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Breakout Session: Mental Health and Traumatic Brain Injury Human Brain Microvascular Transcriptional Responses to African Trypanosomes Under Physiologic Flow. Dennis J Grab1, Nur Atiqah Azhar2, Mohammad Asif Khan2, Brandon J. Sumpio3, Yongqing Zhang4, Kevin G Becker4, Carlos Pardo-Villamizar5, Koichiro Mihara6, Morley Hollenberg6, Conor R. Caffrey7, H. Benjamin Larman5, Andrew Wong5, Peter Searson5, Peter G E Kennedy8, Serap Aksoy3, Bauer E.Sumpio3. 1] 1Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 2Perdana University, Selangor, Malaysia. 3Yale University, New Haven, CT, USA. 4National Institute on Aging (NIH), Baltimore, Maryland USA. 5Johns Hopkins University, Baltimore, MD, USA. 6University of Calgary Cumming School of Medicine, Calgary, Canada. 7University of California San Diego, La Jolla, USA. 8University of Glasgow, Glasgow, Scotland, UK. Disclaimer: The opinions expressed herein are those of the author(s) and are not necessarily representative of those of the Uniformed Services University of the Health Sciences, the Department of Defense, or the United States Army, Navy, or Air Force. MHSRS-23-10694 INTRODUCTION: The African trypanosome, Trypanosoma brucei rhodesiense (Tbr), causes the acute East African variant of human African trypanosomiasis (HAT; sleeping sickness). Dissemination into the brain leads to neurologic involvement characterized by concomitant psychiatric disorders, seizures, night- time insomnia, and daytime drowsiness, progressive coma and, if untreated, death. How African trypanosomes alter the human blood-brain barrier (BBB) function to enter and/or disrupt brain homeostasis and cause central nervous system disease is of vital importance but not fully understood. Gold standard” static in vitro model systems (Transwell™ inserts and Electric Cell-Substrate Electric Impedance Sensing; ECIS) for BBB studies using shuman brain microvascular endothelial cells (MEC) show strong links between BBB dysfunction, pathogen cy, RITM0041103, INTRODUCTION: The African trypanosome, Trypanosoma brucei rhodesiense (Tbr), causes the acute East African variant of human African trypanosomiasis (HAT; sleeping sickness). Dissemination into the brain leads to neurologic involvement characterized by concomitant psychiatric disorders, seizures, night- time insomnia, and daytime drowsiness, progressive coma and, if untreated, death. How African trypanosomes alter the human blood-brain barrier (BBB) function to enter and/or disrupt brain homeostasis and cause central nervous system disease is of vital importance but not fully understood. Gold standard” static in vitro model systems (Transwell™ inserts and Electric Cell-Substrate Electric Impedance Sensing; ECIS) for BBB studies using shuman brain microvascular endothelial cells (MEC) show strong links between BBB dysfunction, pathogen cysteine proteases as major virulence factors (iTbCatL), host protease-activated receptors (PARs) and Ca2+ signaling (Fig 1; Refs 1-3). Infection-induced BMEC proinflammatory cytokine expression and gene-profiling identified pathways that predict G-protein modulation of BBB permeability. In human kidney embryonic cells, recombinant trypanosome cysteine protease TbCatL triggers biased MAPK signaling via PAR1, but not PAR2 and MAPK signaling by both PARs is triggered by other proteases present in trypanosome lysate preparations (Fig 2: unpbublished). The consequence of these events was predicted to be increased permeability of the BBB to parasite transmigration and the initiation of neuroinflammation, events precursory to CNS disease. These static BBB models provided important and predictive information about the early stages of CNS HAT predicting that the parasites would enter the brain of a mouse within hours after entering the bloodstream (Fig 3; Ref 4). However, these models do not address the contribution of brain blood flow dynamics (Ref 5).