Defense-peptides against mycobacteria
Author: Linde, Charlotte M A
Date: 2005-09-28
Location: MTC föreläsningssal, Theorells väg 3
Time: 13.00
Department: Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)
Abstract
Several members of the genus Mycobacterium can cause serious infections
in both man and animal. One of the world's most serious infectious
diseases, tuberculosis, is caused by the pathogen Mycobacterium
tuberculosis. Specific defense to tuberculosis/mycobacteriosis is
dependent on the individual's ability to mount a proficient immune
response. Although the effective immune response to mycobacterial
infections primarily rely on cell-mediated immunity, the innate immunity
has been recognized to play a more prominent role in fighting/controlling
the disease than previously believed.
Peptide antibiotics, or antimicrobial peptides, are multi-functional effector molecules that play a central role in the first-line innate defense against microbial organisms. NKlysin and granulysin are two homologous 78-80-residue antimicrobial peptides produced by pig and human, respectively, cytolytic lymphocytes and natural killer cells. We have shown that NK-lysin kills M. tuberculosis. Others have shown that granulysin directly kill extracellular and is also involved in killing of intracellular M. tuberculosis.
Shorter loop peptides (23- and 29- residue long) were designed based on the native 3-D structure of granulysin and NK-lysin, preserving essential conformational features. The postulated membrane-docking part, helix 2-loop-helix 3, of NK-lysin was found to retain or even improve their antimicrobial activity compared to their parent molecules. It was also demonstrated that the shorter peptides maintained their activity against M. tuberculosis; therefore, we could identify this helix-loop-helix motif to be an antimycobacterial domain.
By computerized homology modeling, the visualized predicted structure of the 23peptide fragments of NK-lysin, granulysin, and chicken NK-lysin as well as the homologous peptides from cow and horse imply that the 3-D structure and spatial distribution of basic amino acids are preserved in the helix-2-3 region.
Experiments with GRANF2 demonstrate that the nature of basic residues (arginines or lysines) is not important for anti-mycobacterial activity neither is an intact intramolecular disulphide bond connecting helix 2 and 3.
A proline-arginine-rich antimicrobial peptide, PR-39, from pig neutrophils was studied and showed activity against drug susceptible and multi-drug-resistant M. tuberculosis (MDRTB). 1 found that PR-39 not only inhibits but also involve killing of MDR-TB. PR-39 has been shown to operate through a none-poreforming mechanism, inhibiting DNA and protein synthesis. Employing surface plasmon resonance (SPR) technology, extracts of M. tuberculosis and M. smegmatis were screened for binding interactions with PR-39. 1 show that heat shock protein (HSP) 70 can be identified as an interacting protein in fractions with PR-39-binding activities.
These findings show that certain antimicrobial peptides are active against M. tuberculosis, and their localization in neutrophils and CTL encourage further investigation on their physiological function in protective immunity against mycobacterial disease.
Peptide antibiotics, or antimicrobial peptides, are multi-functional effector molecules that play a central role in the first-line innate defense against microbial organisms. NKlysin and granulysin are two homologous 78-80-residue antimicrobial peptides produced by pig and human, respectively, cytolytic lymphocytes and natural killer cells. We have shown that NK-lysin kills M. tuberculosis. Others have shown that granulysin directly kill extracellular and is also involved in killing of intracellular M. tuberculosis.
Shorter loop peptides (23- and 29- residue long) were designed based on the native 3-D structure of granulysin and NK-lysin, preserving essential conformational features. The postulated membrane-docking part, helix 2-loop-helix 3, of NK-lysin was found to retain or even improve their antimicrobial activity compared to their parent molecules. It was also demonstrated that the shorter peptides maintained their activity against M. tuberculosis; therefore, we could identify this helix-loop-helix motif to be an antimycobacterial domain.
By computerized homology modeling, the visualized predicted structure of the 23peptide fragments of NK-lysin, granulysin, and chicken NK-lysin as well as the homologous peptides from cow and horse imply that the 3-D structure and spatial distribution of basic amino acids are preserved in the helix-2-3 region.
Experiments with GRANF2 demonstrate that the nature of basic residues (arginines or lysines) is not important for anti-mycobacterial activity neither is an intact intramolecular disulphide bond connecting helix 2 and 3.
A proline-arginine-rich antimicrobial peptide, PR-39, from pig neutrophils was studied and showed activity against drug susceptible and multi-drug-resistant M. tuberculosis (MDRTB). 1 found that PR-39 not only inhibits but also involve killing of MDR-TB. PR-39 has been shown to operate through a none-poreforming mechanism, inhibiting DNA and protein synthesis. Employing surface plasmon resonance (SPR) technology, extracts of M. tuberculosis and M. smegmatis were screened for binding interactions with PR-39. 1 show that heat shock protein (HSP) 70 can be identified as an interacting protein in fractions with PR-39-binding activities.
These findings show that certain antimicrobial peptides are active against M. tuberculosis, and their localization in neutrophils and CTL encourage further investigation on their physiological function in protective immunity against mycobacterial disease.
List of papers:
I. Andreu D, Carreno C, Linde C, Boman HG, Andersson M (1999). "Identification of an anti-mycobacterial domain in NK-lysin and granulysin. " Biochem J 344 Pt 3: 845-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Linde CMA, Grundstrom S, Nordling E, Refai E, Brennan PJ, Andersson M (2005). "Conserved structure and function in the granulysin and NK-lysin peptide family." Infect Immun. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Linde CMA, Hoffner SE, Refai E, Andersson M (2001). "In vitro activity of PR-39, a proline-arginine-rich peptide, against susceptible and multi-drug-resistant Mycobacterium tuberculosis. " J Antimicrob Chemother 47(5): 575-80.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Linde CMA, Refai E, Sigmundsson K, Jornvall H, Andersson M (2005). "PR-39 interacts with molecular chaperone HSP70/DnaK in mycobacteria." [Manuscript]
I. Andreu D, Carreno C, Linde C, Boman HG, Andersson M (1999). "Identification of an anti-mycobacterial domain in NK-lysin and granulysin. " Biochem J 344 Pt 3: 845-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Linde CMA, Grundstrom S, Nordling E, Refai E, Brennan PJ, Andersson M (2005). "Conserved structure and function in the granulysin and NK-lysin peptide family." Infect Immun. [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Linde CMA, Hoffner SE, Refai E, Andersson M (2001). "In vitro activity of PR-39, a proline-arginine-rich peptide, against susceptible and multi-drug-resistant Mycobacterium tuberculosis. " J Antimicrob Chemother 47(5): 575-80.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Linde CMA, Refai E, Sigmundsson K, Jornvall H, Andersson M (2005). "PR-39 interacts with molecular chaperone HSP70/DnaK in mycobacteria." [Manuscript]
Issue date: 2005-09-07
Publication year: 2005
ISBN: 91-7140-480-5
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