Vorhauer, Jennie/M
(2017)
REGULATION OF THE INNATE IMMUNE RESPONSES AUTOPHAGY AND INFLAMMASOME ACTIVATION DURING BACTERIAL INFECTION.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Autophagy is an innate anti-microbial host defense that maintains tissue homeostasis. Autophagy is negatively regulated by the nutrient-sensing mTORC1 complex. In this study, we examined the regulatory mechanisms of autophagy and inflammasome activation during Ehrlichia infection. Monocytic Ehrlichia is a Gram negative intracellular bacterial pathogen that causes fatal human monocytic ehrlichiosis. Ehrlichia lacks LPS, but induces inflammasome activation leading to acute liver damage. In humans, the potentially fatal human monocytic ehrlichiosis (HME) mimics sepsis and toxic shock-like syndrome [1, 2], making Ehrlichia a viable model system for these conditions in the absence of LPS. During virulent Ehrlichia infection confocal data shows that autophagy increased with infection, despite clear activation of the autophagy inhibitor mTORC1. This is likely due to a balance of mTORC1 dependent and independent autophagy. Employing bone marrow derived macrophages (BMM) from mice deficient in MyD88 and TLR9 we reveal a novel signaling pathway for IOE mediated autophagy regulation and inflammasome activation centered around IFNβ production. We have previously shown that the virulent Ehrlichia strain Ixodes ovatus Ehrlichia (IOE) expresses higher levels of IFNβ than the avirulent strain Ehrlichia muris (EM) [3]. When IFNβ is added to BMM mTORC1 activation increases, a phenomenon further increased when IFNβ is added to IOE infected BMM. Both IOE and IFNβ mediated mTORC1 activation are abrogated by knockout of the TLR9 receptor. This placed IFNβ upstream of TLR9 in the IOE mediated mTORC1 signaling pathway. As both TLR9 is activated by dsDNA, we have hypothesized that these receptors are activated by mitochondrial DNA released in response to IFNβ mediated DAMP production. These data suggest that LPS-negative Ehrlichia regulates autophagy with mTORC1, and that this mTORC1 activation is achieved via IFNβ mediated TLR9. Our findings reveal a novel regulation of autophagy and the inflammasome in macrophages via MyD88 and mTORC1 during infection with intracellular pathogens.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
27 September 2017 |
| Date Type: |
Publication |
| Defense Date: |
24 July 2017 |
| Approval Date: |
27 September 2017 |
| Submission Date: |
27 September 2017 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
43 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Autophagy, Inflammasome |
| Date Deposited: |
28 Sep 2017 00:34 |
| Last Modified: |
27 Sep 2018 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33217 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}