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Environmental Factor, March 2012

New grantee discovers treatment that may block Shiga toxin

By Ashley Godfrey

microscope image of the intestine with Shiga toxin

Above is a microscope image showing the Shiga toxin (green) in the intestine. In developed countries, Shiga toxicosis is most common during foodborne outbreaks, like the widespread E. coli outbreak this past summer in Germany and Western Europe, where more than 3,700 people were infected and 45 died. (Photo courtesy of S. Schuller, Wellcome Images)

Somshuvra Mukhopadhyay, Ph.D., and Adam Linstedt, Ph.D., standing together in their lab

Mukhopadhyay, left, and his mentor Linstedt are excited about the possible use of manganese as an inexpensive, accessible treatment for Shiga toxicosis. They plan to continue their research by using situations that more closely mimic Shiga toxin infection in humans. “We have also formed a collaboration to test the protective effect of manganese against Shiga toxicosis in non-human primates,” said Mukhopadhyay. (Photo courtesy of Somshuvra Mukhopadhyay)

Carnegie Mellon postdoctoral researcher Somshuvra Mukhopadhyay, Ph.D., has found that manganese, an essential nutrient commonly found in nature, may prevent the potentially lethal effects of infection by a bacterial compound known as Shiga toxin. Mukhopadhyay’s results, (http://www.ncbi.nlm.nih.gov/pubmed/22267811)  , published in the Jan. 20 issue of Science, show that manganese completely protects against Shiga toxicosis in animal models.

Watch how manganese blocks cellular trafficking of Shiga toxin (01:05)

 

The study was funded by the National Institute of General Medical Sciences and was carried out under the direction of Carnegie Mellon Professor Adam Linstedt, Ph.D. (http://www.cmu.edu/bio/faculty/linstedt.html)  With new funding from NIEHS, Mukhopadhyay plans to advance his research on manganese and Shiga toxin, by building on these preliminary results using other animal models.

“I'm grateful to have the support of NIEHS to develop my independent work on manganese homeostasis and toxicity, and without the new funding, it would be extremely difficult for me to keep moving on the path to independence,” concluded Mukhopadhyay.

Neutralizing a major threat to global health

Infections with Shiga toxin-producing bacteria cause more than a million deaths each year. While these infections do occur worldwide, the majority of Shiga toxin infections arise in developing countries where they cause waterborne epidemics. “The possibility of having an inexpensive and widely available agent like manganese as a treatment for Shiga toxicosis is exciting,” explained Mukhopadhyay.

Shiga toxin is a protein produced by certain strains of Shigella and E. coli bacteria. When cells take up the toxin, it interferes with cellular functions and leads to cell death, which in turn can cause symptoms ranging from mild intestinal disease to kidney failure. Unfortunately, there is no cure for these infections, because antidotes for the toxin are not available and treating patients with antibiotics actually increases the amount of toxin released by the bacteria.

“The challenge is to neutralize the toxin that is released from the bacteria,” emphasized Mukhopadhyay.

He and Linstedt have potentially answered this challenge by focusing their research on the process that Shiga toxin takes advantage of to avoid being degraded by cells. While conducting basic biological research on how cellular components function, they discovered the protective effect manganese had on cells and mice exposed to lethal doses of the Shiga toxin.

Paving the road to independence

Mukhopadhyay is a recent recipient of an NIH Pathway to Independence Award (K99/R00). This competitive award is designed to facilitate the transition into independent research positions for promising young scientists. The initial K99 award provides one to two years of mentored, postdoctoral support and the second phase R00 component supports up to three years of independent research.

Mukhopadhyay applied to NIEHS for this award, due to the significant environmental health focus of his postdoctoral work. His research goals are to understand how manganese homeostasis is regulated, and to learn more about the process by which manganese and other metal toxins can cause toxicity. While low levels of manganese are required for life, and non-toxic levels protect against Shiga toxicosis, manganese itself becomes toxic at high levels.

Manganese toxicity is a significant clinical problem, because environmental and occupational overexposure can lead to the onset of Parkinson's syndrome, a neurological syndrome distinct from Parkinson’s disease, which currently has no treatment.

Mukhopadhyay’s long-term goal is to continue to expand his work on the regulation of manganese homeostasis. In doing so, he hopes to gain a better understanding of the underlying biology behind manganese-induced Parkinsonism, which will hopefully lead to new therapies. This work will also directly aid in the development of manganese, at non-toxic levels, as an intervention for human Shiga toxicosis.

Citation: Mukhopadhyay S, Linstedt AD. (http://www.ncbi.nlm.nih.gov/pubmed/22267811)  2012. Manganese blocks intracellular trafficking of Shiga toxin and protects against Shiga toxicosis. Science 335(6066):332-335.

(Ashley Godfrey, Ph.D. is a postdoctoral fellow in the Molecular and Genetic Epidemiology Group in the NIEHS Laboratory of Molecular Carcinogenesis.)




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