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.

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Acknowledgements

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.

Author information

Author notes

    • Edie Dullaghan
    •  & Neeloffer Mookherjee

    These authors contributed equally to this work.

Affiliations

  1. Inimex Pharmaceuticals Inc., 3650 Wesbrook Mall, Vancouver, British Columbia, Canada V6S 2L2.

    • Monisha G Scott
    • , Edie Dullaghan
    • , Natalie Glavas
    • , Annick Thompson
    • , Aikun Wang
    • , Ken Lee
    • , Oreola Donini
    • , M Marta Guarna
    •  & John R North
  2. Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z4

    • Neeloffer Mookherjee
    • , Matthew Waldbrook
    • , Silvana Doria
    • , Pam Hamill
    • , Jie Jessie Yu
    • , Yuexin Li
    •  & Robert E W Hancock
  3. Michael Smith Laboratories, 2259 Lower Mall Research Station, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z4.

    • B Brett Finlay

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Competing interests

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.

Corresponding author

Correspondence to Robert E W Hancock.

Supplementary information

PDF files

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    Supplementary Fig. 1

    Combination with Antibiotics

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    Supplementary Fig. 2

    Non-local activity of IDR–1 in Thigh Model

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    Supplementary Fig. 3

    Protection in T/B cell Depleted animals

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    Supplementary Fig. 4

    Transcriptional profiling of genes differentially expressed by IDR–1 in CD14 positive monocytes

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    Supplementary Fig. 5

    Activation of C/EBPβ by IDR–1

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    Supplementary Fig. 6

    Differential activation of NFκB by LPS, CpG oligonucleotide and IDR-1

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    Supplementary Fig. 7

    IDR-1 does not block LPS binding to LBP

Word documents

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    Supplementary Table 1

    Representative genes from the microarray analysis

  2. 2.

    Supplementary Methods

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DOI

https://doi.org/10.1038/nbt1288

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