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CHARACTERIZATION OF A NOVEL AB5 CYTOTOXIN

Award Number: R01AI068715
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2006
PERIOD OF PERFORMANCE END DATE: 11/30/2011

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CHARACTERIZATION OF A NOVEL AB5 CYTOTOXIN - We have recently discovered a novel "Subtilase cytotoxin" produced by a strain of Shiga toxigenic Escherichia coli (a category B Priority Pathogen) that was responsible for an outbreak of hemolytic uremic syndrome (HUS). It belongs to a new class of AB5 cytotoxins, because its A subunit has distinct enzymic activity and it has no sequence similarity with any of the other AB5 toxin families (cholera, Shiga and pertussis toxins). Subtilase cytotoxin is extraordinarily cytotoxic for cultured cells and is lethal for mice (with histopathology similar to that of HUS). Apart from its possible role in severe human disease, it is a potential bioterrorism agent which could have global impact. The long-term objective of this response to PA-04-119 is complete structural and functional characterization of the emerging toxin. Its Specific Aims are: 1. Elucidation of the molecular basis for cytotoxicity. A subunit Subtilase-like serine protease activity is essential for cytotoxicity, and preliminary data indicate that the ER chaperone BiP is a key cellular target for the toxin. In this Aim, we will continue our investigation of the molecular basis for cytotoxicity by examining the downstream consequences of BiP cleavage, including whether this results in ER stress and apoptosis. 2. Investigation of toxin trafficking in target cells. We hypothesize that after binding to the cell surface, the toxin must undergo retrograde transport to the ER in order to exert its toxic effects. Intracellular toxin trafficking will therefore be examined by co-localization of labelled toxin with cellular compartmental markers using confocal microscopy. 3. Examination of tissue tropism and in vivo effects of the toxin. The distribution of toxin receptors in mouse tissues and trafficking of labelled toxin in vivo will be examined using fluorescence, confocal and electron microscopy. The direct contribution of Subtilase cytotoxin to the pathogenesis of STEC disease will also be investigated in a mouse model. 4. Determination of the 3Dstructure of the toxin. X-ray crystallography and computer modelling will be used to solve the 3D structure. Relevance: This project will provide essential information on the basic biology of this emerging toxin, particularly its structure and the mechanism whereby it damages cells and tissues. This will provide a foundation for the future development of countermeasures including therapeutic agents and vaccines.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2011 ( Subtotal = $257,004 )
2011	2011	UNIVERSITY OF ADELAIDE	PULTNEY STREET	ADELAIDE				AUS	Allergy and Infectious Diseases Research	000	5	11/8/2010	NON-COMPETING CONTINUATION	$236,001
2011	2011	UNIVERSITY OF ADELAIDE	PULTNEY STREET	ADELAIDE				AUS	Allergy and Infectious Diseases Research	001	5	6/8/2011	NON-COMPETING CONTINUATION	$21,003
														Subtotal = $257,004

Issue Date FY: 2010 ( Subtotal = $262,222 )
2010	2010	UNIVERSITY OF ADELAIDE	PULTNEY STREET	ADELAIDE				AUS	Allergy and Infectious Diseases Research	001	4	6/3/2010	NON-COMPETING CONTINUATION	$23,838
2010	2010	UNIVERSITY OF ADELAIDE	PULTNEY STREET	ADELAIDE				AUS	Allergy and Infectious Diseases Research	000	4	12/2/2009	NON-COMPETING CONTINUATION	$238,384
														Subtotal = $262,222

Issue Date FY: 2009 ( Subtotal = $264,871 )
2009	2009	UNIVERSITY OF ADELAIDE	PULTNEY STREET	ADELAIDE				AUS	Allergy and Infectious Diseases Research	001	3	7/21/2009	NON-COMPETING CONTINUATION	$26,487
2009	2009	UNIVERSITY OF ADELAIDE	PULTNEY STREET	ADELAIDE				AUS	Allergy and Infectious Diseases Research	000	3	11/18/2008	NON-COMPETING CONTINUATION	$238,384
														Subtotal = $264,871

Issue Date FY: 2008 ( Subtotal = $264,871 )
2008	2008	UNIVERSITY OF ADELAIDE	PULTNEY STREET	ADELAIDE		00000		AUS	Allergy and Infectious Diseases Research	000	2	12/17/2007	NON-COMPETING CONTINUATION	$264,871
														Subtotal = $264,871

Issue Date FY: 2007 ( Subtotal = $272,000 )
2007	2007	UNIVERSITY OF ADELAIDE	PULTNEY STREET	ADELAIDE		00000		AUS	Allergy and Infectious Diseases Research	000	1	12/7/2006	NEW	$272,000
														Subtotal = $272,000

Grand Total All Awards = $1,320,968

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CHARACTERIZATION OF A NOVEL AB5 CYTOTOXIN

Award Number: R01AI068715

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/15/2006

PERIOD OF PERFORMANCE END DATE: 11/30/2011

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