Gene expression and involvement of signaling pathways during host-pathogen interplay in Orientia tsutsugamushi infection

Abstract

Scrub typhus is a neglected tropical disease that affects one-third of the world's population. The disease is caused by Orientia tsutsugamushi (OT), an obligate intracellular Gram-negative bacterium. OT efficiently escapes from the endosomal pathway after entering the host cell and replicates inside cytosol. OT infection promotes cellular autophagy, the autonomous defense mechanism unlike other bacteria. This study has discussed the bacterial invasion process through the extracellular matrix and the immune response activated by the bacterium within the hosts. Furthermore, we have emphasized the importance of extracellular matrix and their cross-talk with the immune cells, such as, macrophages, neutrophils, and dendritic cells followed by their inflammatory response. We have also put an insight into the host factors associated with signaling pathways during scrub typhus disease with a special focus on the OT-induced stress response, autophagy, apoptosis, and innate immunity. Multiple cytokines and chemokines play a significant role in activating different immune-related signaling pathways. Due to the presence of high antigenic diversity among strains, the signaling pathways during the host-pathogen interplay of OT with its host is very complicated. Thus, it hinders to mitigate the severity of the pandemic occurred by the respective pathogen. Our investigation will provide a useful guide to better understand the virulence and physiology of this intracellular pathogen which will lead towards a better therapeutic diagnosis and vaccine development.

Keywords: Gene expression; Host–pathogen interaction; Inflammatory response; Orientia tsutsugamushi.

Fig. 1

The genome structure of Orientia tsutsugamushi showing genome size, CDS, distribution of Simple Sequence Repeats (SSR) markers, and GC content. The outermost red rays show the replication rate of each chromosomal region. Origin of replication (Ori) is on the top. The feature of the genome moving inwards from the outermost region shows; Red: repeated genes, Black: singleton gene, Green: core gene, Blue: pseudogene, Orange: OtAGE forward sequence, Greenish yellow: OtAGE reverse sequence

Fig. 2

The repetitive cellular cycle of Orientia tsutsugamushi in nonphagocytic cells. It represents the detailed overview of the invasion and internalization process of OT as well as the active escape process. Different proteins involved in this process were mentioned inside. Invasion of the host through primary barriers, bacterial invasion of host defense, bacterial replication within-host, and host immunological competence to control/eliminate the pathogens are the four phages of host–pathogen interaction represented in this figure

Fig. 3

The participation of 2-ABP can block the increased in Orientia tsutsugamushi induced TNF-α and Ca2 + signaling activity. Ca2 + metabolism can also decrease TNF-α release and expression. TNF-α production can be regulated by the MAPK pathway. 2-ABP inhibits the JNK and p38 signaling pathways while activating ERK to enhance HSP70 over expression. HSP70 inhibits the translocation of NF-κB and suppresses TNF-α expression

Fig. 4

Model of signaling and gene regulatory mechanisms of TNF-α biosynthesis during Orientia tsutsugamushi infection. Orientia tsutsugamushi stimulates receptor(s) and activates host MAPK and NF-κB signaling pathways. Signals from NF-κB and ERK pathways are required to promote strong transcription. Formation of enhanceosome was followed. NF-κB and other transcription factors interact with DNA, co-activators such as CBP/p300, and the RNA polymerase II holoenzyme. Transport of TNF-α mRNA is facilitated by ERK pathway