Abstract
Pseudomonas aeruginosa is a formidable pathogen that is responsible for a diverse spectrum of human infectious diseases, resulting in considerable annual mortality rates. Because of biofilm formation and its ability of rapidly acquires of resistance to many antibiotics, P. aeruginosa related infections are difficult to treat, and therefore, developing an effective vaccine is the most promising method for combating infection. In the present study, we designed a novel trivalent vaccine, PcrV28-294-OprI25-83-Hcp11-162 (POH), and evaluated its protective efficacy in murine pneumonia and burn models. POH existed as a dimer in solution, it induced better protection efficacy in P. aeruginosa lethal pneumonia and murine burn models than single components alone when formulated with Al(OH)3 adjuvant, and it showed broad immune protection against several clinical isolates of P. aeruginosa. Immunization with POH induced strong immune responses and resulted in reduced bacterial loads, decreased pathology, inflammatory cytokine expression and inflammatory cell infiltration. Furthermore, in vitro opsonophagocytic killing assay and passive immunization studies indicated that the protective efficacy mediated by POH vaccination was largely attributed to POH-specific antibodies. Taken together, these data provided evidence that POH is a potentially promising vaccine candidate for combating P. aeruginosa infection in pneumonia and burn infections.
Highlights
III secretion system (T3SS) and a type VI secretion system (T6SS), which directly inject effector molecules into host cells and disrupt cellular functions[11]
The molecular weights of these recombinant proteins were in accordance with their predicted molecular masses (29.6, 6.4, 17.4, and 54.1 kDa for PcrV, Outer membrane protein I (OprI), Hcp[1] and POH, respectively)
This was further confirmed by a cross-linking assay, where a band corresponding to dimerized POH was observed on the gel in the presence of the glutaraldehyde, and the amount of the linked POH dimer increased in a glutaraldehyde dose-dependent manner (Fig. 1E)
Summary
III secretion system (T3SS) and a type VI secretion system (T6SS), which directly inject effector molecules into host cells and disrupt cellular functions[11]. The P. aeruginosa V-antigen (PcrV) is an extracellular component of the T3SS that enables killing of epithelial and immune cells by protein toxin injection[13]. The most promising P. aeruginosa vaccine (IC43), which was evaluated in a phase III clinical trial (NCT01563263), is composed of OprI and a fragment of the outer membrane protein OprF. Hemolysin co-regulated protein 1 (Hcp1) is a central component of the T6SS-dependent intercellular effector transport which can deliver toxin proteins directly into prey prokaryotes and eukaryotic cells during bacterial infection[20]. After a critical review of the immunogenicity, distribution and crucial role of PcrV, OprI and Hcp[1] in P. aeruginosa pathogenesis, we hypothesized that a combination of these proteins could induce a significant immune response and provide full protection against infection. We generated a trivalent vaccine containing PcrV, OprI and Hcp[1] and evaluated its immunogenicity and protective potential in an acute pneumonia and burn mouse model
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