Host immune responses to<i>Toxoplasma gondii</i>

Sasai, Miwa; Pradipta, Ariel; Yamamoto, Masahiro

doi:10.1093/intimm/dxy004

Cited by 166 publications

(128 citation statements)

References 90 publications

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“…Conversely, the transcriptomes from infected miceboth Bystander and TINs-showed evidence for moderate-to-high levels of T cell-, monocyte-, and macrophage-specific transcripts. These data are consistent with prior evidence that, during CNS infection with T. gondii, these cell types infiltrate into the CNS and significantly contribute to the control of CNS toxoplasmosis 41,42,10,[43][44][45][46][47] . Consistent with TINs showing higher levels of immune pathways ( Fig.…”

Section: Bystanderssupporting

confidence: 92%

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.

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Section: Bystanderssupporting

confidence: 92%

Transcriptional profiling reveals T cells cluster around neurons injected withToxoplasma gondiiproteins

Merritt

Johnson

Wong

et al. 2020

Preprint

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“…It has been well-established that T. gondii-mediated type I immunity requires DCs for host defense [25][26][27][28][29]. Work from our lab and others have demonstrated that DC-deficiency results in acute host susceptibility to T. gondii [26,30].…”

Section: T-bet Is Critical To Maintain Inflammatory Dcs During T Gonmentioning

confidence: 99%

ILC1-derived IFN-γ mediates cDC1-dependent host resistance againstToxoplasma gondii

López-Yglesias

Burger

Camanzo

et al. 2020

Preprint

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Host resistance against intracellular pathogens requires a rapid IFN- mediated immune response. We reveal that T-bet-dependent production of IFN- is essential for the maintenance of inflammatory DCs at the site of infection with a common protozoan parasite, Toxoplasma gondii. A detailed analysis of the cellular sources for T-bet-dependent IFN- identified that ILC1s, but not NK or T H 1 cells, were involved in the regulation of inflammatory DCs via IFN-.Mechanistically, we established that T-bet dependent ILC1-derived IFN- is critical for the induction of IRF8, an essential transcription factor for cDC1s. Failure to upregulate IRF8 in DCs resulted in acute susceptibility to T. gondii infection. Our data identifies that ILC1-derived IFN- is indispensable for host resistance against intracellular infection via maintaining IRF8+ inflammatory DCs at the site of infection. Author SummaryMounting a robust type I innate immune response is essential for resistance against numerous intracellular pathogens. The type I immune response is characterized by the production of IFN-, a central cytokine required for multiple non-redundant effector functions against bacterial, viral, and parasitic pathogens. Previous work has shown that group 1 innate lymphocyte cells (ILC1s) together with NK and CD4+ T cells play an indispensable IFN- mediated protective role against Toxoplasma gondii infection; yet, the pathway of how IFN- produced by ILC1s defend against T. gondii remains unknown. In this work we identified that early production of IFN- by ILC1 is essential for maintaining dendritic cells (DCs) during infection. Mechanistically, we reveal that ILC1-derived IFN- is indispensable for inducing the transcription factor IRF8 that is critical for sustaining inflammatory DCs. Finally, we demonstrate that IRF8+ DCs are critical for parasite elimination.

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“…Likewise, the apicomplexan parasite Toxoplasma gondii is also confronted with the challenge of crossing tissue compartments in the body : In order to be able to enter the brain from the vasculature, T. gondii needs to replicate in and lyse endothelial cells of the blood brain barrier .…”

Section: Invasion Barrier Function and Virulence Strategiesmentioning

confidence: 99%

From the Cradle to the Grave of an Infection: Host‐Pathogen Interaction Visualized by Intravital Microscopy

2019

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During infections, interactions between host immune cells and the pathogen occur in distinct anatomical locations and along defined time scales. This can best be assessed in the physiological context of an infection in the living tissue. Consequently, intravital imaging has enabled us to dissect the critical phases and events throughout an infection in real time in living tissues. Specifically, advances in visualizing specific cell types and individual pathogens permitted tracking the early events of tissue invasion of the pathogen, cellular interactions involved in the induction of the immune response as well the events implicated in clearance of the infection. In this respect, two vantage points have evolved since the initial employment of this technique in the field of infection biology. On the one hand, strategies acquired by the pathogen to establish within the host and circumvent or evade the immune defenses have been elucidated. On the other hand, analyzing infections from the immune system's perspective has led to insights into the dynamic cellular interactions that are involved in the initial recognition of the pathogen, immune induction as well as effector function delivery and immunopathology. Furthermore, an increasing interest in probing functional parameters in vivo has emerged, such as the analysis of pathogen reactivity to stress conditions imposed by the host organism in order to mediate clearance upon pathogen encounter. Here, we give an overview on recent intravital microscopy findings of hostpathogen interactions along the course of an infection, from both the immune system's and pathogen's perspectives. We also discuss recent developments and future perspectives in extracting intravital information beyond the localization of pathogens and their interaction with immune cells. Such reporter systems on the pathogen's physiological state and immune cell functions may prove useful in dissecting the functional dynamics of hostpathogen interactions.

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Host immune responses toToxoplasma gondii

Cited by 166 publications

References 90 publications

Transcriptional profiling reveals T cells cluster around neurons injected withToxoplasma gondiiproteins

Transcriptional profiling reveals T cells cluster around neurons injected withToxoplasma gondiiproteins

ILC1-derived IFN-γ mediates cDC1-dependent host resistance againstToxoplasma gondii

From the Cradle to the Grave of an Infection: Host‐Pathogen Interaction Visualized by Intravital Microscopy

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