The presence of dsDNA in the cytoplasm signals serious problems in eukaryotic cells, ranging from dysfunctional mitochondria to pathogen invasion. In mammals, the innate immune system detects these rogue dsDNA and initiate inflammatory responses. Cytoplasmic dsDNA sensing pathways are integral to host defense against numerous pathogens, and their malfunctions are also implicated in various human maladies. Here, we will define the molecular mechanisms by which cytoplasmic dsDNA sensors initiate host innate immune responses in a coordinated fashion.
In Aim 1, we will resolve several controversies regarding the activation mechanism of cGAS such as why dsDNA length matters (or not), what the role of N-domain is, and how cGAS dimerizes on dsDNA.
In Aim 2, we will resolve a fundamental mechanistic question in innate immunology as to what defines the dsDNA specificity of cGAS, AIM2, and IFI16. We will then test whether cellular RNA can act as a buffer to minimize the spurious activation of these sensors.
In Aim 3, we will determine whether differential kinetics of cGAS, AIM2, IFI16, and the TREX1 nuclease can shape the overall host response against cytoplasmic dsDNA. We will then investigate agonism and antagonism among these sensors in generating well-balanced host responses against cytoplasmic dsDNA.

Public Health Relevance

Cytoplasmic dsDNA sensing pathways play key roles in regulating inflammatory responses. We will define how various cytoplasmic dsDNA sensors coordinate the sequence and balance of inflammatory responses at the molecular level. In the future, the outcome of the present proposal will also aid in developing novel therapeutic strategies targeting these pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM129342-03
Application #
9980945
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Zhao, Xiaoli
Project Start
2018-09-20
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205