Robust Control of a Brain-Persisting Parasite through MHC I Presentation by Infected Neurons

Salvioni, Anna; Belloy, Marcy; Lebourg, Aurore; Bassot, Emilie; Cantaloube-Ferrieu, Vincent; Vasseur, Virginie; Blanié, Sophie; Liblau, Roland; Suberbielle, Elsa; Robey, Ellen; Blanchard, Nicolas

doi:10.1016/j.celrep.2019.05.051

Cited by 50 publications

(56 citation statements)

References 71 publications

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“…Collectively, these data are consistent with prior work showing upregulated inflammatory pathways and an increase in immune cell infiltration in the CNS during infection ( 49 – 52 ). Our identification of immune cell transcripts within our “neuron” transcriptomes and visualization of CD3 + T cells suggest our samples contain transcripts from nonneuronal cells, such as CD8 + T cells, that may be in extreme proximity to the isolated neurons.…”

Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

“…We chose to use type II-infected mice because the transcripts from type II TINs showed the highest level of T cell contamination ( Fig. 4B ) and recent elegant work by the Blanchard lab has indirectly suggested that CD8 + T cells interact with neurons infected with type II parasites in vivo ( 49 ). To evaluate the distance between T cells and TINs or Bystander neurons, 200-μm-thick brain sections from type II-infected mice were optically cleared and stained using anti-CD3ε antibodies and NeuroTrace fluorescent Nissl stain to identify T cells and neurons, respectively ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Transcriptional Profiling Suggests T Cells Cluster around Neurons Injected with Toxoplasma gondii Proteins

Merritt

Johnson

Wong

et al. 2020

mSphere

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Toxoplasma gondii’s tropism for and persistence in the central nervous system (CNS) underlies the symptomatic disease that T. gondii causes in humans. Our recent work has shown that neurons are the primary CNS cell with which Toxoplasma interacts and which it infects in vivo. This predilection for neurons suggests that T. gondii’s persistence in the CNS depends specifically upon parasite manipulation of the host neurons. Yet, most work on T. gondii-host cell interactions has been done in vitro and in nonneuronal cells. We address this gap by utilizing our T. gondii-Cre system that allows permanent marking and tracking of neurons injected with parasite effector proteins in vivo. Using laser capture microdissection (LCM) and RNA sequencing using RNA-seq, we isolated and transcriptionally profiled T. gondii-injected neurons (TINs), Bystander neurons (nearby non-T. gondii-injected neurons), and neurons from uninfected mice (controls). These profiles show that TIN transcriptomes significantly differ from the transcriptomes of Bystander and control neurons and that much of this difference is driven by increased levels of transcripts from immune cells, especially CD8+ T cells and monocytes. These data suggest that when we used LCM to isolate neurons from infected mice, we also picked up fragments of CD8+ T cells and monocytes clustering in extreme proximity around TINs and, to a lesser extent, Bystander neurons. In addition, we found that T. gondii transcripts were primarily found in the TIN transcriptome, not in the Bystander transcriptome. Collectively, these data suggest that, contrary to common perception, neurons that directly interact with or harbor parasites can be recognized by CD8+ T cells. IMPORTANCE Like other persistent intracellular pathogens, Toxoplasma gondii, a protozoan parasite, has evolved to evade the immune system and establish a chronic infection in specific cells and organs, including neurons in the CNS. Understanding T. gondii’s persistence in neurons holds the potential to identify novel, curative drug targets. The work presented here offers new insights into the neuron-T. gondii interaction in vivo. By transcriptionally profiling neurons manipulated by T. gondii, we unexpectedly revealed that immune cells, and specifically CD8+ T cells, appear to cluster around these neurons, suggesting that CD8+ T cells specifically recognize parasite-manipulated neurons. Such a possibility supports evidence from other labs that questions the long-standing dogma that neurons are often persistently infected because they are not directly recognized by immune cells such as CD8+ T cells. Collectively, these data suggest we reconsider the broader role of neurons in the context of infection and neuroinflammation.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Transcriptional Profiling Suggests T Cells Cluster around Neurons Injected with Toxoplasma gondii Proteins

Merritt

Johnson

Wong

et al. 2020

mSphere

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“…Collectively, these data are consistent with previous work which has shown upregulated inflammatory pathways and an increase in immune cell infiltrate during infection [48][49][50][51] . Our identification of immune cell transcripts within our "neuron" transcriptomes suggest our samples contain transcripts from nonneuronal cells, such as CD8 + T cells, that were in extremely close proximity to the isolated neurons.…”

Section: Bystanderssupporting

confidence: 93%

“…6). While future work will focus on distinguishing between these possibilities, either model adds to the growing literature that, contrary to dogma, infected neurons have robust immune responses to microbes and cytokines and can present antigens to T cells in vivo 7,59,50 .…”

Section: Especially Cd8 T Cells Hone-in On Tinsmentioning

confidence: 99%

Transcriptional profiling reveals T cells cluster around neurons injected withToxoplasma gondiiproteins

Merritt

Johnson

Wong

et al. 2020

Preprint

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Toxoplasma gondii's tropism for and persistence in the CNS underlies the symptomatic disease Toxoplasma causes in humans. Our recent work has shown that neurons are the primary CNS cell with which Toxoplasma interacts and infects in vivo.This predilection for neurons suggests that Toxoplasma's persistence in the CNS depends specifically upon parasite manipulation of the host neurons. Yet, most work on Toxoplasma-host cell interactions has been done in vitro and in non-neuronal cells. We address this gap by utilizing our Toxoplasma-Cre system that allows permanent marking and tracking of neurons injected with parasite effector proteins in vivo. Using laser capture microdissection (LCM) and RNA-seq, we isolated and transcriptionally profiled Toxoplasma-injected neurons (TINs), Bystander neurons (nearby non-Toxoplasma injected neurons), and neurons from uninfected mice (controls). These profiles show that TINs transcriptomes significantly differ from the transcriptomes of Bystander and control neurons and that much of this difference is driven by increased levels of transcripts from immune cells, especially CD8 + T cells and monocytes. These data suggest that when we used LCM to isolate neurons from infected mice, we also picked up fragments of CD8 + T cells and monocytes clustering in extreme proximity around TINs and, to a lesser extent, Bystander neurons. In addition, we found that Toxoplasma transcripts were primarily found in the TINs transcriptome, not in the Bystander transcriptome. Collectively, these data suggest that, contrary to common perception, neurons that directly interact with or harbor parasites can be recognized by CD8 + T cells.

show abstract

Cerebral toxoplasmosis

Koshy¹,

Harris²,

Lodoen³

2020

Toxoplasma Gondii

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Robust Control of a Brain-Persisting Parasite through MHC I Presentation by Infected Neurons

Cited by 50 publications

References 71 publications

Transcriptional Profiling Suggests T Cells Cluster around Neurons Injected with Toxoplasma gondii Proteins

Transcriptional Profiling Suggests T Cells Cluster around Neurons Injected with Toxoplasma gondii Proteins

Transcriptional profiling reveals T cells cluster around neurons injected withToxoplasma gondiiproteins

Cerebral toxoplasmosis

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