Researchers at UC Davis have discovered an unexpected link between how the immune system sounds an alarm when its cells are taken over by pathogens during an infection and how an inflammatory response is triggered.
The finding of this novel link, published in the journal Nature on March 23, is important because it helps researchers understand how a cell senses bacterial or viral infection, and how these pathways are linked to inflammatory diseases, such as inflammatory bowel disease, diabetes and atherosclerosis.
“Some bacteria are able to hijack the cell’s own manufacturing machinery to gain nutrients and grow within our cells,” said Mariana Byndloss, co-author of the study and postdoctoral scholar in the Department of Medical Microbiology and Immunology at the UC Davis School of Medicine.
“However, our cells can sense this disruption and trigger an alarm that leads to inflammation," she said. "We have found that the same two proteins involved in alerting the immune system to bacterial infection, NOD1 and NOD2, are also involved in how a cell responds to cellular stress."
The cell’s manufacturing processes take place in a specialized organelle in the cell, called the endoplasmic reticulum (ER), and are critical to making many components needed to maintain and repair cells. During a hostile takeover of the cell by bacteria or viruses, these manufacturing processes are disturbed, and the assembly line for producing these components becomes backed up. This condition is known as ER stress, which triggers an alarm that causes the cell to shut down production to try and resolve the problem. It also triggers a host response, termed inflammation, which is designed to fight infection.
In this study, UC Davis researchers studying the response to infection with the bacterial pathogen Brucella, a cause of chronic febrile illness, discovered a novel link between ER stress and the innate immune response to bacterial infection. Two proteins, NOD1 and NOD2, which were already known to sense bacterial infection, turned out also to be involved in sensing ER stress, whether it was caused by infection with bacteria, such as Brucella and Chlamydia, or by chemicals that disrupt the endoplasmic reticulum’s function.
“ER stress in various cells plays an important role in the pathogenesis of several diseases, including obesity, diabetes, cancer, and intestinal bowel and airway diseases,” Byndloss said. “Moreover, it has been suggested that ER stress-induced inflammation contributes substantially to disease progression. But it was not known how this response was linked to infection until now.”
The discovery that the NOD1/NOD2 and ER stress pathways are linked helps researchers understand how a cell senses bacterial or viral infection, and how these pathways are linked to inflammatory diseases.
The title of the journal paper is “NOD1 and NOD2 signalling links ER stress with inflammation.”
Other authors include: A. Marijke Keestra-Gounder, Núbia Seyffert, Briana M. Young, Alfredo Chávez-Arroyo, April Y. Tsai, Stephanie A. Cevallos, Maria G. Winter, Tobias Kerrinnes, Connor R. Tiffany, Marteen F. deJong, Andreas J. Bäumler and Renée M. Tsolis at UC Davis Department of Medical Microbiology and Immunology; and Oanh H. Pham, Resmi Ravindran, Paul A. Luciw and Stephen J. McSorley at the UC Davis Center for Comparative Medicine.
The research is supported with grants from the U.S. Public Health Service (USPHS A/112258, A/109799, A/044170, A/076246, A/096528, A/076278, A/117303, and GM056765) the American Heart Association (12SDG12220022) and a CAPES Science without Borders fellowship.