IHW 2015 Talk
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Transcript of IHW 2015 Talk
![Page 1: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/1.jpg)
A Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins Promotes Survival of HCMV-
Infected Monocytes
Donna Collins-McMillen, E.V. Stevenson, M.T. Nogalski, J. Caskey, G.C.T. Chan, and A.D. Yurochko
Louisiana State University Health – Shreveport, LA
![Page 2: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/2.jpg)
Monocytes as Vehicles for Viral Spread
1. 2.
3.4.
5.6.
7.
![Page 3: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/3.jpg)
Monocyte Survival Hurdle
MФmonocyte
![Page 4: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/4.jpg)
Monocyte Survival Hurdle
MФmonocyte 48hpi
apoptotic programming
“default”
![Page 5: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/5.jpg)
Monocyte Survival Hurdle
MФmonocyte 48hpi
“default” apoptotic programming
Anti-viral
pro-apoptotic response
![Page 6: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/6.jpg)
HCMV Engages a Distinct Pro-Survival Mechanism to Prevent
Monocyte Apoptosis 1) Bi-phasic regulation of Mcl-1 and Bcl-2
2) Distinct & overlapping signaling through EGFR/integrins
3) Promotes survival at multiple apoptotic checkpoints • bypasses viability checkpoint at 48 h
(stabilizes Mcl-1, Chan et al., 2010)• adapts to anti-viral pro-apoptotic response
(Bcl-2 up in response to Bax)
![Page 7: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/7.jpg)
Bi-Phasic Mcl-1/Bcl-2 Shift
Mcl-1 in HCMV-infected monocytes
MФmonocyte 48hpi
Mcl-1 Bcl-2
(1) (1.2)(1.4) (3.9)(1.9)(5.1) (2.0) (6.2))
Bcl-2 in HCMV-infected monocytes
Chan et al., 2010
![Page 8: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/8.jpg)
Bi-Phasic Mcl-1/Bcl-2 Shift
• Bcl-2 controls late survival in HCMV-infected monocytes (Mcl-1 early, Chan et al., 2010)
• Mcl-1 and Bcl-2 are both required for early survival in mock-infected cells
![Page 9: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/9.jpg)
HCMV Signaling Through EGFR/Integrins
Chan et al., 2010
![Page 10: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/10.jpg)
Bcl-2 Combats the Anti-Viral Pro-Apoptotic Response (Bax Up-
Regulation)
MФmonocyte 48hpi
Mcl-1 Bcl-2
(1) (1.4) (1.2)(4) (2.8)(5.6)(3.3)(10.5))
Bcl-2 (but not Mcl-1) can bind & inactivate Bax
![Page 11: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/11.jpg)
Bax Expression Drives Bcl-2 Up-Regulation
![Page 12: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/12.jpg)
Bax Depletion Rescues Infected Bcl-2-Defective Cells From Apoptosis
![Page 13: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/13.jpg)
![Page 14: IHW 2015 Talk](https://reader035.fdocuments.us/reader035/viewer/2022081605/587bcd071a28ab6c3c8b72fd/html5/thumbnails/14.jpg)
AcknowledgementsMentorDr. Andrew Yurochko
Dissertation Committee
Dr. Robert ChervenakDr. Lindsey Hutt-FletcherDr. Dennis O’CallaghanDr. Kelly Tatchell Dr. Felicia Goodrum (U of AZ)
Funding:
Yurochko LabLiesl MilfordDr. Maciej NogalskiDr. Gary ChanDr. Emily Stevenson Dr. Yanjie LiStephen CieplyDr. Jung Heon KimJoshua Caskey
A156077P30GM110703
Pre-Doctoral Fellowship
14PRE20310027