Bacterial meningitis is the most common serious infection of the central nervous system (CNS) and a major cause of death and disability worldwide, especially in children. Although antibiotic therapy has changed bacterial meningitis from a uniformly fatal disease to an often curable one, the overall outcome remains unfavorable, with mortality of 5 to 10% and permanent neurologic sequelae occurring in 5 to 40% of survivors, depending on patient age and pathogen. Disruption and dysfunction of the blood-brain barrier (BBB) is a hallmark event in the pathophysiology of bacterial meningitis. Little is known, however, about the very first and crucial interaction between a bacterial pathogen with the BBB that initiates this chain of events, and may ultimately determine a poor or favorable neurological outcome in meningitis patients. This proposal seeks to elucidate the molecular mechanisms of BBB response and function during bacterial infection, and why it fails as a neuroprotective barrier during bacterial meningitis. I hypothesize that BBB disruption may be due to the combined effect of bacterial entry and penetration of brain microvascular endothelium, direct cellular injury by bacterial cytotoxins, and/or activation of host inflammatory pathways that compromise barrier function. These hypotheses will be addressed with both in vitro and in vivo models of BBB penetration using Group B streptococcus as a model human pathogen associated with meningitis. Studies will also utilize isogenic bacterial mutants lacking important virulence factors such as regulators, "invasins", and cytotoxins;various knockout and transgenic mice;and key molecular tools to modulate host response pathways in the following specific aims:
AIM 1 : Characterize the bacterial-host interactions leading to immune activation and bacterial BBB invasion;
AIM 2 : Elucidate the mechanisms of bacterial intracellular trafficking and BBB traversal;
AIM 3 : Determine the contribution of bacterial factors and host innate immune response pathways to BBB permeability and the pathogenesis of bacterial meningitis. These data will build upon and complement our observations to clarify the crucial position of the brain endothelium in innate immune defense against bacterial pathogens. The knowledge gained as a result of this proposal into the mechanisms of leukocyte and bacterial-brain penetration will provide fundamental and novel insights in the pathogenesis and treatment strategies of bacterial meningitis and other neurodegenerative disorders.

Public Health Relevance

Bacterial meningitis is the most common serious infection of the central nervous system (CNS) and a major cause of death and disability worldwide, especially in children. Disruption and dysfunction of the blood-brain barrier (BBB) is a hallmark event in the pathophysiology of bacterial meningitis. My research proposal seeks to characterize, at the molecular and cellular level, BBB response and function during bacterial infection, and why it fails as a neuroprotective barrier.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051247-08
Application #
8318073
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Wong, May
Project Start
2005-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$327,031
Indirect Cost
$108,281
Name
San Diego State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
073371346
City
San Diego
State
CA
Country
United States
Zip Code
92182
Doran, Kelly S; Fulde, Marcus; Gratz, Nina et al. (2016) Host-pathogen interactions in bacterial meningitis. Acta Neuropathol 131:185-209
Mu, Rong; Cutting, Andrew S; Del Rosario, Yvette et al. (2016) Identification of CiaR Regulated Genes That Promote Group B Streptococcal Virulence and Interaction with Brain Endothelial Cells. PLoS One 11:e0153891
Patras, K A; Rösler, B; Thoman, M L et al. (2015) Characterization of host immunity during persistent vaginal colonization by Group B Streptococcus. Mucosal Immunol 8:1339-48
Stoner, Terri D; Weston, Thomas A; Trejo, JoAnn et al. (2015) Group B streptococcal infection and activation of human astrocytes. PLoS One 10:e0128431
Gendrin, Claire; Lembo, Annalisa; Whidbey, Christopher et al. (2015) The sensor histidine kinase RgfC affects group B streptococcal virulence factor expression independent of its response regulator RgfA. Infect Immun 83:1078-88
Patras, Kathryn A; Wescombe, Philip A; Rösler, Berenice et al. (2015) Streptococcus salivarius K12 Limits Group B Streptococcus Vaginal Colonization. Infect Immun 83:3438-44
Kim, Brandon J; Hancock, Bryan M; Del Cid, Natasha et al. (2015) Streptococcus agalactiae infection in zebrafish larvae. Microb Pathog 79:57-60
Kim, Brandon J; Hancock, Bryan M; Bermudez, Andres et al. (2015) Bacterial induction of Snail1 contributes to blood-brain barrier disruption. J Clin Invest 125:2473-83
Puccini, Jenna M; Ruller, Chelsea M; Robinson, Scott M et al. (2014) Distinct neural stem cell tropism, early immune activation, and choroid plexus pathology following coxsackievirus infection in the neonatal central nervous system. Lab Invest 94:161-81
Faralla, Cristina; Metruccio, Matteo M; De Chiara, Matteo et al. (2014) Analysis of two-component systems in group B Streptococcus shows that RgfAC and the novel FspSR modulate virulence and bacterial fitness. MBio 5:e00870-14

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