Approximately 750,000 Americans each year experience a life-threatening episode of severe sepsis. Twenty five to 30% die acutely. The survivors will experience diminished cognitive function. Moreover, many will die within the next five years due to immunocompetence and infection. This research program will address these late sequelae of sepsis. The model we propose links these two impairments. Systemic inflammation leads to both brain inflammation and an altered splenic microenvironment. We ask whether systemic cytokines are necessary to sustain brain inflammation and whether impairment in the function of the efferent vagus nerve sustains the immunosuppression. In support of this model, and of obvious clinical significance, we have shown that intervening with cytokine blockade after apparent resolution of the acute event improves both brain and immune function. Three coordinated research projects, support by an administrative core and 3 scientific cores will explore the initiation and nature of brain inflammation, the nature and cause of persisting monocyte dysfunction and the optimal therapy to prevent the long term morbidity that is triggered by severe sepsis.

Public Health Relevance

Following an episode of severe sepsis, individuals may develop impaired cognition and inadequate immune function, which contributes to poor long-term outcome. This research program will explore these persistent impairments, the links between them and therapeutic strategies for their prevention or reversal. These late sequelae have not been well studies, nor targeted therapeutically Project 1: Nervous system alterations in sepsis-surviving mice Project Leader (PL): Bruce Volpe DESCRIPTION (as provided by applicant): Survivors of sepsis often experience persistent cognitive impairment. Our preliminary data show that this can be ameliorated by reducing systemic inflammation at a time when acute, life-threatening immune activation has resolved. In this project, we will explore the brain inflammation that is triggered by an episode of sepsis and whether TNF, IL-1 or HMGB1, or some combination of these is 1) the critical cytokine in the circulation that initiates brain inflammation or 2) a key cytokine within the brain that contribute to histologic and functional damage. Further, we will explore how systemic inflammation is communicated to the brain: whether by neural circuitry or by activation of brain microvascular endothelial cells. These studies will identify pathways connecting brain inflammation to systemic inflammation and will dissect those components of brain inflammation that lead to a persistent cognitive deficit.

Public Health Relevance

Individuals surviving sepsis often experience persistent cognitive impairment. This study will explore how systemic inflammation causes brain dysfunction.

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)
Program Officer
Minnicozzi, Michael
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
Zaghloul, Nahla; Addorisio, Meghan E; Silverman, Harold A et al. (2017) Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors. Front Immunol 8:1673
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:
Olofsson, Peder S; Steinberg, Benjamin E; Sobbi, Roozbeh et al. (2016) Blood pressure regulation by CD4(+) lymphocytes expressing choline acetyltransferase. Nat Biotechnol 34:1066-1071
Vingtdeux, Valérie; Chang, Eric H; Frattini, Stephen A et al. (2016) CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice. Sci Rep 6:24250
Honig, Gerard; Mader, Simone; Chen, Huiyi et al. (2016) Blood-Brain Barrier Deterioration and Hippocampal Gene Expression in Polymicrobial Sepsis: An Evaluation of Endothelial MyD88 and the Vagus Nerve. PLoS One 11:e0144215
Brimberg, L; Mader, S; Jeganathan, V et al. (2016) Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice. Mol Psychiatry 21:1663-1671
Valdés-Ferrer, Sergio I; Papoin, Julien; Dancho, Meghan E et al. (2015) HMGB1 mediates anemia of inflammation in murine sepsis survivors. Mol Med :
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
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 36:709-724

Showing the most recent 10 out of 12 publications