The role of the stress-induced transcription factor, CHOP, in the induction of IL-23 by intracellular bacteria.

Lead Research Organisation: University of Cambridge
Department Name: Medicine

Abstract

Cells are like factories: a conveyor belt production line produces proteins with a myriad of different functions needed by the cell and the body. If the quality of the product is compromised, the alarm is raised by a quality control manager, and a brake is put on the system. This allows the cell time to respond and adapt to whatever has upset production. The response of the cell to adapt is called the ?unfolded protein response?. We have data that shows that bacterial infection of cells can also induce this response. At the same time, bacteria also induce the expression of immune hormones by cells they have infected. These immune hormones help protect the body against infection, but inappropriate expression of these molecules can produce the wrong kinds of responses that can lead to chronic disease. One such immune hormone is IL-23, it has been implicated to play a role in diseases such as arthritis, multiple sclerosis and inflammation of the gut. We have important evidence that IL-23 relies on this unfolded protein response to enhance its expression, and that bacterial infection induces these important factors. This project proposal asks for the opportunity to investigates how bacteria induce the unfolded protein response and expression of the factors that enhance IL-23. Our approach is to examine the unfolded response in detail and block particular arms of the unfolded protein response to see if this affects the production of the factors that are crucial for IL-23 expression. Most importantly this will identify how the unfolded protein response is switched on by bacteria and provide the potential to target this pathway as away to modulate disease that are known to be caused by this immune hormone.

Technical Summary

We have recently made the seminal observation that ER stress profoundly and qualitatively alters APC cytokine secretion, boosting the production of a specific group of mediators including interleukin (IL-23). We have identified that the ER stress induced transcription factor CHOP is activated by intracellular bacterial infection, and is involved in the regulation of IL-23 gene expression. We hypothesize that the ability of intracellular bacteria to induce the expression of stress proteins can profoundly affect the nature of innate and adaptive immune responses they elicit. Here, we propose to identify the host cell stress pathways that induce CHOP transcription in response to infection of myeloid APCs with intracellular bacteria. We will also determine if other intracellular bacterial pathogens induce CHOP activation, and identify specific bacterial components that are able to initiate host cell stress. Thus, we will elucidate how cell stress induced by important human pathogens influences the quality of innate immune responses. Moreover, we will characterise stress responses as novel mechanisms linking intracellular bacterial infection to diseases where IL-23 is known to play an important role in pathology.
 
Description Analysis of responses to dectin 1 agonists 
Organisation East Tennessee State University
Country United States 
Sector Academic/University 
PI Contribution Analysis of the reagents in vivo and in vitro
Collaborator Contribution Provision of reagents
Impact 2 publications
Start Year 2012
 
Description Collaboration with Dr. Simon Clare 
Organisation Babraham Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We are utilising Dr. Clare's knockout mice.
Collaborator Contribution Provision of knockout mice.
Impact Paper submitted to Journal of Biological Chemistry.
Start Year 2012
 
Description Collaboration with Professor Ronnie Chee 
Organisation University College London
Department Division of Infection and Immunity
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of human blood samples
Collaborator Contribution He is providing us with CGD patients who exhibit deficiencies in NADPH oxidase.
Impact N/A
Start Year 2012
 
Description The role of c-gas in chlamydia infection 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Academic/University 
PI Contribution The collaboration involves our use of tissue from c-Gas KO mice. We will utilise the tissue using in vitro experiments to investigate the mechanism of STING activation in chlamydia infected cells.
Collaborator Contribution Jan Rehwinkel will provide tissues from transgenic mice that lack c-GAS expression
Impact The research has been submitted to PLOS pathogens and is currently under its second review
Start Year 2016
 
Description Outreach activities 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Discussions take place and interest is shown.

Interest shown.
Year(s) Of Engagement Activity 2014
 
Description Presentation to BSI Bright Sparks in Immunology Post Doc Session 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact A seven minute presentation to the 'Bright Sparks in Immunology 2014 Post Doc Session' during the British Society for Immunology Annual Congress.

Too recent to determine impact.
Year(s) Of Engagement Activity 2014
 
Description Talk to the Babraham Institute 6th Form Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact To give talk at the Babraham Institute 6th Form Conference: Immunology from Research to health.

Interest from students.
Year(s) Of Engagement Activity 2014