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)
Type
Research Project (R01)
Project #
5R01NS051247-10
Application #
8636497
Study Section
Immunity and Host Defense (IHD)
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
San Diego State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92182
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Patras, Kathryn A; Wang, Nai-Yu; Fletcher, Erin M et al. (2013) Group B Streptococcus CovR regulation modulates host immune signalling pathways to promote vaginal colonization. Cell Microbiol 15:1154-67
Doran, Kelly S; Banerjee, Anirban; Disson, Olivier et al. (2013) Concepts and mechanisms: crossing host barriers. Cold Spring Harb Perspect Med 3:
Krishnan, Vengadesan; Dwivedi, Prabhat; Kim, Brandon J et al. (2013) Structure of Streptococcus agalactiae tip pilin GBS104: a model for GBS pili assembly and host interactions. Acta Crystallogr D Biol Crystallogr 69:1073-89
Cavaco, Courtney K; Patras, Kathryn A; Zlamal, Jaime E et al. (2013) A novel C5a-derived immunobiotic peptide reduces Streptococcus agalactiae colonization through targeted bacterial killing. Antimicrob Agents Chemother 57:5492-9
van Sorge, Nina M; Doran, Kelly S (2012) Defense at the border: the blood-brain barrier versus bacterial foreigners. Future Microbiol 7:383-94
Ebrahimi, Celia M; Sheen, Tamsin R; Renken, Christian W et al. (2011) Contribution of lethal toxin and edema toxin to the pathogenesis of anthrax meningitis. Infect Immun 79:2510-8

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