1. Microbiology and Infectious Disease

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
https://doi.org/10.7554/eLife.67029
Share this article
Cite this article
  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
(2021)
Interferon receptor-deficient mice are susceptible to eschar-associated rickettsiosis
eLife 10:e67029.
https://doi.org/10.7554/eLife.67029
  2. Download BibTeX
  3. Download .RIS

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.

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

  • 1,804
    views
  • 163
    downloads
  • 16
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  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
(2021)
Interferon receptor-deficient mice are susceptible to eschar-associated rickettsiosis
eLife 10:e67029.
https://doi.org/10.7554/eLife.67029

Share this article

https://doi.org/10.7554/eLife.67029

Categories and tags

Research organism

Further reading

    1. Microbiology and Infectious Disease

    Machine learning approaches identify immunologic signatures of total and intact HIV DNA during long-term antiretroviral therapy

    Lesia Semenova, Yingfan Wang ... Edward P Browne
    Research Article

    Understanding the interplay between the HIV reservoir and the host immune system may yield insights into HIV persistence during antiretroviral therapy (ART) and inform strategies for a cure. Here, we applied machine learning (ML) approaches to cross-sectional high-parameter HIV reservoir and immunology data in order to characterize host–reservoir associations and generate new hypotheses about HIV reservoir biology. High-dimensional immunophenotyping, quantification of HIV-specific T cell responses, and measurement of genetically intact and total HIV proviral DNA frequencies were performed on peripheral blood samples from 115 people with HIV (PWH) on long-term ART. Analysis demonstrated that both intact and total proviral DNA frequencies were positively correlated with T cell activation and exhaustion. Years of ART and select bifunctional HIV-specific CD4 T cell responses were negatively correlated with the percentage of intact proviruses. A leave-one-covariate-out inference approach identified specific HIV reservoir and clinical–demographic parameters, such as age and biological sex, that were particularly important in predicting immunophenotypes. Overall, immune parameters were more strongly associated with total HIV proviral frequencies than intact proviral frequencies. Uniquely, however, expression of the IL-7 receptor alpha chain (CD127) on CD4 T cells was more strongly correlated with the intact reservoir. Unsupervised dimension reduction analysis identified two main clusters of PWH with distinct immune and reservoir characteristics. Using reservoir correlates identified in these initial analyses, decision tree methods were employed to visualize relationships among multiple immune and clinical–demographic parameters and the HIV reservoir. Finally, using random splits of our data as training-test sets, ML algorithms predicted with approximately 70% accuracy whether a given participant had qualitatively high or low levels of total or intact HIV DNA . The techniques described here may be useful for assessing global patterns within the increasingly high-dimensional data used in HIV reservoir and other studies of complex biology.

    1. Microbiology and Infectious Disease

    Rifampicin tolerance and growth fitness among isoniazid-resistant clinical Mycobacterium tuberculosis isolates from a longitudinal study

    Srinivasan Vijay, Nguyen Le Hoai Bao ... Nguyen Thuy Thuong
    Research Article

    Antibiotic tolerance in Mycobacterium tuberculosis reduces bacterial killing, worsens treatment outcomes, and contributes to resistance. We studied rifampicin tolerance in isolates with or without isoniazid resistance (IR). Using a minimum duration of killing assay, we measured rifampicin survival in isoniazid-susceptible (IS, n=119) and resistant (IR, n=84) isolates, correlating tolerance with bacterial growth, rifampicin minimum inhibitory concentrations (MICs), and isoniazid-resistant mutations. Longitudinal IR isolates were analyzed for changes in rifampicin tolerance and genetic variant emergence. The median time for rifampicin to reduce the bacterial population by 90% (MDK90) increased from 1.23 days (IS) and 1.31 days (IR) to 2.55 days (IS) and 1.98 days (IR) over 15–60 days of incubation, indicating fast and slow-growing tolerant sub-populations. A 6 log10-fold survival fraction classified tolerance as low, medium, or high, showing that IR is linked to increased tolerance and faster growth (OR = 2.68 for low vs. medium, OR = 4.42 for low vs. high, p-trend = 0.0003). High tolerance in IR isolates was associated with rifampicin treatment in patients and genetic microvariants. These findings suggest that IR tuberculosis should be assessed for high rifampicin tolerance to optimize treatment and prevent the development of multi-drug-resistant tuberculosis.

    1. Evolutionary Biology
    2. Microbiology and Infectious Disease

    Recombinant origin and interspecies transmission of a HERV-K(HML-2)-related primate retrovirus with a novel RNA transport element

    Zachary H Williams, Alvaro Dafonte Imedio ... Welkin E Johnson
    Research Article Updated

    HERV-K(HML-2), the youngest clade of human endogenous retroviruses (HERVs), includes many intact or nearly intact proviruses, but no replication competent HML-2 proviruses have been identified in humans. HML-2-related proviruses are present in other primates, including rhesus macaques, but the extent and timing of HML-2 activity in macaques remains unclear. We have identified 145 HML-2-like proviruses in rhesus macaques, including a clade of young, rhesus-specific insertions. Age estimates, intact open reading frames, and insertional polymorphism of these insertions are consistent with recent or ongoing infectious activity in macaques. 106 of the proviruses form a clade characterized by an ~750 bp sequence between env and the 3′ long terminal repeat (LTR), derived from an ancient recombination with a HERV-K(HML-8)-related virus. This clade is found in Old World monkeys (OWM), but not great apes, suggesting it originated after the ape/OWM split. We identified similar proviruses in white-cheeked gibbons; the gibbon insertions cluster within the OWM recombinant clade, suggesting interspecies transmission from OWM to gibbons. The LTRs of the youngest proviruses have deletions in U3, which disrupt the Rec Response Element (RcRE), required for nuclear export of unspliced viral RNA. We show that the HML-8-derived region functions as a Rec-independent constitutive transport element (CTE), indicating the ancestral Rec–RcRE export system was replaced by a CTE mechanism.