This proposal is designed to support the career development of Susan Fink, MD, PhD, a laboratory medicine physician (clinical pathologist) trained in cellular biology who has begun postdoctoral research under the guidance of Dr. Akiko Iwasaki. The proposed mentored research experience and career development activities describe a 5-year training program to give Dr. Fink the skills to become an independent investigator at an academic medical center, studying innate immune responses to viral infections. She will achieve this goal through the guidance of her mentors and advisory committee, coursework and seminars and development of scientific expertise in virology and immunology. Her mentor, Dr. Iwasaki is an established leader in immunology with a history of training successful young scientists, and the Departments of Immunobiology and Laboratory Medicine at Yale provide a rich scientific environment. Programmed cell death is a defense mechanism used by multicellular organisms to eliminate potentially harmful cells, including pathogen-infected cells. Dr. Fink's graduate research allowed her to identify pyroptosis, a novel form of pro-inflammatory programmed cell death triggered during bacterial infection. She seeks to build on her prior training to study cellular responses to infection in a setting in which she has less experience, namely viral infection. Dr. Fink's initial postdoctoral research has revealed the importance of apoptotic host cell death in response to two viruses: herpes simplex virus-1 and vesicular stomatitis virus. Her findings uncovered a pathway whereby activation of the host protein Ire1? inhibits apoptosis. Ire1? is activated during the unfolded protein response, a cellular pathway to detect and alleviate dysfunctional protein folding in the endoplasmic reticulum. Ire1? is also activated by genetic deficiency of it downstream target, Xbp1. Dr. Fink found that activation of Ire1? in Xbp1 genetically deficient cells caused resistance to apoptosis during infection with herpes simplex virus-1 and vesicular stomatitis virus. The inability of these infected cells to undergo apoptosis prolonged viral replication and significantly increased production of virus. These findings suggest the hypothesis that infections and cellular stresses that activate Ire1? will also cause resistance to apoptosis. The experiments outlined in this proposal will determine the molecular mechanisms of Ire1?-mediated apoptosis resistance (Aim 1A) and examine whether viruses that trigger ER stress utilize this pathway (Aim 1B). In addition, this proposal will address the hypothesis that inhibition of basal Ire1? activity increases susceptibility to apoptosis (Aim 2A) and examine whether apoptosis susceptibility can be modulated as an antiviral therapeutic strategy (Aim 2B). Together these aims will illuminate inhibition of Ire1? s a novel therapeutic strategy to enhance the host response to diverse viral infections.

Public Health Relevance

Some viruses trigger cells to undergo programmed cell death, which prevents viral replication and contributes to defense against infection. We have recently found that a protein called Ire1? regulates cellular susceptibility to programmed cell death and propose to determine how this occurs and whether this affects replication of a number of medically important viruses. Findings from this work will guide the development of new anti-viral medications and inform our understanding of the many diseases in which Ire1? has been implicated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI119142-04
Application #
9273359
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2016-09-01
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
4
Fiscal Year
2017
Total Cost
$187,312
Indirect Cost
$13,875
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yockey, Laura J; Varela, Luis; Rakib, Tasfia et al. (2016) Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection. Cell 166:1247-1256.e4