Much of the work on inhalation anthrax has exclusively focused on the exotoxins. Our recent studies indicate that the peptidoglycan component of the B. anthracis cell wall induces the production of inflammatory cytokines and chemokines. The production of the cytokines and chemokines is exclusively from peripheral blood monocytes;lymphocytes and neutrophils do not respond. We have preliminary and on-going structural work to chemically characterize B. anthracis peptidoglycan. We have novel tools to identify the currently unknown extracellular receptor for Gram-positive peptidoglycan and to understand the signaling events induced by the receptor and causing the changes in monocyte biology. Additionally, we have new data indicating that peptidoglycan induces monocyte apoptosis in a subpopulation distinct from the monocytes producing inflammatory cytokines. We present an experimental plan to identify the mechanism of peptidoglycan-triggered apoptosis. The monocyte apoptosis might contribute to the high mortality of B. anthracis and possibly of other Gram-positive pathogens by eliminating an important component of the innate immune system. We will test this possibility by challenging rodents and non-human primates with B. anthracis peptidoglycan and measuring monocyte levels.

Public Health Relevance

Inhalation Bacillus anthracis infection remains a significant bioterrorist health threat because (a) the disease is associated with a high percentage of fatalities, (b) the spores are long-lived and can be manufactured with inexpensive equipment, (c) the vaccine is cumbersome, associated with adverse effects and not provided to the general public. Furthermore, causing public terror - the real goal of the terrorist - can be achieved with a relatively few highly-publicized public deaths caused by an exotic disease like anthrax.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI062629-10
Application #
8716420
Study Section
Special Emphasis Panel (ZAI1-KS-I (J3))
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$385,765
Indirect Cost
$94,366
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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