Bacterial pneumonia and sepsis are leading preventable causes of death in the intensive care unit and Streptococcus pneumoniae (Sp) is a major etiology. Current therapies are mostly focused on the use of antibiotics and have led to the rapid emergence of drug resistance and hypervirulent strains. A fundamental aspect of successful pathogen-host interactions is the ability to keep harmful, tissue-damaging inflammatory immune responses in check while successfully clearing the pathogen. The exaggerated morbidity and mortality seen with bacterial infection can be the result of dysregulated inflammation. There are currently no viable therapeutic modalities to augment host defense while reducing unnecessary inflammation. Further, it is poorly understood how signaling cascades converge to control host defenses while minimizing inflammatory tissue injury. With this in mind, we have identified Chitinase 3-like 1 (Chi3l1), a prototypic Chitinase-like protein of 18- glycosyl hydrolase family, to be important in this process. We find that Chi3l1 is a potent innate immune regulator elevated in patients with diseases characterized by inflammation and tissue repair. Chi3l1, along with its newly discovered receptor IL13RD2, is induced during Sp infection and is critical in antibacterial responses. The Chi3l1-IL13RD2 axis is important as a therapeutic target for controlling potentially harmful innate immune activation during bacterial infection. Our data show that the Chi3l1-IL13RD2 interaction critically dampens potentially harmful type I interferon (IFN-1) responses during infection. The absence of Chi3l1 or IL13RD2 results in heightened IFN-1s during infection associated with increased co-localization of endosomal Toll-like receptor 9 (TLR9) and interferon regulatory factor 7 (IRF7). Our overall hypothesis is that the Chi3l1-IL13RD2 dampens excessive inflammation and tissue injury by regulating IFN-1 pathway. We will test this hypothesis with the following specific aims:
Specific Aim 1. Characterize the mechanisms by which Chi3l1 and its receptor IL13RD2 regulate IFN-1 production and signaling in a murine model of bacterial infection.
Specific Aim 2. Examine the role of Chi3l1 and IL13RD2 in the regulation of endosomal trafficking of TLR9 during bacterial infection in vitro and in a mouse model.
Specific Aim 3. Determine which cells are critically required for Chi3l1 and IFN-1 production during infection, and determine the clinical significance of Chi3l1 and IFN-1 in bacterial infection. This project aims to understand the mechanisms of pathogen-related immunopathology during bacterial infection, including the mechanisms by which Chi3l1 modulates the IFN-1 response to control immunopathology. We will also explore the role of Chi3l1 in endosomal trafficking of TLRs during infection and assess the use of Chi3l1 as a prognostic biomarker in infected patients. The data generated from this application are expected to provide novel insights that promote the development of new therapies for bacterial infection.

Public Health Relevance

Streptococcus pneumoniae is a major etiology of pneumonia and sepsis and a major cause of morbidity and mortality in the United States and worldwide. We have identified a critical role for Chi3l1 and its receptor IL13RD2 in dampening exuberant hyperinflammatory response potentially detrimental to the host lung during bacterial infections. This research application will contribute to the understanding of how this pathway modulates excessive and harmful innate immune responses upon sensing pathogens with the potential of identifying novel immunotherapeutics for patients with bacterial infections.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL126094-02
Application #
8966696
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Caler, Elisabet V
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
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