Anthrax toxins inhibit neutrophil signaling pathways in brain endothelium and contribute to the pathogenesis of meningitis.
BACKGROUND
Anthrax meningitis is the main neurological complication of systemic infection with Bacillus anthracis approaching 100% mortality. The presence of bacilli in brain autopsies indicates that vegetative bacteria are able to breach the blood-brain barrier (BBB). The BBB represents not only a physical barrier but has been shown to play an active role in initiating a specific innate immune response that recruits neutrophils to the site of infection. Currently, the basic pathogenic mechanisms by which B. anthracis penetrates the BBB and causes anthrax meningitis are poorly understood.


RESULTS
Using an in vitro BBB model, we show for the first time that B. anthracis efficiently invades human brain microvascular endothelial cells (hBMEC), the single cell layer that comprises the BBB. Furthermore, transcriptional profiling of hBMEC during infection with B. anthracis revealed downregulation of 270 (87%) genes, specifically key neutrophil chemoattractants IL-8, CXCL1 (Gro alpha) and CXCL2 (Gro beta), thereby strongly contrasting hBMEC responses observed with other meningeal pathogens. Further studies using specific anthrax toxin-mutants, quantitative RT-PCR, ELISA and in vivo assays indicated that anthrax toxins actively suppress chemokine production and neutrophil recruitment during infection, allowing unrestricted proliferation and dissemination of the bacteria. Finally, mice challenged with B. anthracis Sterne, but not the toxin-deficient strain, developed meningitis.


CONCLUSIONS
These results suggest a significant role for anthrax toxins in thwarting the BBB innate defense response promoting penetration of bacteria into the central nervous system. Furthermore, establishment of a mouse model for anthrax meningitis will aid in our understanding of disease pathogenesis and development of more effective treatment strategies.
van Sorge
Nina M
NM
Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
Ebrahimi
Celia M
CM
McGillivray
Shauna M
SM
Quach
Darin
D
Sabet
Mojgan
M
Guiney
Donald G
DG
Doran
Kelly S
KS
D000942:Antigens, Bacterial / Q000494:pharmacology*; D001408:Bacillus anthracis; D001427:Bacterial Toxins / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D016920:Meningitis, Bacterial / Q000139:chemically induced* / Q000473:pathology*; D008833:Microcirculation / Q000187:drug effects*; D008959:Models, Neurological; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin