool, designed to mimic the function, instead of the sequence of a protein; thus there is no natural ortholog of [II].…”