Toxoplasmastrikes preemptively to swiftly suppress macrophage immune response during active infection
Authors: Murza Dominykas , Lastovka Filip , Wood George , Brember Matthew P. , Chan Ollie , Ajioka James W. , Chung Betty Y. W. 
Published: February 2025

The apicomplexan parasiteToxoplasma gondiiis known to manipulate its host in multiple ways, ranging from proteins secreted into the host cell to hormone balance disruption and behavioral changes. Host immune system is crucial in managing the outcome with macrophages as part of the first line of defense. However, the initial triggers that ultimately result in characteristic complex responses and, at times, health hazards, remain poorly understood. This study focuses on filling the gaps in our knowledge of acute transcriptomic changes taking place in a mouse macrophageT. gondiiinfection model. We performed time-resolved transcriptomic profiling to simultaneously capture host and parasite gene expression profiles during the course of infection, focusing on the initial time frame of fifteen to 120 minutes, a crucial window for the host to activate innate immunity but also for the parasite to establish within the host macrophage. Further, utilization of inactivated parasite stimulation enabled dissection of transcriptomic response to active parasite infection from innate immune responses. Here, we observed that macrophages upregulate transcripts encoding suppressors of cytokine signaling by 30 minutes, specific to live parasite infection. Additionally, both pro-growth and stress marker genes were dysregulated. Concurrently, transcriptional response ofT. gondiiwas milder in magnitude, with initial changes pointing at increasing transcription and growth capacity, followed by a delayed transcriptional response pertaining to secreted proteins. Taken together, these results demonstrate that macrophages mount a rapid transcriptional response upon active invasion byT. gondii. In contrast, the delayed transcriptional activation in the invadingToxoplasmahighlights its reliance on alternative regulatory mechanisms to establish its replicative niche within the host.

Author summary

Toxoplasma gondii,a eukaryotic intracellular parasite, is often regarded as one of the most globally successful parasites because it can infect virtually any warm-blooded animal. It uses a repertoire of secretory proteins to gain a foothold in a host cell, often resulting in a dormant infectionin vivodue to sufficient immune suppression. However, the timing of the signaling events asToxoplasmainvades is not yet fully understood. In this work we implement our user-friendly transcriptomic method to simultaneously captureT. gondiiand murine macrophage protein-coding RNA contents over a time course to track cellular responses during infection. In particular, we focus on the first 2 hours of infection, a time window where the initial transcriptomic changes within macrophage are generally expected to take place and potentially define further course of infection. Our analysis reveals a robust host macrophage immune response and a moderate more gradualT. gondiiresponse. These findings complement the currently existing picture of all the cellular regulation layers involved inToxoplasma–macrophage interaction.