Temporal analysis of mRNA expression profiles in Orientia infected C3HeB/FeJ mouse

Chien-Chung Chao,Rasha Hammamieh,Stacy-Ann Miller,Ruoting Yang,Wei-Mei Ching,Chye-Teik Chan,Marti Jett,Tatyana Belinskaya,Zhiwen Zhang

doi:10.1186/s12866-019-1684-3

Abstract

BackgroundScrub typhus causes up to 35% mortality if left untreated. One billion people living in the endemic regions are at risk. In spite of its heavy disease burden in some of the most populated areas in the world, there is no vaccine available. Although the disease can be effectively treated by proper antibiotics, timely and accurate diagnosis remains a challenge. Orientia tsutsugamushi infects a variety of mammalian cells in vitro and replicates in the cytoplasm of the infected cells. Microarray analysis has been used extensively to study host-pathogen interactions in in vitro models to understand pathogenesis. However there is a lack of in vivo studies.ResultsIn this study, C3HeB/FeJ (C3H) mice were infected by O. tsutsugamushi via the intraperitoneal route and monitored gene expression at 10 different time points post infection. We observed two distinct types of expression profiles in the genes that we analyzed. There are two valleys (4–18 h and 2–4 days) with low number of differentially expressed genes (DEG) with three peaks with high number of DEG at 2 h, 1-day and 7-day post infection. Further analysis revealed that pathways like complement and coagulation cascade, and blood clotting cascade pathways showed significant global changes throughout entire time course. Real time quantitative Polymerase Chain Reaction (RT-qPCR) confirmed the change of expression for genes involved in complement and coagulation cascade. These results suggested dynamic regulation of the complement and coagulation cascades throughout most of the time post infection while some other specific pathways, such as fatty acid metabolism and tryptophan metabolism, are turned on or off at certain times post infection.ConclusionsThe findings highlight the complex interconnection among all different biological pathways. It is conceivable that specific pathways such as cell growth control and cell development in the host are affected by Orientia in the initial phase of infection for Orientia to grow intracellularly. Once Orientia is replicating successfully inside the host as infection progresses, the infection could activate pathways involved in cellular immune responses to defend for host cell survival and try to eliminate the pathogen.

Highlights

Scrub typhus causes up to 35% mortality if left untreated
The IP challenge route resulted in dissemination of Orientia to different tissues in a time-dependent fashion with the maximum copy number of Orientia detected in the liver
The infection by chiggers may involve an exchange of proteins between chigger and animal host, while IP injection does not. It is Conclusions Many pathways are dynamically regulated at different time points post Orientia IP infection in a mouse model

Summary

Introduction

Scrub typhus causes up to 35% mortality if left untreated. One billion people living in the endemic regions are at risk. Scrub typhus is endemic within a “tsutsugamushi” triangle area that is about 13 million square kilometers which includes Pakistan, India and Nepal to the west, Japan to the east, southeastern Siberia, China, and Korea to the north and Indonesia, Philippines, northern Australia and the intervening Pacific islands to the south [3,4,5,6,7,8,9,10,11,12] This area is one of the most populated areas and an estimated 1 billion people living in this area are at risk. Cases of ineffective doxycycline treatment have been documented in Thailand and India, suggesting the potential rise of antibiotic resistant strains of O. tsutsugamushi in endemic areas [18, 19]

Methods

Results

Discussion

Conclusion