Both pathogenic and non-pathogenic bacteria produce pathogen-associated molecular patterns (PAMPs) that stimulate innate immune responses in their eukaryotic hosts via pattern-recognition receptors such as toll-like receptors. Virulence factors of pathogens provide additional signals that allow the innate immune system to differentiate between harmless commensals and pathogens. These signals include virulence factors, such as Type III and Type IV secretion systems that translocate effector proteins into the host cell. Collectively, these processes are detected by the immune system as ?patterns of pathogenesis? and can activate cytosolic signaling pathways. Brucella abortus is a stealthy pathogen expressing modified PAMPs that no longer serve as agonists for pattern recognition receptors. As a result, host responses generated during B. abortus infection are entirely dependent on detecting the function of its T4SS, as a pathogen-induced process. Here we propose to use this organism to interrogate novel innate immune signaling pathways linking perturbation of endoplasmic reticulum function to inflammation. The objectives of this application are to determine how activation of the IRE1? pathway of the host cell?s unfolded protein response influences the outcome of infection with intracellular bacteria, by eliciting inflammatory responses and providing inputs that drive survival or death of the infected cell. The proposed research will test the hypothesis is that in macrophages, a NOD1/NOD2-containing signaling complex detects perturbation of ER function during B. abortus infection to induce inflammatory responses and promote survival of infected macrophages, while in a secretory cell type infection-induced ER stress triggers immunogenic cell death, resulting in placentitis and abortion. Successful completion of this work will move the field forward by determining how cells detects pathogen-induced perturbation of ER function and how the resulting response drives cell survival vs cell death outcomes in different cell types. This concept has important ramifications not only for bacterial pathogenesis, but also for understanding host-virus interactions, innate immunity and the pathogenesis of inflammatory disorders associated with ER stress, such as type 1 diabetes, inflammatory bowel disease and neuroinflammatory disease.
During bacterial infection, the immune system senses both components of the bacteria (known as PAMPS) and perturbation of cellular function by virulence factors of pathogenic bacteria, and this sensing can trigger inflammation. Our results show that manipulation of the endoplasmic reticulum during infection with the bacterial pathogen Brucella abortus triggers inflammatory responses involving two innate immune receptors, NOD1 and NOD2. This application proposes to determine how this pathway is activated during bacterial infection and how endoplasmic reticulum stress can lead to survival or death of infected cells, a process that is central to the development of many inflammatory diseases.
| Yokoyama, Christine C; Baldridge, Megan T; Leung, Daisy W et al. (2018) LysMD3 is a type II membrane protein without an in vivo role in the response to a range of pathogens. J Biol Chem 293:6022-6038 |
| Byndloss, Mariana X; Olsan, Erin E; Rivera-Chávez, Fabian et al. (2017) Microbiota-activated PPAR-? signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357:570-575 |
| Keestra-Gounder, A Marijke; Tsolis, Renée M (2017) NOD1 and NOD2: Beyond Peptidoglycan Sensing. Trends Immunol 38:758-767 |
| Kerrinnes, Tobias; Winter, Maria G; Young, Briana M et al. (2017) Utilization of host polyamines in alternatively activated macrophages promotes chronic infection by Brucella abortus. Infect Immun : |
| Keestra-Gounder, A Marijke; Byndloss, Mariana X; Seyffert, Núbia et al. (2016) NOD1 and NOD2 signalling links ER stress with inflammation. Nature 532:394-7 |
| Byndloss, Mariana X; Keestra-Gounder, Arina Marijke; Bäumler, Andreas J et al. (2016) NOD1 and NOD2: New Functions Linking Endoplasmic Reticulum Stress and Inflammation. DNA Cell Biol 35:311-3 |
| Faber, Franziska; Tran, Lisa; Byndloss, Mariana X et al. (2016) Host-mediated sugar oxidation promotes post-antibiotic pathogen expansion. Nature 534:697-9 |
| Byndloss, Mariana X; Tsolis, Renee M (2016) Chronic Bacterial Pathogens: Mechanisms of Persistence. Microbiol Spectr 4: |
| Celli, Jean; Tsolis, Renée M (2015) Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes? Nat Rev Microbiol 13:71-82 |
| Kerrinnes, Tobias; Young, Briana M; Leon, Carlos et al. (2015) Phospholipase A1 modulates the cell envelope phospholipid content of Brucella melitensis, contributing to polymyxin resistance and pathogenicity. Antimicrob Agents Chemother 59:6717-24 |
