Antimycobacterial agent based on mRNA encoding human beta-defensin 2 enables primary macrophages to restrict growth of Mycobacterium tuberculosis.
Human macrophages are hosts for Mycobacterium tuberculosis, the causative agent of tuberculosis, which killed approximately 1.87 million people in 1997. Human alveolar macrophages do not express alpha- or beta-defensins, broad-spectrum antimicrobial peptides which are expressed in macrophages from other species more resistant to infection with M. tuberculosis. It has been previously reported that M. tuberculosis is susceptible to killing by defensins, which may explain the difference in resistance. Defensin peptides have been suggested as a possible therapeutic strategy for a variety of infectious diseases, but development has been hampered by difficulties in their large-scale production. Here we report the cellular synthesis of human beta-defensin 2 via highly efficient mRNA transfection of human macrophages. This enabled mycobactericidal and mycobacteristatic activity by the macrophages. Although human macrophages are difficult to transfect with plasmid vectors, these studies illustrate that primary macrophages are permissive for mRNA transfection, which enabled expression of a potentially therapeutic protein.
Department of Immunology, National Jewish Medical and Research Center, Denver, Colorado 80206, USA. kisichk@njc.org
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Kisich
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Heifets
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Higgins
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Diamond
D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology; D012333:RNA, Messenger / Q000627:therapeutic use*; D014162:Transfection; D023083:beta-Defensins / Q000096:biosynthesis / Q000235:genetics*
D000900:Anti-Bacterial Agents; C106641:DEFB4A protein, human; D012333:RNA, Messenger; D023083:beta-Defensins