Scott, M. G. et al. An anti-infective peptide that selectively modulates the innate immune response. Nature Biotech. 4, 465-472

University of British Columbia - Vancouver, Vancouver, British Columbia, Canada
Nature Biotechnology (Impact Factor: 41.51). 05/2007; 25(4):465-72. DOI: 10.1038/nbt1288
Source: PubMed


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.

Download full-text


Available from: Neeloffer Mookherjee
  • Source
    • "Plant AMPs are assigned to different families on the basis of their overall charge, the presence of disulfide bonds and their structural stability (Barbosa Pelegrini et al., 2011). In addition to their direct role against pathogens, plant AMPs can also function as modulators of defence signalling pathways (Rahnamaeian and Vilcinskas, 2012), associate with innate immune responses (Bowdish et al., 2005; Scott et al., 2007) and potentially act as signalling molecules (Salzet, 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Plants express a diverse repertoire of functionally and structurally distinct antimicrobial peptides (AMPs) that provide innate immunity by acting directly against a wide range of pathogens. AMPs are expressed in nearly all plant organs, either constitutively or in response to microbial infections. In addition to their direct activity, they also contribute to plant immunity by modulating defense responses resulting from pathogen-associated molecular pattern/effector-triggered immunity as well as interacting with other AMPs and pathways involving mitogen-activated protein kinases, reactive oxygen species, hormonal cross-talk and sugar signaling. Such links among AMPs and defense signaling pathways are poorly understood and there is no clear model for their interactions. This article provides a critical review of the empirical data to shed light on the wider role of AMPs in the robust and resource-effective defense responses of plants. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jul 2015 · Molecular Plant Pathology
  • Source
    • "Cytotoxicity was evaluated by monitoring lactate dehydrogenase release in tissue culture supernatants after 24 h stimulation (Fig. 6). We tested several USCL concentrations from 5 μM up to 80 μM and saw no appreciable cytotoxicity (less than 20 % cytotoxicity after the control is subtracted) until 20–40 μM range, concentrations that are typically used in preclinical murine models of infection (Scott et al. 2007). USCL-K2 and USCL-P Cat 2, both having a C16OH lipid tail, showed less than 20 % cytotoxicity even at a very high concentration of 80 μM. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Taking a minimalistic approach in efforts to lower the cost for the development of new synthetic antimicrobial peptides, ultrashort cationic lipopeptides were designed to mimic the amphiphilic nature crucial for their activity but with only a very short peptide sequence ligated to a lipidic acid. Nine ultrashort cationic lipopeptides were prepared to study the effects of ring constraint in the amino acid side chain of the peptide component. USCL-PCat1, consisting of only four L-4R-aminoproline residues and acylated with palmitic acid at the N-terminus, was found to populate a polyproline II helical secondary conformation that is stable to different pHs and temperatures using circular dichroism. The synthesized lipopeptides were found to have a micellar structure in water using negative staining transmission electron microscopy. We found that constraining the side chain of the amino acid component is not beneficial to the antimicrobial activity. USCL-Dab1, USCL-Dab3 and USCL-K1 showed promising activity against a panel of laboratory reference and clinically isolated Gram-positive and Gram-negative bacterial strains, some of which are multidrug resistant. No appreciable cytotoxicity against human monocytic THP-1 cells was observed up to concentrations of 20-40 µM for all synthesized compounds. Moreover, all USCLs did not induce the production of either pro-inflammatory cytokines or chemokines up to 40 µM.
    Full-text · Article · Jul 2014 · Amino Acids
  • Source
    • "The respective roles of interindividual variation and effects of diet, environment and lifestyle in defining the host–microbe interactions in the gut of mammals are furthermore difficult to dissect owing to the coordinate influences of both innate and adaptive immunity along the length of the gut. Several mechanisms underlying the homeostasis of the gut have been defined (Duerkop et al., 2009) and include (a) a compartmentalized gut with epithelial renewal properties and a mucin-glycocalyx barrier (Johansson, 2012; Johansson et al., 2011a,b, 2008), (b) complex epithelial interactions with the lumenal microbial communities (Artis, 2008; Saenz et al., 2008) including the polarized expression patterns of PRRs (Gewirtz et al., 2001; Vijay-Kumar et al., 2008), and (c) multifunctional innate effectors (Diamond et al., 2009; Scott et al., 2007; Semple and Dorin, 2012). Although much is known about how the host protects itself from pathogenic invasion, much less is understood about how symbiotic communities are tolerated and cultivated by the immune system. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The animal gut serves as a primary location for the complex host-microbe interplay that is essential for homeostasis and may also reflect the types of ancient selective pressures that spawned the emergence of immunity in metazoans. In this review, we present a phylogenetic survey of gut host-microbe interactions and suggest that host defense systems arose not only to protect tissue directly from pathogenic attack but also to actively support growth of specific communities of mutualists. This functional dichotomy resulted in the evolution of immune systems much more tuned for harmonious existence with microbes than previously thought, existing as dynamic but primarily cooperative entities in the present day. We further present the protochordate Ciona intestinalis as a promising model for studying gut host-bacterial dialogue. The taxonomic position, gut physiology and experimental tractability of Ciona offer unique advantages in dissecting host-microbe interplay and can complement studies in other model systems.
    Full-text · Article · Jun 2014 · Developmental & Comparative Immunology
Show more