The major focus of my research program is to elucidate pathways of innate immunity that can control pathogenic microbial infections with a special emphasis on the connection between endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and the pattern recognition receptors (PRR) NOD1 and NOD2. NOD1 and NOD2 are cytosolic PRRs that are strongly associated with metabolic and inflammatory disorders such as inflammatory bowel disease (IBD) and type 2 diabetes. NOD1/2 are activated by and respond to many different stimuli including bacterial peptidoglycan, ER stress, viral and parasitic infections, activated Rho GTPases and changes to the actin cytoskeleton. Our prior research showed that UPR-induced activation of pro-inflammatory mediators by ER stress is dependent on NOD1 and NOD2. Activation of the UPR restores cellular homeostasis by inhibiting protein synthesis and activation of signaling pathways. Three transmembrane receptors, ATF6, PERK and IRE1a mediate the UPR. Activated IRE1a leads to the activation of MAP kinases and NF-κB and the subsequent production of pro-inflammatory cytokines, such as IL-6 and TNFa, which requires NOD1/2. We are investigating the mechanisms behind this process and how it is activated during infections to potentially influence pathogenic outcomes using cell culture and animal models. Our research program further tests our central hypothesis that NOD1 and NOD2 help monitor the integrity of the host cell by integrating cellular signals to induce pro-inflammatory responses. The association of NOD1/2 with the ER stress-induced pro-inflammatory responses may have great implications for pathogenic microbial infections as well as other ER stress-related chronic inflammatory diseases such as inflammatory bowel disease (IBD) and type 2 diabetes.
Main projects in the lab include:
1. Defining the effect of ER stress on immunity and infection during enteropathogenic bacterial infections (Citrobacter rodentium and Salmonella enterica Typhimurium).
2. Understanding the mechanisms underlying ER stress sensing by NOD1 and NOD2.
3. Characterizing the roles of NOD1 and NOD2 during viral infections (Coxsackievirus and Influenza A virus).
Click here for a list of Dr. Keestra-Gounder's recent publications.
NOD1/2 are activated during ER stress via IRE1a leading to upregulation of inflammatory genes. Many viral, parasitic and bacterial infections induce ER stress, but for many, it is unknown whether NOD1/2 are activated during this process to mediate an innate immune response. (Kuss-Duerkop and Keestra-Gounder. 2020, Infection and Immunity 88(7):e00898-19.)
