Immunization strategies that elicit robust memory CD8+T cell responses in mucosal tissues are important to facilitate early containment of nascent infections, as it is estimated that 70% of pathogens initiate infection via mucosal surfaces. While neutralizing antibody responses are clinical correlates of protection, tissue-resident memory CD8+T cells have been shown to protect against infections by immediately recognizing and killing infected cells. Therefore mucosal immunization strategies capable of eliciting robust memory CD8+T cell populations in target mucosal tissue are of great interest. However, a major limiting factor to the development of successful mucosal vaccines is the lack of effective and safe immune adjuvants. In the current project, we will develop and investigate the efficacy of self-assembling peptide nanomaterials for eliciting protective mucosal CD8+T cell responses Mycobacterium tuberculosis (Mtb), which is a major global health burden. We will utilize peptide nanofibers constructed from self-assembling peptides linked to antigenic epitopes from Mycobacterium tuberculosis (Mtb) and investigate effector and memory CD8+T cell responses after intranasal immunization in mice.
In aim 1, we will synthesize peptide nanofibers bearing native CD8+T cell epitopes alone or co-assembled with Mtb-specific CD4+T helper epitopes to elicit robust cellular immunity in the lung. Formulations with a strong immunogenicity profile will be tested for protection against infection using an aerosolized Mtb challenge to mimic natural route of Mtb infection. Bacterial load in the lung, liver, and other organs will be determined to assess protection.
In Aim 2, we will incorporate synthetic toll-like receptor (TLR) agonists into protective peptide nanofiber vaccine formulations from Aim 1 to expand memory CD8+T cell populations with multifunctional recall activity. Mucosal and systemic effector and memory responses will be determined after intranasal delivery of nanofiber vaccines and enhanced protection will be assessed using an aerosolized Mtb model. Completion of the proposed work will integrate the fields of synthetic chemistry, nanotechnology, immunology, and infection prophylaxis to significantly impact human health. These studies will lay the foundation for prototypic nanomaterials-based immunization platforms to elicit robust mucosal CD8+T cell immunity, which can be adapted to combat numerous mucosal pathogens.
CD8+T cell-based immunity in mucosal tissues such as the lung provides the first line of defense against invading pathogens and facilitates containment of infection. Safety concerns associated with live attenuated pathogens, needle-based injections, and toxicity of adjuvants has prompted the development of alternative immunization strategies. This research will develop self-assembling peptide nanofiber vaccines that can be delivered intranasal to elicit robust CD8+T cell immunity in the respiratory mucosa.
| Chesson, Charles B; Huante, Matthew; Nusbaum, Rebecca J et al. (2018) Nanoscale Peptide Self-assemblies Boost BCG-primed Cellular Immunity Against Mycobacterium tuberculosis. Sci Rep 8:12519 |
| Rudra, Jai S; Khan, Arshad; Clover, Tara M et al. (2017) Supramolecular Peptide Nanofibers Engage Mechanisms of Autophagy in Antigen-Presenting Cells. ACS Omega 2:9136-9143 |
