Host-pathogen interaction in leptospirosis

Active Project Grant Awarded Last action

Award ID
P01AI168148
Recipient
Awarding agency
Obligated
$25,482,816

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 69% complete
Place of performance
VETERANS ADMINISTRATION, CA 90073, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Overall component leptospirosis is a widespread and frequently fatal human health problem that disproportionately impacts low resource settings. Research on host-pathogen dynamics in leptospirosis are significant because little is known about leptospiral virulence factors or host response to leptospirosis. The proposed studies will involve highly synergistic collaborations between program project investigators who are leaders in studies of leptospiral virulence genes (haake and picardeau), endothelial interactions (coburn), inflammasome pathways (sutterwala), and field studies of acute febrile illness (reller and woods). With the description of many new leptospiral genomes, a striking pattern of massive species diversity has emerged leading to central hypothesis #1, which is that a core set of leptospiral virulence factors have evolved with roles in survival in mammalian host phagocytes, translocation, and dissemination, which are upregulated in response to the host microenvironment. Central hypothesis #1 will be tested by correlating genome-scale leptospiral evolutionary changes with virulence phenotypes, examining the roles of transcriptional regulators and non-coding small rnas in adaptation to and survival within host phagocytes, and translocation across endothelial barriers. The correlation of inflammatory markers such as IL-1SS levels with disease severity leads to central hypothesis #2, which is that human inflammatory response pathways drive disease outcomes. Central hypothesis #2 will be tested in vitro (interactions with macrophages and endothelial cells), in animal models (infections in hamsters and mice), and in human field studies in tanzania, nicaragua, and SRI lanka. Specifically, we will follow up on our innovative discovery of a striking dichotomy between the high level of inflammasome activation in human macrophages and the low level in macrophages from mice, which are reservoir hosts and do not exhibit disease. We will also follow up on our innovative discovery of dramatic disruption of endothelial VE-cadherins by pathogenic leptospires in terms of the role of intercellular invasion in dissemination. Animal model studies will provide longitudinal host response data in support of human studies that will have a positive impact through development and validation of rapid biomarker diagnostic and triage tools to identify serious infections at an early stage when antibiotics and other interventions can prevent and/or treat critical illness including fatal hepatorenal failure.

Transactions

Action Obligated Date
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Original award $2,463,023
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Subawards

Subrecipient Amount Awarded
Centro De Investigaciones Tecnologicas, Biomedicas Y Medioambientales Citbm A prospectively enrolled pilot study for hospital-based accrual: Preparation, initiation, and management of participant enrollment, including data management,… $167,178
Northern Arizona University Drs. Nathan Stone and Dave Wagner at Northern Arizona University (NAU) are recognized leaders in genetic and genomic characterization of pathogenic Leptospira… $131,113
The Good Samaritan Foundation Founders Of The Kilimanjaro Christian Medical Centre This project seeks to develop and refine host immune response classifiers that can reliably identify leptospirosis among febrile patients presenting to care… $209,226
Universite DU Quebec The work proposed in this project will therefore seek to identify and characterize bacterial determinants that promote mammalian host adaptation and enable… $56,525
Institut Pasteur The overarching goal of this Core is to supply targeted knock-down mutants, sequencing support and expertise from a centralized facility to the overall Program.… $53,325
Corporacion De Participacion Mixta Instituto Colombiano De Medicina Tropical Antonio Roldan Betancur Margarita Arboleda, MD, PhD is the Medical director, Apartadó branch of Instituto Colombiano de Medicina Tropical (ICMT), which is based in Antioquia… $272,223
Chulalongkorn University Dr. Srisawat will manage the project subaward from UCLA and maintain compliance with US NIH policies. Local research ethics committee and other regulatory… $564,430
The Good Samaritan Foundation Founders Of The Kilimanjaro Christian Medical Centre This project seeks to develop and refine host immune response classifiers that can reliably identify leptospirosis among febrile patients presenting to care… $271,726
Universite DU Quebec The work proposed in this project will therefore seek to identify and characterize bacterial determinants that promote mammalian host adaptation and enable… $55,620
Duke University Aim 1. Expand our biorepository of specimens and metadata from patients with leptospirosis vs other AFI to support development of diagnostic and prognostic host… $2,657,211
Duke University 1. Provide administrative support for international site activities. Primary administrative activities will involve ensuring timely local IRB/ethical approval… $1,082,320
The Medical College Of Wisconsin, Inc. Year 1: Acquire up to 18 sequenced Leptospira isolates from Institut PasteurBegin analysis of these isolates in cell culture and in mice as described in Aim 1… $1,239,108
Institut Pasteur The work proposed in this program project seeks to identify and characterize bacterial determinants that promote mammalian host adaptation and enable… $1,152,696
Cedars-Sinai Medical Center Dr. Sutterwala will be directly involved in both aims of this project. In particular the Sutterwala lab will perform in vitro studies outlined in Aim 1 to… $520,616
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Quick answers

Who received award P01AI168148?

P01AI168148 was awarded to University Of California, LOS Angeles by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on May 16, 2023.

How much is award P01AI168148 worth?

$25,482,816 has been obligated on P01AI168148.

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