Abstract
Acinetobacter baumannii is emerging as a serious nosocomial pathogen with multidrug resistance that has made it difficult to cure and development of efficacious treatment against this pathogen is direly needed. This has led to investigate vaccine approach to prevent and treat A. baumannii infections. In this work, an outer membrane putative pilus assembly protein, FilF, was predicted as vaccine candidate by in silico analysis of A. baumannii proteome and was found to be conserved among the A. baumannii strains. It was cloned and expressed in E. coli BL21(DE3) and purified by Ni-NTA chromatography. Immunization with FilF generated high antibody titer (>64,000) and provided 50% protection against a standardized lethal dose (108 CFU) of A. baumannii in murine pneumonia model. FilF immunization reduced the bacterial load in lungs by 2 and 4 log cycles, 12 and 24 h post infection as compared to adjuvant control; reduced the levels of pro-inflammatory cytokines TNF-α, IL-6, IL-33, IFN-γ, and IL-1β significantly and histology of lung tissue supported the data by showing considerably reduced damage and infiltration of neutrophils in lungs. These results demonstrate the in vivo validation of immunoprotective efficacy of a protein predicted as a vaccine candidate by in silico proteomic analysis and open the possibilities for exploration of a large array of uncharacterized proteins.
Highlights
A. baumannii has, over the last decade, emerged as a threatening cause of bacteremia, pneumonia, septicemia, urinary tract infections, wound sepsis, endocarditis and meningitis in hospitalized patients
An uncharacterized protein FilF was selected for further analysis as it was conserved among the strains of A. baumannii
FilF shared no structural similarity in Protein Data Bank (PDB) and I-TASSER used pilus adhesin (RrgA) from Streptococcus pneumoniae as the closest template to generate a 3D structure for FilF but quality of predicted structure was not acceptable as 13 residues out of 641 amino acids of FilF fell into disallowed region of Ramachandran plot (Supplementary Figure S3)
Summary
A. baumannii has, over the last decade, emerged as a threatening cause of bacteremia, pneumonia, septicemia, urinary tract infections, wound sepsis, endocarditis and meningitis in hospitalized patients. In certain parts of the world, it is a serious cause of community-acquired infections (Peleg et al, 2008). Previously it was ignored as a “low-grade pathogen” due to its low virulence but its ability to cause disease and its profile of extensive drug resistance is recognized, making A. baumannii an “untreatable pathogen,” especially among the patients in intensive care units (Joly-Guillou, 2005; Fournier and Richet, 2006). The extensive drug resistance of this pathogen and the predictable failure of future antibiotic treatment options warrant the development of vaccine against A. baumannii
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