jessica-hook@uiowa.edu
Mentor: William M. Nauseef, M.D.
Lab Phone: 335-4241

Neisseria meningitidis-induced Polymorphonuclear Leukocyte-Endothelial Cell Interactions

Neisseria meningitidis (NMB) causes life-threatening sepsis characterized by a severe systemic inflammatory response. Despite advances in detection methods, antibiotics, and supportive therapy, morbidity and mortality from meningococcal sepsis remain high. In NMB, the endotoxin is a lipooligosaccharide (LOS) that stimulates proinflammatory mediator release and initiates a cascade of events resulting in sepsis. NMB releases LOS rich membrane vesicles, blebs, both during bacterial growth in vitro and during meningococcal infection in vivo. We assessed the ability of purified LOS, blebs or live, intact NMB to elicit cytokine and adhesion molecule expression by human dermal microvascular endothelial cells (HMVEC-d) and to promote transendothelial migration of polymorphonuclear leukocytes (PMN), both early events in the inflammatory response. IL-8 and MCP-1 were upregulated in a dose-dependent manner by HMVEC-ds stimulated with purified LOS, blebs or live, intact NMB. ICAM-1was upregulated in a dose-dependent manner by HMVEC-ds stimulated with purified LOS or blebs. Among the agonists, purified LOS elicited the greatest increase in both cytokine and adhesion molecule expression. Each agonist elicited a dose-dependent increase in PMN transendothelial migration, although purified LOS was more potent than were blebs at equivalent LOS concentrations. These differential cellular responses to LOS suggest that specific microbial structural determinants may contribute to the type and magnitude of acute proinflammatory response.

Abstracts:

Hook JS, Moreland JG, M.D., Nauseef WM, M.D. Neisseria meningitidis-induced Polymorphonuclear Leukocyte-Endothelial Cell Interactions. Unraveling Inflammation Abstract # 90, October 2-5, 2003.

Publications:

Moreland JG, Hook JS, Bailey G, Ulland T, Nauseef WM. Francisella tularensis directly interacts with the endothelium and recruits neutrophils with a blunted inflammatory phenotype. Am J Physiol Lung Cell Mol Physiol. 2009 Apr 3. [Epub ahead of print] PubMed PMID: 19346432.

Moreland JG, Davis AP, Matsuda JJ, Hook JS, Bailey G, Nauseef WM, Lamb FS. Endotoxin priming of neutrophils requires NADPH oxidase-generated oxidants and is regulated by the anion transporter ClC-3. J Biol Chem. 2007 Nov 23;282(47):33958-67. Epub 2007 Oct 1. PubMed PMID: 17908687.