Abstract
Toxoplasma gondii is a resilient parasite that infects a multitude of warm-blooded hosts and results in a lifelong chronic infection requiring continuous responses by the host. Chronic infection is characterized by a balanced immune response and neuropathology that are driven by changes in gene expression. Previous research pertaining to these processes has been conducted in various mouse models, and much knowledge of infection-induced gene expression changes has been acquired through the use of high throughput sequencing techniques in different mouse strains and post-mortem human studies. However, lack of infection time course data poses a prominent missing link in the understanding of chronic infection, and there is still much that is unknown regarding changes in genes specifically relating to neuropathology and resulting repair mechanisms as infection progresses throughout the different stages of chronicity. In this paper, we present a targeted approach to gene expression analysis during T. gondii infection through the use of NanoString nCounter gene expression assays. Wild type C57BL/6 and BALB/c background mice were infected, and transcriptional changes in the brain were evaluated at 14, 28, and 56 days post infection. Results demonstrate a dramatic shift in both previously demonstrated and novel gene expression relating to neuropathology and resolution in C57BL/6 mice. In addition, comparison between BALB/c and C57BL/6 mice demonstrate initial differences in gene expression that evolve over the course of infection and indicate decreased neuropathology and enhanced repair in BALB/c mice. In conclusion, these studies provide a targeted approach to gene expression analysis in the brain during infection and provide elaboration on previously identified transcriptional changes and also offer insights into further understanding the complexities of chronic T. gondii infection.
Highlights
Toxoplasma gondii is a resilient parasite that infects ~ 10% of the population older than 6 years in the United States alone and more than 60% of populations in other countries worldwide (Prevention, 2018)
To determine broad transcriptomic changes that occur over the course of infection, RNA from infected C57BL/6 mouse brains was harvested at day 14, 28 and 56 days post infection representing time points associated with transitionary, stable and late chronic infection respectively
While much is known about changes in gene expression at specific stages of infection via commonly used sequencing techniques like RNAseq, there is a gap in knowledge regarding how gene expression fluctuates as infection progresses through chronicity and how these changes relate to development of the parasite (Montoya and Liesenfeld, 2004; Jia et al, 2013; Ngô et al, 2017)
Summary
Toxoplasma gondii is a resilient parasite that infects ~ 10% of the population older than 6 years in the United States alone and more than 60% of populations in other countries worldwide (Prevention, 2018). The parasite itself goes through genetic changes in order to convert from a fast-replicating tachyzoite during acute systemic infection to a cyst-forming bradyzoite during the early stage of chronic infection after crossing the blood brain barrier (Lachenmaier et al, 2011; Feustel et al, 2012; Hong et al, 2017; Radke et al, 2018). Control of infection is maintained for the lifetime of the host and pathology at this stage can vary depending on the genetics of the parasite as well as the background of the host (Liesenfeld et al, 1996; Denkers, 1999; Lee and Kasper, 2004; Lilue et al, 2013; Mukhopadhyay et al, 2020) These changes in parasite phenotype, host immune response, and neuropathology have yet to be fully explored in the context of progressive chronic infection
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