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Clinical and Vaccine Immunology, June 2009, p. 806-810, Vol. 16, No. 6
1071-412X/09/$08.00+0     doi:10.1128/CVI.00120-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Evaluation of a Novel Therapeutic Approach to Treating Severe Pneumococcal Infection Using a Mouse Model{triangledown}

Nikkol Melnick,{dagger} Gowrisankar Rajam,{dagger} George M. Carlone, Jacquelyn S. Sampson, and Edwin W. Ades*

Division of Bacterial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333

Received 18 March 2009/ Returned for modification 6 April 2009/ Accepted 16 April 2009

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.

* Corresponding author. Mailing address: Building 18, Room B-104, MS G-05, Immunology Laboratories, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333. Phone: (404) 639-3739. Fax: (404) 639-4518. E-mail: EAdes{at}cdc.gov

{triangledown} Published ahead of print on 22 April 2009.

{dagger} These authors contributed equally to this work.

Clinical and Vaccine Immunology, June 2009, p. 806-810, Vol. 16, No. 6
1071-412X/09/$08.00+0     doi:10.1128/CVI.00120-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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