Project 3 Each year up to 500,000 individuals survive hospitalization with severe sepsis, but within five years half of them will be dead. Early clinical and experimental evidence indicates that a non-resolving inflammatory response persists long after the discharge from hospital, and contributes to cognitive dysfunction, impaired immune responses, and poor quality of life. The hypothesis addressed in this project is that cytokines produced in the periphery activate production of cytokines in the brain. These mediate behavioral and immunological sequelae in sepsis survivors. Based on our previous work, the data available in the published literature, and our preliminary studies we will address this hypothesis through the following specific ainis.
Aim 1 : Determine effects of therapeutically targeting brain cytokine release in sepsis survivors.
Aim 2 : Determine effects of therapeutically targeting systemic cytokine release in sepsis survivors.
Aim 3 : To study the inflammatory reflex in sepsis survivors. The anticipated results will provide mechanistic insights and potentially identify therapeutic strategies.

Public Health Relevance

Recent evidence indicates that sepsis survivors experience cognitive and immune impairment, and more than half of the survivors die within 5 years. The studies proposed here will provide significant data that can be used to modulate neural and immune function to develop therapeutic modalities for the prevention and treatment of sepsis induced cognitive and immune impairments.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Feinstein Institute for Medical Research
United States
Zip Code
Huerta, Patricio T; Robbiati, Sergio; Huerta, Tomás Salvador et al. (2016) Preclinical models of overwhelming sepsis implicate the neural system that encodes contextual fear memory. Mol Med 22:
Chang, Eric H; Volpe, Bruce T; Mackay, Meggan et al. (2015) Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-d-Aspartate Receptor. EBioMedicine 2:755-64
Brimberg, Lior; Mader, Simone; Fujieda, Yuichiro et al. (2015) Antibodies as Mediators of Brain Pathology. Trends Immunol 36:709-24
Volpe, Bruce T; Berlin, Rose Ann; Frankfurt, Maya (2015) The brain at risk: the sepsis syndrome and lessons from preclinical experiments. Immunol Res 63:70-4
Valdés-Ferrer, Sergio I; Papoin, Julien; Dancho, Meghan E et al. (2015) HMGB1 mediates anemia of inflammation in murine sepsis survivors. Mol Med :
Huerta, Patricio T; Gibson, Elizabeth L; Rey, Carson et al. (2015) Integrative neuroscience approach to neuropsychiatric lupus. Immunol Res 63:11-7