The role of hisF from Acinetobacter baumannii in persistence and pneumonia infection

Overview & Synopsis

Background: Acinetobacter baumannii shows a great capacity to persist in the hospital environment and developing resistances. It is necessary to search new therapeutic targets. HisF, involved in histidine metabolism, generates a by-product called AICAR. AICAR may act as negative regulator in the production of pro-inflammatorycytokines, as IL-6. The aim of the present research was the evaluation of the role of the hisF gene in the pathogenesis and virulence of A. baumannii ATCC 17978 strain.Materials/methods: Transcriptomic analysis was performed using total RNA during a pneumonia in mice caused by A. baumannii ATCC 17978 strain. The isogenic knockout derivative strain (Δ3245) was obtained by double crossover recombination. Murine pneumonia and sepsis in BALB/c mice, as well as Galleria mellonella infectionmodels were performed to evaluate the virulence of the mutant against the WT strain. Later, mice infected by intratracheal inoculation with the WT and the Δ3245 strains were sacrificed at 4 and 24 hours, where BAL was obtained. IL-6 production and leukocytes counts were analyzed in BAL samples. RAW 264.7 cells were infectedwith ATCC 17978 strain and Δ3245 strains and their IL-6 production was analyzed.Results: Illumina RNA-Seq revealed that the A1S_3245 gene was over-expressed in bacteria during lung infection (7.2-fold). Murine pneumonia showed that mice infected with the Δ3245 strain presented a higher survival rate (100%) than mice infected with the parental strain (20%, p value= 0.0002). However, no decrease in virulence wasobserved using murine bacteriemia or G. mellonella models. IL-6 production (p value 0.0283) and leukocytes counts (p value 0.0192) at 24 hours were 2-fold higher in the infection caused by Δ3245 mutant than that caused by the WT strain. IL-6 production of RAW 264.7 cells (p value 0.0157) was 2-fold higher in the infection caused byΔ3245 mutant than that caused by the ATCC 17978 strain.Conclusions: The hisF gene of A. baumannii was over-expressed during the course of a pneumonia infection in mice. This gene is involved in virulence when a pneumonia infection occurs. The absence of the A1S_3245 gene in A. baumannii causes a great stimulation of leukocytes during a pneumonia infection.