1. Immunology and Inflammation
  2. Neuroscience
Download icon

Intestinal infection regulates behavior and learning via neuroendocrine signaling

  1. Jogender Singh
  2. Alejandro Aballay  Is a corresponding author
  1. Oregon Health and Science University, United States
Research Article
  • Cited 20
  • Views 3,928
  • Annotations
Cite this article as: eLife 2019;8:e50033 doi: 10.7554/eLife.50033

Abstract

The recognition of pathogens and subsequent activation of defense responses are critical for the survival of organisms. The nematode Caenorhabditis elegans recognizes pathogenic bacteria and elicits defense responses by activating immune pathways and pathogen avoidance. Here we show that chemosensation of phenazines produced by pathogenic Pseudomonas aeruginosa, which leads to rapid activation of DAF-7/TGF-β in ASJ neurons, is insufficient for the elicitation of pathogen avoidance behavior. Instead, intestinal infection and bloating of the lumen, which depend on the virulence of P. aeruginosa, regulates both pathogen avoidance and aversive learning by modulating not only the DAF-7/TGF-β pathway but also the G-protein coupled receptor NPR-1 pathway, which also controls aerotaxis behavior. Modulation of these neuroendocrine pathways by intestinal infection serves as a systemic feedback that enables animals to avoid virulent bacteria. These results reveal how feedback from the intestine during infection can modulate the behavior, learning, and microbial perception of the host.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Jogender Singh

    Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Alejandro Aballay

    Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, United States
    For correspondence
    aballay@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5975-3352

Funding

National Institute of General Medical Sciences (GM0709077)

  • Alejandro Aballay

National Institute of Allergy and Infectious Diseases (AI117911)

  • Alejandro Aballay

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

Reviewing Editor

  1. Yuichi Iino, University of Tokyo, Japan

Publication history

  1. Received: July 9, 2019
  2. Accepted: October 31, 2019
  3. Accepted Manuscript published: November 1, 2019 (version 1)
  4. Version of Record published: November 29, 2019 (version 2)

Copyright

© 2019, Singh & Aballay

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

  • 3,928
    Page views
  • 552
    Downloads
  • 20
    Citations

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

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. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Meghan E Garrett et al.
    Research Article

    Background: Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including different vaccine platforms, is needed to achieve this goal.

    Methods: The epitopes and pathways of escape for Spike-specific antibodies in individuals with diverse infection and vaccination history were profiled using Phage-DMS. Principal component analysis was performed to identify regions of antibody binding along the Spike protein that differentiate the samples from one another. Within these epitope regions we determined potential sites of escape by comparing antibody binding of peptides containing wildtype residues versus peptides containing a mutant residue.

    Results: Individuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection. Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in mildly infected individuals. In the case of antibodies targeting the fusion peptide region, which was a common response to both infection and vaccination, the escape profile after infection was not altered by subsequent vaccination.

    Conclusions: The finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests protection could vary depending on the route of exposure to Spike antigen. The relatively conserved escape pathways to vaccine-induced antibodies relative to infection-induced antibodies suggests that if escape variants emerge, they may be readily selected for across vaccinated individuals. Given that the majority of people will be first exposed to Spike via vaccination and not infection, this work has implications for predicting the selection of immune escape variants at a population level.

    Funding: This work was supported by NIH grants AI138709 (PI Overbaugh) and AI146028 (PI Matsen). Julie Overbaugh received support as the Endowed Chair for Graduate Education (FHCRC). The research of Frederick Matsen was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and the Simons Foundation. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685.

    1. Cell Biology
    2. Immunology and Inflammation
    Manuela Ecker et al.
    Research Article Updated

    T cell activation requires engagement of a cognate antigen by the T cell receptor (TCR) and the co-stimulatory signal of CD28. Both TCR and CD28 aggregate into clusters at the plasma membrane of activated T cells. While the role of TCR clustering in T cell activation has been extensively investigated, little is known about how CD28 clustering contributes to CD28 signalling. Here, we report that upon CD28 triggering, the BAR-domain protein sorting nexin 9 (SNX9) is recruited to CD28 clusters at the immunological synapse. Using three-dimensional correlative light and electron microscopy, we show that SNX9 generates membrane tubulation out of CD28 clusters. Our data further reveal that CD28 clusters are in fact dynamic structures and that SNX9 regulates their stability as well as CD28 phosphorylation and the resulting production of the cytokine IL-2. In summary, our work suggests a model in which SNX9-mediated tubulation generates a membrane environment that promotes CD28 triggering and downstream signalling events.