15 November 2013

Deadly Anthrax Toxin Can Go Undetected in Human Body For Days

Anthrax is an infectious disease that is caused by the Bacillus anthracis bacteria. Bacillus anthracis is a gram positive, rod shaped bacteria that can be found in soil and commonly infects domestic and wild animals.

Animals can be infected with anthrax by breathing in or ingesting the bacterial spores present in the soil, vegetation, or water. Once active, the bacteria starts multiplying in the body and produces toxins that causes severe illness and even death.

Humans can get anthrax through contact with infected animals or contaminated animal products. Although infectious, the disease is not contagious.

The latest study on the disease show that the toxin produced by the bacteria can go undetected for days as it enters the cell. The toxin is invisible to the body's immune system and the cellular machinery responsible for destroying proteins which explains why antibiotics are not enough to combat the infection.

The pathogen can also exit the cell days after and continue to infect other cells. This explains why some succumb to the disease weeks after the last signs of bacterial presence.

The image above (Credit: EPFL / Global Health Institute) is a schematic representation of the long-term and long-distance Lethal Factor (LF) delivery modes. Anthrax LF is internalized via a dynamin dependent pathway and 34 delivered to early endosomes. There the toxin receptor complex is sorted into nascent ILVs. Anthrax PA forms a channel into the membrane of the ILV and translocates LF into the lumen. LF, encapsulated in the ILVs is transported in a microtubule dependent manner to later stages of the endocytic pathway. There, two fates are observed: LF is either delivered to the cytosol, presumably by back fusion, over periods of days or LF-containing ILVs are released into the extracellular medium as exosomes. These exosomes can be taken up by naïve recipient cell via an anthrax toxin receptor independent dynamin-dependent mechanism. LF is subsequently released into the cytosol of the recipient cell in a Tgs101 and Alix dependent manner (inspired from (Raposo and Stoorvogel, 2013)).

Invisible Anthrax Toxin

The deadly toxin produced by anthrax bacteria can hide out in human cells for days, invisible both to our immune systems and to the cellular machinery responsible for destroying proteins. The findings reported in the Cell Press journal Cell Reports on November 14th explain why antibiotics aren't always enough to cure anthrax infections.

"The anthrax bacteria kills people in a very short period of time, and this is in large part due to the production of the anthrax lethal toxin," said Gisou van der Goot of the École Polytechnique Fédérale de Lausanne. "This toxin disarms our immune system, but also, as very recently shown, affects our heart."

"Many years ago, we had noticed that the effect of anthrax lethal toxin was detectable for more than a week in cells that had been exposed to the toxin for less than one single hour," she added. "We wanted to understand how this was possible."

To find out just how the anthrax toxin could do its damage over time and space, in the new study the researchers examined the toxin's complex delivery route. The toxin itself has two main ingredients: the damaging lethal factor itself and a protective antigen required for cells to take up and move that killer protein.

Video: Anthrax and Bacillus anthracis

Protective antigen helps the lethal factor enter cells by forming channels. Van der Goot and her colleagues now confirm their earlier suspicion that those channels might be capable of delivering toxin not just into cells themselves, but also into smaller sacs or vesicles within the larger cell.

Once safely inside those vesicles, the lethal factor can persist for days without degradation, the researchers show. They were surprised to find that while sheltered inside those vesicles, the toxin can also be passed on from one cell to its daughters and from one cell to another.

The findings help to explain why anthrax infection is so devastatingly deadly, but this new understanding of these bacterial weapons and their sneaky behavior does come with an upside for science.

"By studying these interactions, we can learn more than how to fight anthrax infection," van der Goot said. "We also learn a lot about how cells work. "


Cell Press
Ecole Polytechnique Fédérale de Lausanne (EPFL)
Cell Reports
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