東華大學圖書館 |

Language: English

Help

回圖書館首頁

手機版館藏查詢

Back to Search results for [ null ]

Switch To: Labeled | MARC Mode | ISBD

The Roles of Necroptosis in the Path...

Kitur, Kipyegon.

Linked to FindBook

Google Book

Amazon

博客來

The Roles of Necroptosis in the Pathogenesis of Staphylococcus aureus Infection.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Roles of Necroptosis in the Pathogenesis of Staphylococcus aureus Infection./
Author:	Kitur, Kipyegon.
Description:	92 p.
Notes:	Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
Contained By:	Dissertation Abstracts International77-10B(E).
Subject:	Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10130759
ISBN:	9781339885858

The Roles of Necroptosis in the Pathogenesis of Staphylococcus aureus Infection.
Kitur, Kipyegon.

The Roles of Necroptosis in the Pathogenesis of Staphylococcus aureus Infection. - 92 p.

Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.

Thesis (Ph.D.)--Columbia University, 2016.

Staphylococcus aureus, particularly the epidemic methicillin-resistant S. aureus (MRSA) USA300 strain, is a major cause of severe necrotizing lung, skin and systemic infection. Although these infections are generally attributed to the pathogen's multiple toxins, exactly how S. aureus cause disease is not clearly defined. In this research, we sought to establish the role of necroptosis, a programmed form of necrosis, in the pathophysiology of S. aureus pneumonia, skin infection and sepsis. S. aureus, mainly through its multiple toxins, induced RIPK1/RIPK3/MLKL-mediated necroptosis in multiple host cells including human cell lines, freshly obtained alveolar macrophages, peripheral blood macrophages and epithelial cells. S. aureus toxin-associated pore-formation was essential for necroptosis, as cell death was blocked by exogenous K+ or dextran as well as by MLKL inhibition. To understand the role of necroptosis in S. aureus pneumonia, we used Ripk3-/- mice and mice treated with necrostatin-1s (Nec-1s), a potent inhibitor of RIPK1. Inhibition of necroptosis in a mouse model of pneumonia led to significantly improved outcome from S. aureus infection marked by increased bacterial clearance, preserved lung architecture, decreased inflammatory markers in the airway and retention of an anti-inflammatory macrophage population. In contrast, inhibiting necroptosis in vivo during skin infection led to worse outcome as determined by bacterial clearance and lesion sizes, which occurred in spite of the presence of neutrophils, macrophages and gammasigma T cells. Nec-1s-treated mice and Mlkl-/- mice had significantly larger lesions, increased cytokine response and more S. aureus recovered from the infected areas compared to control groups. We observed a similar outcome in Casp1/4-/- mice, which have limited ability to process IL-1beta. Unlike Mlkl-/- mice, Ripk3-/- mice had improved outcome with increased bacterial clearance and decreased inflammation because of the effects of RIPK3 in activating the NLRP3 inflammasome and apoptosis during S. aureus skin infection. Casp1/4-/- immune cells showed a significant defect in their ability to kill S. aureus, whereas Mlkl-/- peritoneal exudate cells and bone marrow-derived macrophages did not. These results show that caspase-1 is essential for bacterial killing whereas necroptosis is necessary for regulating excessive inflammation. Similar to our findings in skin infection, inhibition of the executioner of necroptosis (using Mlkl-/- mice) or pyroptosis (using Casp1/4-/- mice) decreased survival in a mouse model of S. aureus sepsis. Ripk3-/- and wild type mice were equally resistant to S. aureus sepsis. Overall, these findings provide new insights into the complex roles of necrosome components in different tissues during S. aureus infection and may provide potential therapeutic targets to combat these infections.

ISBN: 9781339885858Subjects--Topical Terms:

611031
Immunology.

The Roles of Necroptosis in the Pathogenesis of Staphylococcus aureus Infection.
LDR:03784nmm a2200289 4500 001 2074348
005 20160926125818.5
008 170521s2016 ||||||||||||||||| ||eng d
020 $a 9781339885858
035 $a (MiAaPQ)AAI10130759
035 $a AAI10130759
040 $a MiAaPQ $c MiAaPQ
100 1 $a Kitur, Kipyegon. $3 3189661
245 1 4 $a The Roles of Necroptosis in the Pathogenesis of Staphylococcus aureus Infection.
300 $a 92 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
500 $a Adviser: Alice Prince.
502 $a Thesis (Ph.D.)--Columbia University, 2016.
520 $a Staphylococcus aureus, particularly the epidemic methicillin-resistant S. aureus (MRSA) USA300 strain, is a major cause of severe necrotizing lung, skin and systemic infection. Although these infections are generally attributed to the pathogen's multiple toxins, exactly how S. aureus cause disease is not clearly defined. In this research, we sought to establish the role of necroptosis, a programmed form of necrosis, in the pathophysiology of S. aureus pneumonia, skin infection and sepsis. S. aureus, mainly through its multiple toxins, induced RIPK1/RIPK3/MLKL-mediated necroptosis in multiple host cells including human cell lines, freshly obtained alveolar macrophages, peripheral blood macrophages and epithelial cells. S. aureus toxin-associated pore-formation was essential for necroptosis, as cell death was blocked by exogenous K+ or dextran as well as by MLKL inhibition. To understand the role of necroptosis in S. aureus pneumonia, we used Ripk3-/- mice and mice treated with necrostatin-1s (Nec-1s), a potent inhibitor of RIPK1. Inhibition of necroptosis in a mouse model of pneumonia led to significantly improved outcome from S. aureus infection marked by increased bacterial clearance, preserved lung architecture, decreased inflammatory markers in the airway and retention of an anti-inflammatory macrophage population. In contrast, inhibiting necroptosis in vivo during skin infection led to worse outcome as determined by bacterial clearance and lesion sizes, which occurred in spite of the presence of neutrophils, macrophages and gammasigma T cells. Nec-1s-treated mice and Mlkl-/- mice had significantly larger lesions, increased cytokine response and more S. aureus recovered from the infected areas compared to control groups. We observed a similar outcome in Casp1/4-/- mice, which have limited ability to process IL-1beta. Unlike Mlkl-/- mice, Ripk3-/- mice had improved outcome with increased bacterial clearance and decreased inflammation because of the effects of RIPK3 in activating the NLRP3 inflammasome and apoptosis during S. aureus skin infection. Casp1/4-/- immune cells showed a significant defect in their ability to kill S. aureus, whereas Mlkl-/- peritoneal exudate cells and bone marrow-derived macrophages did not. These results show that caspase-1 is essential for bacterial killing whereas necroptosis is necessary for regulating excessive inflammation. Similar to our findings in skin infection, inhibition of the executioner of necroptosis (using Mlkl-/- mice) or pyroptosis (using Casp1/4-/- mice) decreased survival in a mouse model of S. aureus sepsis. Ripk3-/- and wild type mice were equally resistant to S. aureus sepsis. Overall, these findings provide new insights into the complex roles of necrosome components in different tissues during S. aureus infection and may provide potential therapeutic targets to combat these infections.
590 $a School code: 0054.
650 4 $a Immunology. $3 611031
650 4 $a Microbiology. $3 536250
650 4 $a Pharmacology. $3 634543
690 $a 0982
690 $a 0410
690 $a 0419
710 2 $a Columbia University. $b Pharmacology and Molecular Signaling. $3 3189662
773 0 $t Dissertation Abstracts International $g 77-10B(E).
790 $a 0054
791 $a Ph.D.
792 $a 2016
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10130759