An anti-infective peptide that selectively modulates the innate immune response.
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.
Scott
Monisha G
MG
Inimex Pharmaceuticals Inc., 3650 Wesbrook Mall, Vancouver, British Columbia, Canada V6S 2L2.
Dullaghan
Edie
E
Mookherjee
Neeloffer
N
Glavas
Natalie
N
Waldbrook
Matthew
M
Thompson
Annick
A
Wang
Aikun
A
Lee
Ken
K
Doria
Silvana
S
Hamill
Pam
P
Yu
Jie Jessie
JJ
Li
Yuexin
Y
Donini
Oreola
O
Guarna
M Marta
MM
Finlay
B Brett
BB
North
John R
JR
Hancock
Robert E W
RE
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001424:Bacterial Infections / Q000188:drug therapy; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018448:Models, Immunological; D010455:Peptides / Q000494:pharmacology* / Q000633:toxicity; D016896:Treatment Outcome
D000890:Anti-Infective Agents; D008070:Lipopolysaccharides; D010455:Peptides