PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of cviPermissionsJournals.ASM.orgJournalAEM ArticleJournal InfoAuthorsReviewers
 
Clin Vaccine Immunol. 2010 November; 17(11): 1823–1824.
Published online 2010 September 15. doi:  10.1128/CVI.00366-10
PMCID: PMC2976101

P4 Peptide Therapy Rescues Aged Mice from Fatal Pneumococcal Sepsis[down-pointing small open triangle]

Gowrisankar Rajam
Division of Bacterial Diseases
Centers for Disease Control and Prevention
Atlanta, Georgia
Mathieu Bangert
Respiratory Infection Group
Liverpool School of Tropical Medicine
Liverpool, United Kingdom

Many studies suggest that with aging, immune capabilities gradually diminish, leading to a decrease in antibody production, cytokines, and various effector cells (1-4). In this study, we examined the effects of an immune-enhancing peptide on aged mice. P4, a 28-amino-acid cationic peptide derived from pneumococcal surface adhesin A (PsaA), is a eukaryotic cellular activator (10). Previously, we demonstrated that the cellular activation properties of P4 can be utilized to rescue severely ill young mice from fatal pneumococcal infection in the presence of pathogen-specific antibodies and active complement (8, 12). While P4 therapy was used to rescue young Swiss Webster mice (6 to 10 weeks old), we questioned its effectiveness in aged mice (11 and 15 months old).

Intranasal inoculation of mice with Streptococcus pneumoniae WU2 (serotype 3) and P4 therapy were done using protocols previously described, with minor modifications (12). Eleven-month-old BALB/c (n = 20) and 15-month-old Swiss Webster mice (n = 20) were infected intranasally with S. pneumoniae WU2 (~2.1 × 107 cells/mouse). Mice were monitored and visually scored twice daily for moribund characteristics as previously described (12). At 48 h postchallenge, 80% (16/20) were moribund. Moribund mice were divided into a control (n = 8) and a treatment group (n = 8). Two doses of P4 therapy with pathogen-specific antibody (intravenous immunoglobulin [IVIG]; Gamunex, Telecris, NC) and P4 were administered intravenously (postinfection) in the treatment group. Treated and untreated animals were monitored for 166 h, and the data computed for significant differences among various groups using a t test for paired samples for the means (MS Excel 2007).

Seventy-three percent of treated 15-month-old Swiss Webster mice survived with complete remission of symptoms, compared to 20% survival in the control group (P = 0.02) (Fig. (Fig.1).1). Ninety-five percent of the treated 11-month-old BALB/c mice survived, while only 45% of the mice from the control group survived (P = 0.0002) (Fig. (Fig.2).2). These findings are consistent with those of our previous studies where P4 therapy successfully rescued young mice from fatal pneumococcal infection (i.e., treated mice had an 80% survival rate and control mice had a 30% survival rate; P = 0.0002) (12).

FIG. 1.
P4 with serotype-specific IgG confers protection to 15-month-old Swiss Webster mice against intranasal S. pneumoniae serotype 3 (WU2) challenge. Intravenous injection of P4 (100 μg/mouse) with gamma globulin (100 μl/mouse) at 48 and 72 ...
FIG. 2.
P4 with serotype-specific IgG confers protection to 11-month-old BALB/c mice against intranasal S. pneumoniae serotype 3 (WU2) challenge. Intravenous injection of P4 (100 μg/mouse) with gamma globulin (100 μl/mouse) at 48 and 72 h after ...

In mice, P4 therapy augments innate immunity and treats severe bacterial infection in different age groups. The presence of pathogen-specific antibody, effector cells, and complement are the critical factors that determine the effectiveness of P4 therapy (11). The exact mechanism is not known. We speculate that polymorphonuclear neutrophils are the major innate immune component activated by the P4 peptide, as we have observed that mice treated with the neutrophil-depleting antibody RB6-8C5 (5) (after pneumococcal infection) failed to respond to in vivo P4 therapy (data not shown). While antibiotics are the first line of treatment for the elderly, antibiotic therapy can be challenging because of multiantibiotic-resistant strains, drug interactions with other medications, and side effects. Passive immune therapy supplemented with agents like P4 may address some of these concerns (6, 7, 9). New approaches are needed to augment passive immunization for infectious diseases, especially in the elderly. Immune enhancement with biomolecules such as the P4 peptide may provide a much needed thrust for patients to overcome severe infections.

Acknowledgments

We thank Dr. Nancy Messonnier, Chief, Meningitis and Vaccine Preventable Diseases, and Dr. Cynthia Whitney, Chief, Respiratory Diseases Branch, DBD, CDC, Atlanta, GA, for critical review of the manuscript.

Footnotes

[down-pointing small open triangle]Published ahead of print on 15 September 2010.

REFERENCES

1. Ginaldi, L., M. De Martinis, A. D'Ostilio, L. Marini, M. F. Loreto, M. P. Corsi, and D. Quaglino. 1999. The immune system in the elderly. I. Specific humoral immunity. Immunol. Res. 20:101-108. [PubMed]
2. Ginaldi, L., M. De Martinis, A. D'Ostilio, L. Marini, M. F. Loreto, V. Martorelli, and D. Quaglino. 1999. The immune system in the elderly. II. Specific cellular immunity. Immunol. Res. 20:109-115. [PubMed]
3. Ginaldi, L., M. De Martinis, A. D'Ostilio, L. Marini, M. F. Loreto, and D. Quaglino. 1999. The immune system in the elderly. III. Innate immunity. Immunol. Res. 20:117-126. [PubMed]
4. Ginaldi, L., M. De Martinis, A. D'Ostilio, L. Marini, M. F. Loreto, and D. Quaglino. 1999. Immunological changes in the elderly. Aging (Milano) 11:281-286. [PubMed]
5. Gong, Y., and D. R. Koh. 2010. Neutrophils promote inflammatory angiogenesis via release of preformed VEGF in an in vivo corneal model. Cell Tissue Res. 339:437-448. [PubMed]
6. Hinojosa, E., A. R. Boyd, and C. J. Orihuela. 2009. Age-associated inflammation and toll-like receptor dysfunction prime the lungs for pneumococcal pneumonia. J. Infect. Dis. 200:546-554. [PubMed]
7. Mares, C. A., S. S. Ojeda, Q. Li, E. G. Morris, J. J. Coalson, and J. M. Teale. 2010. Aged mice display an altered pulmonary host response to Francisella tularensis live vaccine strain (LVS) infections. Exp. Gerontol. 45:91-96. [PubMed]
8. Melnick, N., G. Rajam, G. M. Carlone, J. S. Sampson, and E. W. Ades. 2009. Evaluation of a novel therapeutic approach to treating severe pneumococcal infection using a mouse model. Clin. Vaccine Immunol. 16:806-810. [PMC free article] [PubMed]
9. Pinner, R. W. 1996. Addressing the challenges of emerging infectious disease. Am. J. Med. Sci. 311:3-8. [PubMed]
10. Rajam, G., D. J. Phillips, E. White, J. Anderton, C. W. Hooper, J. S. Sampson, G. M. Carlone, E. W. Ades, and S. Romero-Steiner. 2008. A functional epitope of the pneumococcal surface adhesin A activates nasopharyngeal cells and increases bacterial internalization. Microb. Pathog. 44:186-196. [PubMed]
11. Rajam, G., J. Sampson, G. M. Carlone, and E. W. Ades. 2010. An augmented passive immune therapy to treat fulminant bacterial infections. Recent Pat. Antiinfect. Drug Discov. 5:157-167. [PubMed]
12. Rajam, G., J. Skinner, N. Melnick, J. Martinez, G. M. Carlone, J. S. Sampson, and E. W. Ades. 2009. A 28-aa pneumococcal surface adhesin A-derived peptide, P4, augments passive immunotherapy and rescues mice from fatal pneumococcal infection. J. Infect. Dis. 199:1233-1238. [PubMed]

Articles from Clinical and Vaccine Immunology : CVI are provided here courtesy of American Society for Microbiology (ASM)