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Structure and Function of C. Difficile Toxins

Award Number: R01AI139087
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: 05/15/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Structure and Function of C. Difficile Toxins - Project Summary Clostridioides difficile infection (CDI) is a leading cause of gastrointestinal infections in developed countries, with a quarter million estimated cases and ~30,000 deaths annually in the United States. The threat of CDI has become exacerbated with the emergence and spreading of growing numbers of new hypervirulent strains. The C. difficile toxin B (TcdB) is a major virulence factor responsible for pathogenesis associated with CDI. Hypervirulent strains often express variants of TcdB containing 3-15% sequence variations from the standard TcdB. These sequence differences affect toxin tropism and virulence and poses a major challenge for developing therapeutic antibodies. Our studies during the prior funding period categorized TcdB into 12 subtypes and found that many subtypes do not share the same receptor profile with the standard TcdB. Here our renewal proposal seek to characterize the structure and function of major TcdB variants, aiming to identify their unique receptor and investigate their virulence in vivo (Aim 1), resolve the toxin-receptor complex structure using the co-crystal structural approach and cryo- EM method (Aim 2), and develop and characterize a new generation of pan-neutralizing antibodies against a broad range of TcdB variants (Aim 3). Our studies are built on a long-standing and fruitful collaborations between a structural biology lab (Dr. Rongsheng Jin’s lab at the University of California – Irvine) and a lab focusing on toxin biology and virulence (Dr. Min Dong’s lab at Boston Children’s Hospital). The success of our proposed studies will provide a mechanistic understanding of the specificity and virulence of major TcdB variants associated with epidemic hypervirulent strains and provide novel pan-neutralizing antibodies to address the unmet medical need to treat CDI patients infected with hypervirulent strains.


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: 2026 ( Subtotal = $3,307,473 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	6	4/1/2026	COMPETING CONTINUATION	$3,307,473
														Subtotal = $3,307,473

Issue Date FY: 2025 ( Subtotal = -$57,838 )
2025	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	11/22/2024	NON-COMPETING CONTINUATION	-$57,838
														Subtotal = -$57,838

Issue Date FY: 2022 ( Subtotal = $787,630 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	4/22/2022	NON-COMPETING CONTINUATION	$787,630
														Subtotal = $787,630

Issue Date FY: 2021 ( Subtotal = $797,212 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	4/1/2021	NON-COMPETING CONTINUATION	$797,212
														Subtotal = $797,212

Issue Date FY: 2020 ( Subtotal = $804,015 )
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	4/22/2020	NON-COMPETING CONTINUATION	$804,015
														Subtotal = $804,015

Issue Date FY: 2019 ( Subtotal = $816,888 )
2019	2019	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	4/11/2019	NON-COMPETING CONTINUATION	$816,888
														Subtotal = $816,888

Issue Date FY: 2018 ( Subtotal = $848,063 )
2018	2018	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	5/15/2018	NEW	$848,063
														Subtotal = $848,063

Grand Total All Awards = $7,303,443

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Structure and Function of C. Difficile Toxins

Award Number: R01AI139087

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: 05/15/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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