During chronic opisthorchiasis, pathogenesis is manifested in a series of well-defined stages as the normal tissue architecture of the biliary epithelium is progressively remodeled by the chronic inflammatory response from repeated injury sustained by the biliary epithelium from a combination ofthe mechanical, toxic, and immune mechanisms of the fluke in the bile duct. As individuals are infected with O. viverrini for many years (often a lifetime), a persistent cycle of tissue damage and repair takes place in the intrahepatic biliary ducts, creating a chronic inflammatory milieu that stimulates periductal fibrogenesis and provides the """"""""smoldering and polarized"""""""" inflammatory basis for malignant transformation of biliary epithelial cells to cholangiocarcinoma (CCA). In project 1, we hypothesize the existence of a pro-inflammatory phenotype which is characterized by a inflammatory cytokine dysregulation such that, even after removal ofthe pathogen by PZQ, individuals with the pro-inflammatory phenotype continue to produce high levels of IL-6 and an unreversed (i.e., persistent) form of Advanced Periductal Fibrosis (APF). We further hypothesize that this persistent APF provides the basis for malignant transformation to CCA. Project 1 ofthe TMRC will focus on the processes involved in this chronic inflammatory phenotype and the progression from infection to persistent APF and eventually to malignant transformation (CCA) by undertaking the following specific aims: (1) continuing our a community-based cohort study for the risk factors associated with Advanced Periductal Fibrosis in villages with high O. viverrini transmission along the Chi River basin in Khon Kaen, Thailand to stratify infected individuals into those with """"""""resolved"""""""" and """"""""persistent"""""""" Advanced Periductal Fibrosis;(2) to determine the host inflammatory cytokine signaling pathways, such as the IL-6 signaling pathways, induced during chronic O. viverrini infection on the risk of progressing either resolved or persistent advanced periductal fibrosis, and bile duct cancer;and (3) examine the genetic diversity ofthe O. viverrini parasite by microsatellite DNA analysis and its association with resolved and persistent forms advanced periductal fibrosis. .

Public Health Relevance

Individuals residents in O. viverrini endemic areas can remain infected for a lifetime. However, only 25% of O. viverrini-infected individuals develop periductal fibrosis and 1 % progress to CCA. The observation that individuals living under similar transmission conditions show differing rates of APF and CCA indicates a strong role for diverse host and parasite factors in the disease process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center (P50)
Project #
4P50AI098639-02
Application #
8495206
Study Section
Special Emphasis Panel (ZAI1-AWA-M)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$174,501
Indirect Cost
$11,079
Name
Khon Kaen University
Department
Type
DUNS #
659454446
City
Khon Kaen
State
Country
Thailand
Zip Code
40002
Chaiyadet, Sujittra; Smout, Michael; Laha, Thewarach et al. (2017) Proteomic characterization of the internalization of Opisthorchis viverrini excretory/secretory products in human cells. Parasitol Int 66:494-502
Deenonpoe, Raksawan; Mairiang, Eimorn; Mairiang, Pisaln et al. (2017) Elevated prevalence of Helicobacter species and virulence factors in opisthorchiasis and associated hepatobiliary disease. Sci Rep 7:42744
van Tong, Hoang; Brindley, Paul J; Meyer, Christian G et al. (2017) Parasite Infection, Carcinogenesis and Human Malignancy. EBioMedicine 15:12-23
Sripa, Banchob; Deenonpoe, Raksawan; Brindley, Paul J (2017) Co-infections with liver fluke and Helicobacter species: A paradigm change in pathogenesis of opisthorchiasis and cholangiocarcinoma? Parasitol Int 66:383-389
Kim, Christina Sunyoung; Smith, John F; Suwannatrai, Apiporn et al. (2017) Role of socio-cultural and economic factors in cyprinid fish distribution networks and consumption in Lawa Lake region, Northeast Thailand: Novel perspectives on Opisthorchis viverrini transmission dynamics. Acta Trop 170:85-94
Echaubard, Pierre; León, Tomas; Suwanatrai, Kulwadee et al. (2017) Experimental and modelling investigations of Opisthorchis viverrini miracidia transmission over time and across temperatures: implications for control. Int J Parasitol 47:257-270
Vinh, Hoang Quang; Phimpraphai, Waraphon; Tangkawattana, Sirikachorn et al. (2017) Risk factors for Clonorchis sinensis infection transmission in humans in northern Vietnam: A descriptive and social network analysis study. Parasitol Int 66:74-82
Van, Chinh Dang; Doungchawee, Galayanee; Suttiprapa, Sutas et al. (2017) Association between Opisthorchis viverrini and Leptospira spp. infection in endemic Northeast Thailand. Parasitol Int 66:503-509
Hanpanich, Petcharakorn; Laha, Thewarach; Sripa, Banchob et al. (2017) Decreased risk of cholangiocarcinogenesis following repeated cycles of Opisthorchis viverrini infection-praziquantel treatment: Magnetic Resonance Imaging (MRI) and histopathological study in a hamster model. Parasitol Int 66:464-470
Maksimova, Galina A; Pakharukova, Maria Y; Kashina, Elena V et al. (2017) Effect of Opisthorchis felineus infection and dimethylnitrosamine administration on the induction of cholangiocarcinoma in Syrian hamsters. Parasitol Int 66:458-463

Showing the most recent 10 out of 50 publications