Antibacterial activity of human neutrophil defensins in experimental infections in mice is accompanied by increased leukocyte accumulation.

Abstract

Neutrophil defensins (or human neutrophil peptides-HNP) are major constituents of the azurophilic granules of human neutrophils and have been shown to display broad-spectrum antimicrobial activity. Other activities of these defensins, which are released from stimulated neutrophils, include cytotoxic, stimulatory, and chemotactic activities toward a variety of target cells. We studied the potential use of HNP-1 for antibacterial therapy of experimental bacterial infections in mice. In experimental peritoneal Klebsiella pneumoniae infections in mice, HNP-1 injection was shown to markedly reduce bacterial numbers in the infected peritoneal cavity 24 h after infection. This antibacterial effect was found to be associated with an increased influx of macrophages, granulocytes, and lymphocytes into the peritoneal cavity. These leukocytes appeared to be a requirement for the antibacterial effect, since in leukocytopenic mice administration of HNP-1 did not display antibacterial activity. HNP-1 treatment also reduced bacterial numbers in experimental K. pneumoniae or Staphylococcus aureus thigh muscle infections. In this model, radiolabeled HNP-1 was found to accumulate at the site of infection, whereas most of the injected HNP-1 was rapidly removed from the circulation via renal excretion. These results demonstrate that neutrophil defensins display marked in vivo antibacterial activity in experimental infections in mice and that this activity appears to be mediated, at least in part, by local leukocyte accumulation. ( J. Clin. Invest. 1998. 102:1583-1590.)

The Host Defense Peptide Beta-Defensin 1 Confers Protection against Bordetella pertussis in Newborn Piglets

“…These observations suggest that leukocytes that have been recruited as a result of pBD-1 treatment may clear the local infection. In agreement with this view, Welling et al previously demonstrated in an experimental peritoneal and thigh muscle bacterial infection model that human neutrophil peptide 1 displayed marked in vivo antibacterial activity in mice and that this activity appeared to be mediated by local leukocyte accumulation (55). Also, preliminary studies in our laboratory using porcine PBMCs and lymph node cells demonstrated up-regulation of typical Th1-type cytokines such as IL-12 and gamma interferon after in vitro stimulation with pBD-1 (data not shown).…”

“…They are either constitutively expressed or induced by bacterial products or proinflammatory cytokines. As part of the innate immune system, defensins are thought to play a significant role in protection against respiratory infections (14,19,44,55,57).…”

Immunomodulatory effects of anti-microbial peptides

“…The two major AMP families in humans are defensins and cathelicidins [3], both produced *E-mail: lotvos@comcast.net by neutrophils and epithelial cells and indeed share similar roles in lung and other tissue immunity [4]. In support, administration of a human neutrophil-derived defensin reduces bacterial load in the infected peritoneal cavity 24 h after infection in an experimental Klebsiella pneumoniae infection in mice [5]. Likewise, when administrating post-Francisella tularensis infection, the cathelicidin-derived peptide LL-37 protects against respiratory tularemia in a murine model [6].…”

Microbial Targeting of 99mTc-Labeled Recombinant Human β-Defensin-3 in an Animal Model of Infection: A Feasibility Pilot Study

“…The bacterial strains that we used to assess in vitro antimicrobial testing in cultures were S. aureus (Grampositive bacterium) and E. coli (Gram-negative bacterium): both have been reported to be targeted by native HBD-3 (11,12). Our data showed that the in vitro capability of 99m Tc-HBD-3 in inhibiting bacterial growth is higher with S. aureus than with E. coli.…”