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Protection Against Lethal Multidrug-Resistant Bacterial Infections Using Macrophage Cell Therapy

Infectious Microbes & Diseases 2019年第2期1卷 61-69页

作者： Robert Tacke Josh Sun Satoshi Uchiyama Anya Polovina Deborah G.Nguyen Victor Nizet Cellular Approaches San Diego CA92037USA Collaborative to Halt Antibiotic-Resistant Microbes(CHARM) UC San DiegoLa JollaCA 92093USA Department of Pediatrics UC San DiegoLa JollaCA 92093USA Skaggs School of Pharmacy and Pharmaceutical Sciences UC San DiegoLa JollaCA 92093USA

Multidrug-resistant(MDR)bacterial infections exert a tremendous burden on the public health system throughout the developing and developedworld.Slowing development of novel antibiotic scaffolds,over-prescription of antibiotics,extensive agricultural antibiotic use,and the increasingly complex hospitalized patient populations undergoing treatment,all fuel the rise of highly MDR“superbugs.”Unfortunately,host-directed therapies to boost immune resistance to infection are not currently available for treatment of MDR pathogens.Hematopoietic cells are endowed with a variety ofmechanismsto control microbial invasion.Macrophages in particular have long been appreciated as potent antimicrobial immune cells equipped with several receptors that allow for rapid recognition,phagocytosis,and killing of pathogenic microbes,coupled to secretion of immunostimulatory cytokines to further orchestrate a robust multifaceted antibacterial immune response.To investigate the utility of macrophages as a cell therapy for MDR bacterial infections,we developed a therapeutically translatable process to generate,harvest,and cryopreserve monocyte-derived macrophages(iconimactm).These cells effectively killed both Gram-positive and Gram-negative MDR pathogens in vitro,and conferred protection in vivo against experimental lethal peritonitis and lung infection.Our discoveries provide a proof-of-concept for a novel immunotherapeutic approach against MDR bacterial infections,urgently needed to supplement the diminishing antibiotic pipeline.

关键词： antibiotic resistance innate immunity bacterial infection macrophage cell therapy iconimactm Staphylococcus aureus Pseudomonas aeruginosa Klebsiella pneumoniae

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