TATRasGap317-326: a cancer cell sensitizer peptide with antimicrobial activity


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A Master's thesis.
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Master (thesis) (master)
TATRasGap317-326: a cancer cell sensitizer peptide with antimicrobial activity
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Université de Lausanne, Faculté de biologie et médecine
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The innate immune system plays an important role in host defenses and though in the viability of living being. An important capacity of this system is the recognition of pathogens through a panel of patternrecognition receptors such as Toll-like receptors (TLRs). Triggering these receptors induces NF-κB, MAPK and IRF signaling pathways, gene activation, and production of pro-inflammatory molecules such as TNF or IL-6, required to fight infections. Unfortunately this defense system is sometimes overpassed and patients need external help such as antibiotherapy to clear infection. Antibiotics exist since the discovery of penicillin by Fleming. Since then, numerous other antibiotics have been developed, but due to their great adaptation capacity bacteria became more and more resistant. Nowadays some bacteria are untreatable with the actual antibiotics panoply. The need of new antibiotics is a priority as stated by the WHO. A promising type of molecules with antimicrobial activity is the antimicrobial peptides (AMPs). AMPs directly act against pathogens and also, for some of them, modulate the immune system. Previous studies have described the capacity of a peptide called TAT-RasGAP317-326 to sensitize and kill tumor cells. During these studies, it was found that TAT-RasGAP317-326 has a good bactericidal effect, suggesting it can act as an AMP. In this study, we explored the immunological modulation by TAT-RasGAP317-326 in vitro and its antibiotics capacity in a mouse model of E. coli-induced peritonitis in mice. We observed that TAT-RasGAP317-326 modulates the immune response induced through TLR2, TLR4 and TLR9. TAT-RasGAP317-326 decreased the production of IL-6 and TNF by mouse macrophages stimulated through TLR9, but not TLR2 and TLR4, while it increased cytokine production by human PBMCs stimulated through TLR2 and TLR9. The peptide had marginal effects on human whole blood. TAT-RasGAP317-326 powerfully increased the survival of mice subjected to E. coli peritonitis when injected just after the onset if infection, an effect that was lost if the peptide was injected 3 hours after infection. We conclude that TAT-RasGAP317-326 is a promising molecule that fulfills some of the criteria to be useful in therapy against bacteria. However, more research is needed especially about the mode of action of TAT-RasGAP317-326 and to improve its bio-distribution and stability to increase in vivo effectiveness.
innate immunity, antimicrobial peptide, infection, bacteria, cytokine
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06/09/2018 10:18
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08/09/2020 7:08
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