UC San Diego
Targeting Bacterial Pore Forming Toxins: Implications for Virulence Based Adjunctive Therapy for Invasive Bacterial Infections
- Author(s): Escajadillo, Tamara
- Advisor(s): Nizet, Victor
- et al.
While there is pressing concern over the development of antibiotic resistance, many non-resistant pathogens are capable of causing diseases of such severity that antibiotic treatment alone is insufficient for the development of optimal clinical outcomes. It is therefore imperative to explore new avenues for treatment of bacterial disease states. All bacterial pathogens have developed an arsenal of specialized virulence factors though which they are
capable of causing damage, and death, to host cells. Research focused neutralization of bacterial virulence factors as potential mechanisms for non-antibiotic therapy could help to address these concerns.
For this PhD dissertation project, I began by exploring the mechanisms of streptolysin O (SLO) induced host cell damage and examined the effects of utilizing red blood cell camouflaged nanoparticles (nanosponges) as a decoy capture platform for SLO. RBC derived nanosponges were capable of neutralizing SLO mediated toxicity and increasing immune cell function. The therapeutic potential of a toxin decoy capture platform was further expanded utilizing macrophage membrane derived nanoparticles in models of LPS driven bacteremia and were capable of absorbing bacterial LPS and several pro-inflammatory cytokines. Lastly, I focused on expanding the knowledge of host factors involved in mediating SLO toxicity through the use of gene-trap mutagenesis and CRISPR-Cas9 deletions, and explored potential pharmacological applications based on these results.
Altogether, this dissertation furthered our understanding of the mechanisms involved in bacterial toxin induced host cell damage and provides evidence for selecting toxin neutralization as a viable option for addressing bacterial disease, both through the use of engineered nanoparticles and through the application of knowledge derived from gene-trap mutagenesis strategies.