Evaluation of a novel therapeutic approach to treating severe pneumococcal infection using a mouse model

Clin Vaccine Immunol. 2009 Jun;16(6):806-10. doi: 10.1128/CVI.00120-09. Epub 2009 Apr 22.

Abstract

P4, a 28-amino-acid peptide, is a eukaryotic cellular activator that enhances specific in vitro opsonophagocytic killing of multiple bacterial pathogens. In a previous study, we successfully recreated this phenomenon in mice in vivo by using a two-dose regimen of P4 and pathogen-specific antibodies, which significantly reduced moribundity in mice. For the present study, we hypothesized that the inclusion of a low-dose antibiotic would make it possible to treat the infected mice with a single dose containing a mixture of P4 and a pathogen-specific antibody. A single dose consisting of P4, intravenous immunoglobulin (IVIG), and ceftriaxone effectively reduced moribundity compared to that of untreated controls (n = 10) by 75% (P < 0.05) and rescued all (10 of 10) infected animals (P < 0.05). If rescued animals were reinfected with Streptococcus pneumoniae and treated with a single dose containing P4, IVIG, and ceftriaxone, they could be rerescued. This observation of the repeated successful use of P4 combination therapy demonstrates a low risk of tolerance development. Additionally, we examined the polymorphonuclear leukocytes (PMN) derived from infected mice and observed that P4 enhanced in vitro opsonophagocytic killing (by >80% over the control level; P < 0.05). This finding supports our hypothesis that PMN are activated by P4 during opsonophagocytosis and the recovery of mice from pneumococcal infection. P4 peptide-based combination therapy may offer an alternative and rapid immunotherapy to treat fulminant pneumococcal infection.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use
  • Antibodies, Bacterial / therapeutic use
  • Bacterial Proteins / chemical synthesis
  • Bacterial Proteins / pharmacology
  • Bacterial Proteins / therapeutic use
  • Ceftriaxone / therapeutic use
  • Drug Therapy, Combination
  • Female
  • Immunization, Passive / methods*
  • Immunoglobulins, Intravenous / therapeutic use
  • Immunologic Factors / chemical synthesis
  • Immunologic Factors / pharmacology
  • Immunologic Factors / therapeutic use*
  • Mice
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Peptides / chemical synthesis
  • Peptides / pharmacology
  • Peptides / therapeutic use*
  • Phagocytosis / drug effects
  • Pneumococcal Infections / therapy*
  • Streptococcus pneumoniae / chemistry
  • Streptococcus pneumoniae / immunology*
  • Survival Analysis

Substances

  • Anti-Bacterial Agents
  • Antibodies, Bacterial
  • Bacterial Proteins
  • Immunoglobulins, Intravenous
  • Immunologic Factors
  • Peptides
  • Ceftriaxone