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Circulating lethal toxin decreases the ability of neutrophils to respond to Bacillus anthracis
Zachary P Weiner1, Stephen M Ernst, Anne E Boyer
1Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
Abstract:
Polymorphonuclear leucocytes (PMNs) play a protective role during Bacillus anthracis infection. However, B. anthracis is able to subvert the PMN response effectively as evidenced by the high mortality rates of anthrax. One major virulence factor produced by B. anthracis, lethal toxin (LT), is necessary for dissemination in the BSL2 model of mouse infection. While human and mouse PMNs kill vegetative B. anthracis, short in vitro half-lives of PMNs have made it difficult to determine how or if LT alters their bactericidal function. Additionally, the role of LT intoxication on PMN's ability to migrate to inflammatory signals remains controversial. LF concentrations in both serum and major organs were determined from mice infected with B. anthracis Sterne strain at defined stages of infection to guide subsequent administration of purified toxin. Bactericidal activity of PMNs assessed using ex vivo cell culture assays showed significant defects in killing B. anthracis. In vivo PMN recruitment to inflammatory stimuli was significantly impaired at 24 h as assessed by real-time analysis of light-producing PMNs within the mouse. The observations described above suggest that LT serves dual functions; it both attenuates accumulation of PMNs at sites of inflammation and impairs PMNs bactericidal activity against vegetative B. anthracis.
Insights
Bacillus anthracis lethal toxin (LT) impairs polymorphonuclear leucocytes (PMNs) by reducing their ability to kill bacteria and migrate to infection sites. This study reveals LT
Area of Science:
- Immunology
- Microbiology
- Pathogenesis
Background:
- Polymorphonuclear leucocytes (PMNs) are crucial for combating Bacillus anthracis infections.
- Bacillus anthracis effectively evades the host immune response, leading to high mortality rates.
- Lethal toxin (LT), a key B. anthracis virulence factor, is implicated in disease dissemination.
Purpose of the Study:
- To investigate the impact of B. anthracis lethal toxin (LT) on PMN function, specifically bactericidal activity and migration.
- To elucidate the mechanisms by which B. anthracis subverts the PMN response.
Main Methods:
- Quantification of lethal factor (LF) concentrations in infected mouse serum and organs.
- Ex vivo assessment of PMN bactericidal activity against B. anthracis.
- Real-time in vivo analysis of PMN recruitment to inflammatory stimuli in mice.
Main Results:
- LT significantly impairs the ability of PMNs to kill B. anthracis in vitro.
- In vivo PMN migration to inflammatory signals was markedly reduced at 24 hours post-infection.
- LT demonstrates dual functions: inhibiting PMN accumulation and compromising bactericidal capacity.
Conclusions:
- Lethal toxin (LT) plays a critical role in B. anthracis pathogenesis by disarming PMNs.
- LT attenuates PMN recruitment to inflammatory sites and impairs their direct killing of bacteria.
- Targeting LT or its effects on PMNs could be a potential therapeutic strategy against anthrax.
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