1. Microbiology and Infectious Disease
  2. Neuroscience
Download icon

Injection with Toxoplasma gondii protein affects neuron health and survival

  1. Oscar A Mendez
  2. Emiliano Flores Machado
  3. Jing Lu
  4. Anita Koshy  Is a corresponding author
  1. University of Arizona, United States
Research Article
  • Cited 0
  • Views 372
  • Annotations
Cite this article as: eLife 2021;10:e67681 doi: 10.7554/eLife.67681

Abstract

Toxoplasma gondii is an intracellular parasite that causes a long-term latent infection of neurons. Using a custom MATLAB-based mapping program in combination with a mouse model that allows us to permanently mark neurons injected with parasite proteins, we found that Toxoplasma-injected neurons (TINs) are heterogeneously distributed in the brain, primarily localizing to the cortex followed by the striatum. In addition, we determined that cortical TINs are commonly (>50%) excitatory neurons (FoxP2+) and that striatal TINs are often (>65%) medium spiny neurons (MSNs) (FoxP2+). By performing single neuron patch-clamping on striatal TINs and neighboring uninfected MSNs, we discovered that TINs have highly aberrant electrophysiology. As approximately 90% of TINs will die by 8 weeks post-infection, this abnormal physiology suggests that injection with Toxoplasma protein— either directly or indirectly— affects neuronal health and survival. Collectively, these data offer the first insights into which neurons interact with Toxoplasma and how these interactions alter neuron physiology in vivo.

Data availability

Data for Figures 1,2,3,5,6,7 is provided.

Article and author information

Author details

  1. Oscar A Mendez

    Neuroscience GIDP, University of Arizona, Tucson, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Emiliano Flores Machado

    Neuroscience GIDP, University of Arizona, Tucson, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jing Lu

    College of Nursing, University of Arizona, Tucson, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Anita Koshy

    Neurology; Immunobiology, University of Arizona, Tucson, United States
    For correspondence
    akoshy@arizona.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8705-3233

Funding

National Institute of Neurological Disorders and Stroke (F99 NS108514)

  • Oscar A Mendez

National Institute of Neurological Disorders and Stroke (R25 NS076437 High School Student NeuroResearch Program (HSNRP))

  • Emiliano Flores Machado

Arizona Biomedical Research Commission (ADHS14-082991)

  • Anita Koshy

National Institute of Neurological Disorders and Stroke (R01 NS095994)

  • Anita Koshy

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse studies and breeding were carried out in accordance with the Public Health Service Policy on Human Care and Use of Laboratory Animals. The protocol was approved by the University of Arizona Institutional Animal Care and Use Committee. (#A-3248-01, protocol #12-391).

Reviewing Editor

  1. Malcolm J McConville, The University of Melbourne, Australia

Publication history

  1. Received: February 18, 2021
  2. Accepted: June 9, 2021
  3. Accepted Manuscript published: June 9, 2021 (version 1)

Copyright

© 2021, Mendez et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 372
    Page views
  • 90
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Medicine
    2. Microbiology and Infectious Disease
    Nguyen Lam Vuong et al.
    Research Article

    Background: Early identification of severe dengue patients is important regarding patient management and resource allocation. We investigated the association of ten biomarkers (VCAM-1, SDC-1, Ang-2, IL-8, IP-10, IL-1RA, sCD163, sTREM-1, ferritin, CRP) with the development of severe/moderate dengue (S/MD).

    Methods: We performed a nested case-control study from a multi-country study. A total of 281 S/MD and 556 uncomplicated dengue cases were included.

    Results: On days 1-3 from symptom onset, higher levels of any biomarker increased the risk of developing S/MD. When assessing together, SDC-1 and IL-1RA were stable, while IP-10 changed the association from positive to negative; others showed weaker associations. The best combinations associated with S/MD comprised IL-1RA, Ang-2, IL-8, ferritin, IP-10, and SDC-1 for children, and SDC-1, IL-8, ferritin, sTREM-1, IL-1RA, IP-10, and sCD163 for adults.

    Conclusions: Our findings assist the development of biomarker panels for clinical use and could improve triage and risk prediction in dengue patients.

    1. Microbiology and Infectious Disease
    Karla Marie Márquez-Nogueras et al.
    Research Article Updated

    Transient receptor potential (TRP) channels participate in calcium ion (Ca2+) influx and intracellular Ca2+ release. TRP channels have not been studied in Toxoplasma gondii or any other apicomplexan parasite. In this work, we characterize TgGT1_310560, a protein predicted to possess a TRP domain (TgTRPPL-2), and determined its role in Ca2+ signaling in T. gondii, the causative agent of toxoplasmosis. TgTRPPL-2 localizes to the plasma membrane and the endoplasmic reticulum (ER) of T. gondii. The ΔTgTRPPL-2 mutant was defective in growth and cytosolic Ca2+ influx from both extracellular and intracellular sources. Heterologous expression of TgTRPPL-2 in HEK-3KO cells allowed its functional characterization. Patching of ER-nuclear membranes demonstrates that TgTRPPL-2 is a non-selective cation channel that conducts Ca2+. Pharmacological blockers of TgTRPPL-2 inhibit Ca2+ influx and parasite growth. This is the first report of an apicomplexan ion channel that conducts Ca2+ and may initiate a Ca2+ signaling cascade that leads to the stimulation of motility, invasion, and egress. TgTRPPL-2 is a potential target for combating toxoplasmosis.