1. Microbiology and Infectious Disease
Download icon

Interferon receptor-deficient mice are susceptible to eschar-associated rickettsiosis

  1. Thomas P Burke
  2. Patrik Engström
  3. Cuong J Tran
  4. Ingeborg M Langohr
  5. Dustin R Glasner
  6. Diego A Espinosa
  7. Eva Harris
  8. Matthew D Welch  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Louisiana State University, United States
  3. University of California, San Francisco, United States
  4. Metagenomi, United States
Research Article
  • Cited 0
  • Views 732
  • Annotations
Cite this article as: eLife 2021;10:e67029 doi: 10.7554/eLife.67029

Abstract

Arthropod-borne rickettsial pathogens cause mild and severe human disease worldwide. The tick-borne pathogen Rickettsia parkeri elicits skin lesions (eschars) and disseminated disease in humans; however, inbred mice are generally resistant to infection. We report that intradermal infection of mice lacking both interferon receptors (Ifnar1-/-;Ifngr1-/-) with as few as 10 R. parkeri elicits eschar formation and disseminated, lethal disease. Similar to human infection, eschars exhibited necrosis and inflammation, with bacteria primarily found in leukocytes. Using this model, we find that the actin-based motility factor Sca2 is required for dissemination from the skin to internal organs, and the outer membrane protein OmpB contributes to eschar formation. Immunizing Ifnar1-/-;Ifngr1-/- mice with sca2 and ompB mutant R. parkeri protects against rechallenge, revealing live-attenuated vaccine candidates. Thus, Ifnar1-/-;Ifngr1-/- mice are a tractable model to investigate rickettsiosis, virulence factors, and immunity. Our results further suggest that discrepancies between mouse and human susceptibility may be due to differences in interferon signaling.

Data availability

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

Article and author information

Author details

  1. Thomas P Burke

    Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Patrik Engström

    Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Cuong J Tran

    Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ingeborg M Langohr

    Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Dustin R Glasner

    Laboratory Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9821-6683
  6. Diego A Espinosa

    Cell Therapy, Metagenomi, Emeryville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4364-5031
  7. Eva Harris

    Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7238-4037
  8. Matthew D Welch

    Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    welch@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2537-6349

Funding

National Institute of Allergy and Infectious Diseases (R01AI109044)

  • Matthew D Welch

National Institute of Allergy and Infectious Diseases (R21AI138550)

  • Matthew D Welch

National Institute of Allergy and Infectious Diseases (R01AI124493)

  • Eva Harris

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

Ethics

Animal experimentation: Animal research was conducted under a protocol approved by the University of California, Berkeley Institutional Animal Care and Use Committee (IACUC) in compliance with the Animal Welfare Act and other federal statutes relating to animals and experiments using animals (Welch lab animal use protocol AUP-2016-02-8426). The University of California, Berkeley IACUC is fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International and adheres to the principles of the Guide for the Care and use of Laboratory Animals. Mouse infections were performed in a biosafety level 2 facility. All animals were maintained at the University of California, Berkeley campus, and all infections were performed in accordance with the approved protocols. Mice were immediately euthanized if they exhibited severe degree of infection, as defined by a core body temperature dropping below 90˚ F or lethargy that prevented normal movement.

Reviewing Editor

  1. Kim Orth, HHMI/University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: January 30, 2021
  2. Accepted: July 31, 2021
  3. Accepted Manuscript published: August 23, 2021 (version 1)
  4. Version of Record published: September 9, 2021 (version 2)

Copyright

© 2021, Burke 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

  • 732
    Page views
  • 67
    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. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Jason Neidleman et al.
    Research Article Updated

    While mRNA vaccines are proving highly efficacious against SARS-CoV-2, it is important to determine how booster doses and prior infection influence the immune defense they elicit, and whether they protect against variants. Focusing on the T cell response, we conducted a longitudinal study of infection-naïve and COVID-19 convalescent donors before vaccination and after their first and second vaccine doses, using a high-parameter CyTOF analysis to phenotype their SARS-CoV-2-specific T cells. Vaccine-elicited spike-specific T cells responded similarly to stimulation by spike epitopes from the ancestral, B.1.1.7 and B.1.351 variant strains, both in terms of cell numbers and phenotypes. In infection-naïve individuals, the second dose boosted the quantity and altered the phenotypic properties of SARS-CoV-2-specific T cells, while in convalescents the second dose changed neither. Spike-specific T cells from convalescent vaccinees differed strikingly from those of infection-naïve vaccinees, with phenotypic features suggesting superior long-term persistence and ability to home to the respiratory tract including the nasopharynx. These results provide reassurance that vaccine-elicited T cells respond robustly to emerging viral variants, confirm that convalescents may not need a second vaccine dose, and suggest that vaccinated convalescents may have more persistent nasopharynx-homing SARS-CoV-2-specific T cells compared to their infection-naïve counterparts.

    1. Cell Biology
    2. Microbiology and Infectious Disease
    Deike J Omnus et al.
    Research Article

    The highly conserved protease Lon has important regulatory and protein quality control functions in cells from the three domains of life. Despite many years of research on Lon, only a few specific protein substrates are known in most organisms. Here, we used a quantitative proteomics approach to identify novel substrates of Lon in the dimorphic bacterium Caulobacter crescentus. We focused our study on proteins involved in polar cell differentiation and investigated the developmental regulator StaR and the flagella hook length regulator FliK as specific Lon substrates in detail. We show that Lon recognizes these proteins at their C-termini, and that Lon-dependent degradation ensures their temporally restricted accumulation in the cell cycle phase when their function is needed. Disruption of this precise temporal regulation of StaR and FliK levels in a Δlon mutant contributes to defects in stalk biogenesis and motility, respectively, revealing a critical role of Lon in coordinating developmental processes with cell cycle progression. Our work underscores the importance of Lon in the regulation of complex temporally controlled processes by adjusting the concentrations of critical regulatory proteins. Furthermore, this study includes the first characterization of FliK in C. crescentus and uncovers a dual role of the C-terminal amino acids of FliK in protein function and degradation.