A Little Goes a Long Way: How Circulating Bacillus Anthracis Lethal Toxin Prevents the Neutrophil Response to Infection 557 views

Bacillus anthracis is a Gram-positive spore-forming bacterium that is the causative agent of the disease anthrax, which is traditionally a disease of grazing livestock and a zoonosis of humans that work closely with infected animals. B. anthracis has become of more interest in modern times due to the ease by which it is weaponized for biological warfare or terrorism. Anthrax can be contracted through several routes of exposure: by inhalation, cutaneously through breaks in the skin, and by ingestion. Of the exposure routes, inhalation anthrax elicits the highest mortality rate, while cutaneaous infection has the lowest. The cause of B. anthracis high mortality rates is attributed to two main virulence factors, a tripartite exotoxin and a gamma- linked poly-glutamic acid capsule. The tripartite AB exotoxin consists of a receptor-binding translocase subunit, protective antigen (PA), and two enzymatic subunits, lethal factor (LF) and edema factor (EF). When PA is bound to LF or EF the complex becomes lethal toxin (LT) or edema toxin (ET), respectively. A great deal of research has been devoted to discovering how the exotoxins produced by B. anthracis manipulate macrophages and dendritic cells to the benefit of the bacterium. This is because in the inhalational model of infection it is thought that the exotoxins manipulate phagocytes to act as a “Trojan horse” which transports ungerminated spores to the regional draining lymph node from where germination and dissemination originates. However, recent data suggests that B. anthracis spore germination and dissemination originates at sites outside of the regional draining lymph node. Additionally it has been suggested that LT intoxication of polymorphonuclear leukocytes (PMNs aka neutrophils) is necessary for bacterial dissemination. The goal of the following research was to examine areas of knowledge not covered in the literature, and to determine how and where B. anthracis disseminates from as well as how LT is used to circumvent the innate immune response. The research summarized hereafter demonstrates that, 1) dissemination of B. anthracis originates at the initial site of spore deposit and not from spores which have trafficked to the draining lymph node, 2) low levels of circulating LT are capable of attenuating PMNs ability to both kill vegetative bacilli and accumulate at sites of inflammation, and 3) circulating LT prevents PMNs ability to kill by preventing generation of the oxidative burst.

PHD (Doctor of Philosophy)

English

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2013-08-22