Cryptosporidiosis is a diarrheal disease that disproportionately affects children and immunocompromised adults. The WHO estimates that in 2010, diarrheal disease accounted for 10.5% of deaths in children under the age of five, with the majority of childhood deaths occurring in Africa and Southeast Asia. In developing countries, malnutrition exacerbates diarrheal episodes and prolongs infection. These prolonged childhood infections are known to cause destructive, permanent effects, such as stunted growth, developmental delay, and cognitive deficiency. Of the known diarrheal diseases, cryptosporidiosis appears to one of the most deadly. Tryptophan synthesis enables intracellular bacteria such as Mycobacterium tuberculosis and Chlamydia trachomatis to evade a key mechanism of host innate immunity, IFN-? induced tryptophan catabolism. Through horizontal gene transfer, Cryptosporidium has acquired a bacterial tryptophan synthase gene, tryptophan synthase beta (CpTrpB), and we believe that this gene acquisition was a crucial step to adaptation to the mammalian intestine. We will evaluate the role of CpTrpB in Cryptosporidium metabolism, growth, and survival during host tryptophan catabolism. In this project we propose to 1) define the metabolic activity of CpTrpB during host tryptophan catabolism, both in vitro and in vivo, and 2) determine the impact of CpTrpB gene loss on Cryptosporidium parvum through genetic analysis. The unique tryptophan metabolism in Cryptosporidium is an attractive target for drug development and pathogen attenuation, and studying CpTrpB offers the opportunity to explore the biology of a novel parasite pathogenesis factor.

Public Health Relevance

The objective of this project is to study the horizontally transferred gene, tryptophan synthase beta (CpTrpB), and its effect on Cryptosporidium pathogenesis. Our working hypothesis is that CpTrpB was acquired by Cryptosporidium to evade an important mechanism of immunity in the host intestine, tryptophan catabolism. Therefore, we will evaluate the role of CpTrpB in Cryptosporidium metabolism, growth, and survival during host tryptophan catabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI124518-01
Application #
9122057
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Joy, Deirdre A
Project Start
2016-08-01
Project End
2017-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Georgia
Department
Public Health & Prev Medicine
Type
Organized Research Units
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Manjunatha, Ujjini H; Vinayak, Sumiti; Zambriski, Jennifer A et al. (2017) A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis. Nature 546:376-380
Pawlowic, Mattie C; Vinayak, Sumiti; Sateriale, Adam et al. (2017) Generating and Maintaining Transgenic Cryptosporidium parvum Parasites. Curr Protoc Microbiol 46:20B.2.1-20B.2.32