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.
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We gratefully acknowledge financial support from the Foundation for the National Institutes of Health and Canadian Institutes for Health Research through the Grand Challenges in Global Health Initiative, and from Genome BC for the Pathogenomics of Innate Immunity research program. R.E.W.H. is the recipient of a Canada Research Chair. M.G.S. was the recipient of a Natural Sciences and Engineering Research Council Industrial Fellowship. The authors gratefully acknowledge the technical expertise of Reza Falsafi.
Several of the authors (M.G.S., E.D.,N.G., A.T., A.W., K.L., O.D., M.M.G.,J.R.N.) are or have been employees of Inimex Pharmaceuticals, which is developing Innate Defence Regulators as human therapeutics against bacterial infections and fever, while R.E.W.H. and B.F. are consultants and members of the scientific advisory board of Inimex Pharmaceuticals.
Combination with Antibiotics (PDF 18 kb)
Non-local activity of IDR–1 in Thigh Model (PDF 28 kb)
Protection in T/B cell Depleted animals (PDF 151 kb)
Transcriptional profiling of genes differentially expressed by IDR–1 in CD14 positive monocytes (PDF 47 kb)
Activation of C/EBPβ by IDR–1 (PDF 64 kb)
Differential activation of NFκB by LPS, CpG oligonucleotide and IDR-1 (PDF 37 kb)
IDR-1 does not block LPS binding to LBP (PDF 46 kb)
Representative genes from the microarray analysis (DOC 393 kb)
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Scott, M., Dullaghan, E., Mookherjee, N. et al. An anti-infective peptide that selectively modulates the innate immune response. Nat Biotechnol 25, 465–472 (2007). https://doi.org/10.1038/nbt1288
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