T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus

  1. Matthew D Lauver
  2. Ge Jin
  3. Katelyn N Ayers
  4. Sarah N Carey
  5. Charles S Specht
  6. Catherine S Abendroth
  7. Aron E Lukacher  Is a corresponding author
  1. Pennsylvania State University, United States
  2. Penn State Milton S. Hershey Medical Center, United States

Abstract

JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a life-threatening brain disease in immunocompromised patients. Inherited and acquired T cell deficiencies are associated with PML. The incidence of PML is increasing with the introduction of new immunomodulatory agents, several of which target T cells or B cells. PML patients often carry mutations in the JCPyV VP1 capsid protein, which confer resistance to neutralizing VP1 antibodies (Ab). Polyomaviruses (PyV) are tightly species-specific; the absence of tractable animal models has handicapped understanding PyV pathogenesis. Using mouse polyomavirus (MuPyV), we found that T cell deficiency during persistent infection, in the setting of monospecific VP1 Ab, was required for outgrowth of VP1 Ab-escape viral variants. CD4 T cells were primarily responsible for limiting polyomavirus infection in the kidney, a major reservoir of persistent infection by both JCPyV and MuPyV, and checking emergence of these mutant viruses. T cells also provided a second line of defense by controlling the outgrowth of VP1 mutant viruses that evaded Ab neutralization. A virus with two capsid mutations, one conferring Ab-escape yet impaired infectivity and a second compensatory mutation, yielded a highly neurovirulent variant. These findings link T cell deficiency and evolution of Ab-escape polyomavirus VP1 variants with neuropathogenicity.

Data availability

All data files are uploaded as Source data files with this manuscript. Images are deposited with Dryad at (https://doi.org/10.5061/dryad.prr4xgxqj).

The following data sets were generated

Article and author information

Author details

  1. Matthew D Lauver

    Department of Microbiology and Immunology, Pennsylvania State University, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7001-9730
  2. Ge Jin

    Department of Microbiology and Immunology, Pennsylvania State University, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Katelyn N Ayers

    Department of Microbiology and Immunology, Pennsylvania State University, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6156-8685
  4. Sarah N Carey

    Department of Microbiology and Immunology, Pennsylvania State University, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Charles S Specht

    Department of Pathology and Laboratory Medicine, Penn State Milton S. Hershey Medical Center, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Catherine S Abendroth

    Department of Pathology and Laboratory Medicine, Penn State Milton S. Hershey Medical Center, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Aron E Lukacher

    Department of Microbiology and Immunology, Pennsylvania State University, Hershey, United States
    For correspondence
    alukacher@pennstatehealth.psu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7969-2841

Funding

National Institutes of Health (5R01NS088367)

  • Aron E Lukacher

National Institutes of Health (5R01NS092662)

  • Aron E Lukacher

National Institutes of Health (R35NS127217)

  • Aron E Lukacher

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to an approved institutional animal care and use committee (IACUC) protocol (#PRAMS201447619) of The Pennsylvania State University.

Reviewing Editor

  1. Karla Kirkegaard, Stanford University School of Medicine, United States

Publication history

  1. Preprint posted: February 25, 2022 (view preprint)
  2. Received: August 26, 2022
  3. Accepted: October 4, 2022
  4. Accepted Manuscript published: November 7, 2022 (version 1)
  5. Version of Record published: November 18, 2022 (version 2)

Copyright

© 2022, Lauver 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.

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  1. Matthew D Lauver
  2. Ge Jin
  3. Katelyn N Ayers
  4. Sarah N Carey
  5. Charles S Specht
  6. Catherine S Abendroth
  7. Aron E Lukacher
(2022)
T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus
eLife 11:e83030.
https://doi.org/10.7554/eLife.83030

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    Background:

    Dog-mediated rabies is endemic across Africa causing thousands of human deaths annually. A One Health approach to rabies is advocated, comprising emergency post-exposure vaccination of bite victims and mass dog vaccination to break the transmission cycle. However, the impacts and cost-effectiveness of these components are difficult to disentangle.

    Methods:

    We combined contact tracing with whole-genome sequencing to track rabies transmission in the animal reservoir and spillover risk to humans from 2010-2020, investigating how the components of a One Health approach reduced the disease burden and eliminated rabies from Pemba Island, Tanzania. With the resulting high-resolution spatiotemporal and genomic data we inferred transmission chains and estimated case detection. Using a decision tree model we quantified the public health burden and evaluated the impact and cost-effectiveness of interventions over a ten-year time horizon.

    Results:

    We resolved five transmission chains co-circulating on Pemba from 2010 that were all eliminated by May 2014. During this period, rabid dogs, human rabies exposures and deaths all progressively declined following initiation and improved implementation of annual islandwide dog vaccination. We identified two introductions to Pemba in late 2016 that seeded re-emergence after dog vaccination had lapsed. The ensuing outbreak was eliminated in October 2018 through reinstated islandwide dog vaccination. While post-exposure vaccines were projected to be highly cost-effective ($256 per death averted), only dog vaccination interrupts transmission. A combined One Health approach of routine annual dog vaccination together with free post-exposure vaccines for bite victims, rapidly eliminates rabies, is highly cost-effective ($1657 per death averted) and by maintaining rabies freedom prevents over 30 families from suffering traumatic rabid dog bites annually on Pemba island.

    Conclusions:

    A One Health approach underpinned by dog vaccination is an efficient, cost-effective, equitable and feasible approach to rabies elimination, but needs scaling up across connected populations to sustain the benefits of elimination, as seen on Pemba, and for similar progress to be achieved elsewhere.

    Funding:

    Wellcome [207569/Z/17/Z, 095787/Z/11/Z, 103270/Z/13/Z], the UBS Optimus Foundation, the Department of Health and Human Services of the National Institutes of Health [R01AI141712] and the DELTAS Africa Initiative [Afrique One-ASPIRE/DEL-15-008] comprising a donor consortium of the African Academy of Sciences (AAS), Alliance for Accelerating Excellence in Science in Africa (AESA), the New Partnership for Africa's Development Planning and Coordinating (NEPAD) Agency, Wellcome [107753/A/15/Z], Royal Society of Tropical Medicine and Hygiene Small Grant 2017 [GR000892] and the UK government. The rabies elimination demonstration project from 2010-2015 was supported by the Bill & Melinda Gates Foundation [OPP49679]. Whole-genome sequencing was partially supported from APHA by funding from the UK Department for Environment, Food and Rural Affairs (Defra), Scottish government and Welsh government under projects SEV3500 & SE0421.