Article abstract
Nature Biotechnology 25, 465 - 472 (2007)
Published online: 25 March 2007 | doi:10.1038/nbt1288
An anti-infective peptide that selectively modulates the innate immune response
Monisha G Scott1, Edie Dullaghan1,4, Neeloffer Mookherjee2,4, Natalie Glavas1, Matthew Waldbrook2, Annick Thompson1, Aikun Wang1, Ken Lee1, Silvana Doria2, Pam Hamill2, Jie Jessie Yu2, Yuexin Li2, Oreola Donini1, M Marta Guarna1, B Brett Finlay3, John R North1 & Robert E W Hancock2
Abstract
We show that an innate defense–regulator peptide (IDR-1) was protective in mouse models of infection with important Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and Salmonella enterica serovar Typhimurium. When given from 48 h before to 6 h after infection, the peptide was effective by both local and systemic administration. Because protection by IDR-1 was prevented by in vivo depletion of monocytes and macrophages, but not neutrophils or B- and T-lymphocytes, we conclude that monocytes and macrophages are key effector cells. IDR-1 was not directly antimicrobial: gene and protein expression analysis in human and mouse monocytes and macrophages indicated that IDR-1, acting through mitogen-activated protein kinase and other signaling pathways, enhanced the levels of monocyte chemokines while reducing pro-inflammatory cytokine responses. To our knowledge, an innate defense regulator that counters infection by selective modulation of innate immunity without obvious toxicities has not been reported previously.
- Inimex Pharmaceuticals Inc., 3650 Wesbrook Mall, Vancouver, British Columbia, Canada V6S 2L2.
- Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z4
- Michael Smith Laboratories, 2259 Lower Mall Research Station, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z4.
- These authors contributed equally to this work.
Correspondence to: Robert E W Hancock2 e-mail: bob@cmdr.ubc.ca
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