A live auxotrophic vaccine confers mucosal immunity and protection against lethal pneumonia caused by Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is one of the leading causes of nosocomial pneumonia and its associated mortality. Moreover, extensively drug-resistant high-risk clones are globally widespread, presenting a major challenge to the healthcare systems. Despite this, no vaccine is available against this high-concerning pathogen. Here we tested immunogenicity and protective efficacy of an experimental live vaccine against P. aeruginosa pneumonia, consisting of an auxotrophic strain which lacks the key enzyme involved in D-glutamate biosynthesis, a structural component of the bacterial cell wall. As the amounts of free D-glutamate in vivo are trace substances in most cases, blockage of the cell wall synthesis occurs, compromising the growth of this strain, but not its immunogenic properties. Indeed, when delivered intranasally, this vaccine stimulated production of systemic and mucosal antibodies, induced effector memory, central memory and IL-17A-producing CD4 + T cells, and recruited neutrophils and mononuclear phagocytes into the airway mucosa. A significant improvement in mice survival after lung infection caused by ExoU-producing PAO1 and PA14 strains was observed. Nearly one third of the mice infected with the XDR high-risk clone ST235 were also protected. These findings highlight the potential of this vaccine for the control of acute pneumonia caused by this bacterial pathogen.

Understanding Pseudomonas aeruginosa–Host Interactions: The Ongoing Quest for an Efficacious Vaccine

“…Recently, Cabral et al used a live auxotrophic strain (PAO1∆murI) lacking an enzyme involved in D-glutamate biosynthesis, an essential component of peptidoglycan. Both humoral and cellular responses were triggered when delivered intranasally in a two-dose vaccination schedule, leading to murine survival of 86-88% against lethal pneumonia [190].…”

Multi-drug resistant gram-negative bacterial pneumonia: etiology, risk factors, and drug resistance patterns

“…A randomized clinical trial evaluated recombinant IC43 100 μg vaccination against potentially lethal P. aeruginosa infection in mechanically ventilated non-surgical ICU patients and found that it was both immunogenic and well-tolerated [ 127 ]. A live vaccine containing auxotrophic strain that lacks the key enzyme involved in D-glutamate biosynthesis, a structural component of the bacterial cell wall, confers mucosal immunity and protection against lethal pneumonia caused by P. aeruginosa [ 128 ] .…”

Protective Effect against Neosporosis Induced by Intranasal Immunization with Neospora caninum Membrane Antigens Plus Carbomer-Based Adjuvant

“…Moreover, these cells have been implicated in protective mechanisms against protozoan infections [52,53]. It would therefore be worth determining whether these cells could be mediating the pulmonary protective effect observed in the NcMP/CARB mouse group, since IL-17-mediated responses in the lungs induced by intranasal immunization have been previously associated with host protection from diverse infections [54][55][56][57]. The intranasal immunization used here also induced N. caninum antigen responsive liver leukocyte cells producing IL-17A.…”