AUTHOR=Kamoshida Go , Akaji Takuya , Takemoto Norihiko , Suzuki Yusuke , Sato Yoshinori , Kai Daichi , Hibino Taishi , Yamaguchi Daiki , Kikuchi-Ueda Takane , Nishida Satoshi , Unno Yuka , Tansho-Nagakawa Shigeru , Ubagai Tsuneyuki , Miyoshi-Akiyama Tohru , Oda Masataka , Ono Yasuo 

TITLE=Lipopolysaccharide-Deficient Acinetobacter baumannii Due to Colistin Resistance Is Killed by Neutrophil-Produced Lysozyme

JOURNAL=Frontiers in Microbiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.00573

DOI=10.3389/fmicb.2020.00573

ISSN=1664-302X

ABSTRACT=<p><italic>Acinetobacter baumannii</italic> causes nosocomial infections due to its multidrug resistance and high environmental adaptability. Colistin is a polypeptide antibacterial agent that targets lipopolysaccharide (LPS) and is currently used to control serious multidrug-resistant Gram-negative bacterial infections, including those caused by <italic>A. baumannii</italic>. However, <italic>A. baumannii</italic> may acquire colistin resistance by losing their LPS. In mouse models, LPS-deficient <italic>A. baumannii</italic> have attenuated virulence. Nevertheless, the mechanism through which the pathogen is cleared by host immune cells is unknown. Here, we established colistin-resistant <italic>A. baumannii</italic> strains and analyzed possible mechanisms through which they are cleared by neutrophils. Colistin-resistant, LPS-deficient strains harbor mutations or insertion sequence (IS) in <italic>lpx</italic> genes, and introduction of intact <italic>lpx</italic> genes restored LPS deficiency. Analysis of interactions between these strains and neutrophils revealed that compared with wild type, LPS-deficient <italic>A. baumannii</italic> only weakly stimulated neutrophils, with consequent reduced levels of reactive oxygen species (ROS) and inflammatory cytokine production. Nonetheless, neutrophils preferentially killed LPS-deficient <italic>A. baumannii</italic> compared to wild-type strains. Moreover, LPS-deficient <italic>A. baumannii</italic> strains presented with increased sensitivities to antibacterial lysozyme and lactoferrin. We revealed that neutrophil-secreted lysozyme was the antimicrobial factor during clearance of LPS-deficient <italic>A. baumannii</italic> strains. These findings may inform the development of targeted therapeutics aimed to treat multidrug-resistant infections in immunocompromised patients who are unable to mount an appropriate cell-mediated immune response.</p>