Autotransporter-Mediated Display of Complement Receptor Ligands by Gram-Negative Bacteria Increases Antibody Responses and Limits Disease Severity
Abstract
The targeting of immunogens/vaccines to specific immune cells is a promising approach for amplifying immune responses in the absence of exogenous adjuvants. However, the targeting approaches reported thus far require novel, labor-intensive reagents for each vaccine and have primarily been shown as proof-of-concept with isolated proteins and/or inactivated bacteria. We have engineered a plasmid-based, complement receptor-targeting platform that is readily applicable to live forms of multiple gram-negative bacteria, including, but not limited to, Escherichia coli, Klebsiella pneumoniae, and Francisella tularensis. Using F. tularensis as a model, we find that targeted bacteria show increased binding and uptake by macrophages, which coincides with increased p38 and p65 phosphorylation. Mice vaccinated with targeted bacteria produce higher titers of specific antibody that recognizes a greater diversity of bacterial antigens. Following challenge with homologous or heterologous isolates, these mice exhibited less weight loss and/or accelerated weight recovery as compared to counterparts vaccinated with non-targeted immunogens. Collectively, these findings provide proof-of-concept for plasmid-based, complement receptor-targeting of live gram-negative bacteria.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 14, 2020
- Source ID
- 10.3390/pathogens9050375
Entities
People
- Anju Singh
- Donald Steiner
- Edmund J. Gosselin
- Karsten R O Hazlett
- Kristen M Holland-tummillo
- Lauren E Shoudy
- Prachi Namjoshi
- Sarah J. Rosa
- Sudeep Kumar
- Timothy J. Sellati
Organizations
- National Institutes of Health Clinical Center
- United States Department of Defense