Chagas disease (CHD) caused by Trypanosoma cruzi (T. cruzi) is endemic in Latin America and an emerging disease in the US and other developed countries. The overall prevalence of human T. cruzi infection is at ~16-18 million cases, and ~120 million people are at risk of infection. CHD is a complex disease with two clinically distinct phases: acute Chagas disease, which appears shortly after infection and lasts 4-8 weeks, and chronic Chagas disease, which develops from an asymptomatic indeterminate form to a chronic symptomatic phase 10-30 years later in about one-third of all cases. Immunopathology due to parasite persistence is considered a key element in the development of chagasic cardiomyopathy. The overall goal of these studies is to gain insight into how T. cruzi dysregulate macrophages to enhance its survival and whether activation of inflammasomes is useful in controlling parasite burden. Our hypothesis is that T. cruzi escapes macrophage-mediated clearance by a suboptimal activation of inflammasomes and IL-1? and the resultant parasite persistence establishes an atmosphere conducive to chronic disease. We propose that parasite molecules (e.g. kinetoplast (kDNA)) and host molecules (i.e. mitochondrial DNA (mtDNA)) are released during infection and provide a signal for the activation of inflammasomes in macrophages. This study will also focus on the role of host cell mtDNA (DAMPs) and kDNA (PAMPs) of T. cruzi in inflammasome activation to gain an insight into the relative contribution of each during T. cruzi pathogenesis and the evolution of Chagasic cardiomyopathy. These hypotheses will be examined by two specific aims:
AIM 1 : To test the hypothesis that T. cruzi infection of macrophages results in suboptimal ROS dependent inflammasome activation and IL-1? production, and contributes to parasite survival.
Aim 2 : To test the hypothesis that T. cruzi kinetoplast DNA (kDNA) and host mitochondrial DNA (mtDNA) direct inflammasome activation in macrophages. Our results will pave the way for designing therapeutic interventions against this debilitating disease.

Public Health Relevance

Chagas disease caused by the parasite Trypanosoma cruzi (T. cruzi) is endemic in Latin America and an emerging disease in the US and other developed countries. Drug development against Chagas disease has been dramatically limited because of extensive debate on how this parasite causes human infection. Our study is designed to determine how this infection is caused and thus pave the way for designing therapeutic interventions against this debilitating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
1R03AI103771-01A1
Application #
8584044
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Wali, Tonu M
Project Start
2013-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$77,250
Indirect Cost
$27,250
Name
University of Texas Medical Br Galveston
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555