P4 Peptide Therapy Rescues Aged Mice from Fatal Pneumococcal Sepsis

Rajam, Gowrisankar; Bangert, Mathieu; Hammons, Gabrielle M.; Melnick, Nikkol; Carlone, George M.; Sampson, Jacquelyn S.; Ades, Edwin W.

doi:10.1128/cvi.00366-10

Cited by 7 publications

(4 citation statements)

References 14 publications

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“…140csG1, 140G11 and 140csH1 protected mice from mortality in an intranasal challenge model with highly encapsulated WU2 [ 24 ]; 24 h after infection, no statistically significant differences in blood CFU were observed ( Fig 3B ). 139G3 was not tested as it does not bind WU2.…”

Section: Resultsmentioning

confidence: 99%

Generation and Improvement of Effector Function of a Novel Broadly Reactive and Protective Monoclonal Antibody against Pneumococcal Surface Protein A of Streptococcus pneumoniae

et al. 2016

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A proof-of-concept study evaluating the potential of Streptococcus pneumoniae Pneumococcal Surface Protein A (PspA) as a passive immunization target was conducted. We describe the generation and isolation of several broadly reactive mouse anti-PspA monoclonal antibodies (mAbs). MAb 140H1 displayed (i) 98% strain coverage, (ii) activity in complement deposition and opsonophagocytic killing (OPK) assays, which are thought to predict the in vivo efficacy of anti-pneumococcal mAbs, (iii) efficacy in mouse sepsis models both alone and in combination with standard-of-care antibiotics, and (iv) therapeutic activity in a mouse pneumonia model. Moreover, we demonstrate that antibody engineering can significantly enhance anti-PspA mAb effector function. We believe that PspA has promising potential as a target for the therapy of invasive pneumococcal disease by mAbs, which could be used alone or in conjunction with standard-of-care antibiotics.

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Section: Resultsmentioning

confidence: 99%

Generation and Improvement of Effector Function of a Novel Broadly Reactive and Protective Monoclonal Antibody against Pneumococcal Surface Protein A of Streptococcus pneumoniae

et al. 2016

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“…We have hypothesized a mechanism of P4-therapy [ 18 ]; although the exact mechanism is still under investigation, previous studies suggest that P4 therapy augments innate immunity [ 9 ]. Polymorphonuclear neutrophils (PMNs) are the major innate immune component activated by P4 peptide as we have observed that mice treated with a neutrophil-depleting antibody, RB6-8C5, failed to respond to in vivo P4 therapy [ 7 ]. Recently, we have demonstrated that both altered trafficking and enhanced capacity of professional phagocytes are also associated with the potential protective mechanism for P4-therapy [ 9 ].…”

Section: Resultsmentioning

confidence: 99%

A Novel Innate Immune-Enhancement Strategy Combined with IVIG Rescues Mice from FatalStaphylococcus aureusSepticemia

Rajam

Hammons

Carlone

et al. 2011

International Journal of Microbiology

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Staphylococcus aureus (SA) is a major community-acquired pathogen. The emergence of drug-resistant strains like, methicillin-resistant SA (MRSA), poses stiff challenges to therapeutic intervention. Passive immune-therapy with specific antibodies is being actively examined to treat fulminant infections with limited success. In this study, we demonstrate that P4, a 28-amino acid peptide, derived from pneumococcal surface adhesin A along with pathogen-specific antibody (IVIG; P4 therapy) is successful in enhancing the opsonophagocytic killing (OPK) of S. aureus in vitro. We questioned if it is possible to expand P4 therapy to treat staphylococcal infections in vivo. P4 therapy in combination with IVIG rescued 7/10 morbidly ill S. aureus-infected mice while only 2/10 survived in the control group.

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“…Murine models of acute infection have demonstrated the therapeutic benefits of API administered by either intranasal or intravenous routes. Such treatment has been demonstrated to rescue mice from invasive pneumonia (3, 4), influenza-pneumonia coinfections (5), and methicillin-resistant Staphylococcus aureus (MRSA) (6), independent of age (7) and strain background (8), although to date there are no data from human lung samples. Since P4 peptide treatment of Streptococcus pneumoniae (pneumococcus)-infected murine lungs prevented the onset of sepsis and subsequent host mortality (4), we hypothesized that ex vivo P4 treatment of human alveolar macrophages would lead to enhanced phagocytic function with no or limited generalized inflammation.…”

Section: Textmentioning

confidence: 99%

Immunoactivating Peptide P4 Augments Alveolar Macrophage Phagocytosis in Two Diverse Human Populations

Bangert

Wright

Rylance

et al. 2013

Antimicrob Agents Chemother

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New treatment strategies are urgently needed to overcome early mortality in acute bacterial infections. Previous studies have shown that administration of a novel immunoactivating peptide (P4) alongside passive immunotherapy prevents the onset of septicemia and rescues mice from lethal invasive disease models of pneumococcal pneumonia and sepsis. In this study, using two diverse populations of adult volunteers, we determined whether P4 treatment of human alveolar macrophages would upregulate phagocytic killing of Streptococcus pneumoniae ex vivo. We also measured macrophage intracellular oxidation, cytokine secretion, and surface marker expression following stimulation. Peptide treatment showed enhanced bacterial killing in the absence of nonspecific inflammation, consistent with therapeutic potential. This is the first demonstration of P4 efficacy on ex vivo-derived human lung cells.

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P4 Peptide Therapy Rescues Aged Mice from Fatal Pneumococcal Sepsis

Cited by 7 publications

References 14 publications

Generation and Improvement of Effector Function of a Novel Broadly Reactive and Protective Monoclonal Antibody against Pneumococcal Surface Protein A of Streptococcus pneumoniae

Generation and Improvement of Effector Function of a Novel Broadly Reactive and Protective Monoclonal Antibody against Pneumococcal Surface Protein A of Streptococcus pneumoniae

A Novel Innate Immune-Enhancement Strategy Combined with IVIG Rescues Mice from FatalStaphylococcus aureusSepticemia

Immunoactivating Peptide P4 Augments Alveolar Macrophage Phagocytosis in Two Diverse Human Populations

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