Haslam, David B., M.D.

Associate Professor of Pediatrics and Molecular Microbiology

Infectious Diseases
Pathobiology

Shiga toxin (Stx), the agent studied by our laboratory, is responsible for thousands of cases of gastroenteritis annually, and is the most common cause of hemolytic uremic syndrome, a potentially fatal illness that predominantly affects young children.

Our laboratory is interested in the intracellular trafficking of shiga toxin within host cells. Using a genetic screen for molecules involved in toxin trafficking, we isolated the cDNA for a novel ER-localized chaperone, which we named HEDJ. We found that shiga toxin is capable of transport across the ER membrane after interaction with HEDJ. Apparently, shiga toxin “pretends” to be a misfolded host protein in order to exploit HEDJ and and the “ER quality-control pathway” to gain access to the cytoplasm. We are currently investigating the role of HEDJ and other chaperones in normal cellular biology as well as toxin trafficking.

Our laboratory has recently undertaken a 'chemical genomics' approach to studying the toxin transport pathway. Using high throughput screening we are identifying small molecule inhibitors of Stx, ricin, and cholera toxin transport. These compounds are used as tools to dissect the toxin transport pathway and we believe some will show promise as potential therapeutic agents.  In addition to screening for inhibitors of toxin transport, we have developed approaches to identify inhibitors of the toxin activity of shiga, ricin and the toxins produced by Clostridium difficile.  We anticipate that some of these inhibitors will be developed as new therapies against toxin-mediated disease.

Haslam, David B., M.D.

Associate Professor of Pediatrics and Molecular Microbiology

Infectious Diseases
Pathobiology

Shiga toxin (Stx), the agent studied by our laboratory, is responsible for thousands of cases of gastroenteritis annually, and is the most common cause of hemolytic uremic syndrome, a potentially fatal illness that predominantly affects young children.

Our laboratory is interested in the intracellular trafficking of shiga toxin within host cells. Using a genetic screen for molecules involved in toxin trafficking, we isolated the cDNA for a novel ER-localized chaperone, which we named HEDJ. We found that shiga toxin is capable of transport across the ER membrane after interaction with HEDJ. Apparently, shiga toxin “pretends” to be a misfolded host protein in order to exploit HEDJ and and the “ER quality-control pathway” to gain access to the cytoplasm. We are currently investigating the role of HEDJ and other chaperones in normal cellular biology as well as toxin trafficking.

Our laboratory has recently undertaken a 'chemical genomics' approach to studying the toxin transport pathway. Using high throughput screening we are identifying small molecule inhibitors of Stx, ricin, and cholera toxin transport. These compounds are used as tools to dissect the toxin transport pathway and we believe some will show promise as potential therapeutic agents.  In addition to screening for inhibitors of toxin transport, we have developed approaches to identify inhibitors of the toxin activity of shiga, ricin and the toxins produced by Clostridium difficile.  We anticipate that some of these inhibitors will be developed as new therapies against toxin-mediated disease.