Thursday, November 21, 2024
11/21/2024
Immunization against filamentous bacteriophages to prevent bacterial infection Pseudomonas aeruginosa (Pa) is a deadly pathogen and a major cause of infections in diabetic wounds and other settings. Due to extensive antibiotic resistance, it is increasingly difficult to treat Pa infections once they are established. It would be ideal to vaccinate diabetic patients against Pa before they develop infected ulcers. However, there are no approved vaccines that prevent Pa infections. One major challenge is identifying microbial targets that are amenable to immunization and common across all Pa strains and serotypes. Pf bacteriophage (phage) are a novel virulence factor in Pa infections. Unlike most bacteriophage that parasitize bacteria, Inoviruses like Pf do not typically lyse (kill) their bacterial hosts. Instead, Pf increases Pa fitness. We recently reported that Pf phage increase bacterial aggregation and decrease motility of Pa—phenotypes that facilitate initial colonization of wounds and other surfaces. In addition, Pf phage act as structural elements that promote the formation and pathogenic functions of biofilms. Based on these results, we hypothesized that immunization against Pf phage would protect against Pa infection. Our preliminary data indicate that immunity against Pf phage is indeed protective against Pa infection. Using a peptide sequence from the major coat protein (CoaB) of Pf as an antigen, we find that vaccination promotes opsonization and reduces Pa infection in a mouse wound infection model. To develop Pf phage vaccination as a therapy, further proof-of-concept studies are needed. The optimal adjuvant and vaccine formulation needs to be determined and the efficacy of this vaccine needs to be demonstrated in physiologically relevant animal models of human wound infections. The sensitivity and specificity of our vaccine against diverse Pa strains and serotypes also needs to be demonstrated. In light of our striking preliminary data, we hypothesize that a vaccine against Pf phage will protect against Pa wound infections. To test this hypothesis, we have established a team of microbiologists, immunologists, and wound infection scientists and partnered with Inimmune, Corp., an industry leader in vaccine development. In Aim 1, we will optimize our candidate vaccine that targets Pf phage to prevent Pa infection. In Aim 2, we will demonstrate the efficacy of our vaccine in animal models of Pa wound infection. In Aim 3, we will define the sensitivity and specificity of anti-Pf phage immunity against Pa clinical isolates. Together, these aims represent a bold, imaginative, and radically unconventional approach to preventing Pa wound infections. If successful, this work will give rise to the first vaccine against Pa and the first vaccine to target a bacteriophage.
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