for treating inflammation caused by Streptococcus by inhibiting Toll Like Receptor-induced cytokine secretion
Inventors
Hefeneider, Steven H. • McCoy, Sharon L.
Assignees
Oregon Health and Science University • US Department of Veterans Affairs
Publication Number
US-7557086-B2
Publication Date
2009-07-07
Expiration Date
2025-07-12
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Abstract
Method and peptide for regulating cellular activity includes a panel of synthesized peptides that have biological effects on inhibiting or enhancing cellular activity. Selected peptides can be used as therapy to reduce and/or inhibit, or initiate and/or enhance, an inflammatory response in a subject.
Core Innovation
The invention relates to methods and peptides for regulating cellular activity, specifically by using peptides derived from the vaccinia virus A52R protein to modulate toll-like receptor (TLR)-induced cytokine secretion in cells. These synthesized peptides can be used to either inhibit or enhance cellular activity, particularly the inflammatory response initiated by TLR activation.
The problem addressed by this invention is the need to control inflammation caused by bacterial and viral infections that activate the innate immune system via TLRs. Chronic inflammation due to ongoing TLR signaling can lead to diseases like otitis media with effusion (OME), sepsis, and autoimmune conditions. Current treatments often do not effectively target the intracellular signaling cascade triggered by TLRs.
The core innovation includes identification and characterization of specific peptides from the vaccinia virus A52R protein, such as the peptide with the amino acid sequence DIVKLTVYDCI (SEQ ID NO: 13), linked to a cell transduction sequence that enables cellular internalization. These peptides selectively inhibit cytokine secretion induced by multiple TLR ligands, reducing inflammation both in vitro and in vivo, including in a murine model of middle ear inflammation caused by heat-inactivated Streptococcus pneumoniae.
Claims Coverage
The patent contains multiple independent claims focused on methods of inhibiting TLR-induced cytokine secretion and inflammation using specified peptides derived from the vaccinia virus A52R protein.
Use of a specific peptide to inhibit TLR-induced cytokine secretion
Administering an effective amount of a peptide consisting of the amino acid sequence set forth in SEQ ID NO: 13 to a subject in need thereof to inhibit Toll Like Receptor-induced cytokine secretion.
Use of a peptide with a transducing sequence to inhibit TLR-induced cytokine secretion
Administering an effective amount of a peptide consisting of SEQ ID NO: 13 combined with a cell transducing sequence (e.g., SEQ ID NO: 20) to a subject in need thereof thereby inhibiting TLR-induced cytokine secretion.
Method to reduce or inhibit TLR-induced inflammation caused by bacteria
Administering an effective amount of a peptide consisting of SEQ ID NO: 13, alone or with a transducing sequence, to reduce or inhibit Toll Like Receptor-induced inflammation, specifically including inflammation caused by bacteria such as Streptococcus pneumoniae.
Treatment of otitis media with peptide therapy
Employing the peptide consisting of SEQ ID NO: 13 and a transducing sequence to treat or inhibit inflammation in subjects with otitis media.
Targeting multiple Toll Like Receptors
The method applies to inhibiting cytokine secretion induced by one or more of TLR 2, TLR3, TLR4, TLR5, and TLR9.
The claims cover methods of administering peptides derived from the vaccinia virus A52R protein, with or without a cell transducing sequence, for inhibiting TLR-induced cytokine secretion and inflammation. They specify the sequences used, their application in bacterial inflammation including otitis media, and identify multiple TLR targets.
Stated Advantages
The peptides selectively inhibit TLR-dependent cytokine secretion without affecting non-TLR pathways, allowing targeted modulation of immune responses.
Administration of the peptide significantly reduces bacterial-induced inflammation in vivo, including fluid accumulation and mucosal hypertrophy in a murine model of otitis media.
The peptide works against cytokine secretion induced by multiple TLR ligands, demonstrating broad applicability for various bacterial and viral triggers.
Peptide P13 can inhibit cytokine secretion even when administered several hours after TLR activation, suggesting potential as a therapeutic intervention post-inflammation initiation.
The peptides may reduce pro-inflammatory mediators in conditions such as septic shock, indicating potential clinical application beyond otitis media.
Documented Applications
Treatment of bacterial-induced inflammation, particularly middle ear inflammation (otitis media) caused by Streptococcus pneumoniae.
Use in reducing cytokine secretion caused by activation of toll-like receptors in immune cells responding to bacterial and viral pathogen-associated molecular patterns.
Potential use in treating chronic inflammation initiated by bacterial or viral infections including models like sepsis and inflammatory diseases involving TLR activation.
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