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

Version 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.

Metrics

  • 386
    Page views
  • 69
    Downloads
  • 1
    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)

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. 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

Further reading

    1. Computational and Systems Biology
    2. Microbiology and Infectious Disease
    Vanessa Dumeaux, Samira Massahi ... Michael T Hallett
    Research Article Updated

    Candida albicans, an opportunistic human pathogen, poses a significant threat to human health and is associated with significant socio-economic burden. Current antifungal treatments fail, at least in part, because C. albicans can initiate a strong drug tolerance response that allows some cells to grow at drug concentrations above their minimal inhibitory concentration. To better characterize this cytoprotective tolerance program at the molecular single-cell level, we used a nanoliter droplet-based transcriptomics platform to profile thousands of individual fungal cells and establish their subpopulation characteristics in the absence and presence of antifungal drugs. Profiles of untreated cells exhibit heterogeneous expression that correlates with cell cycle stage with distinct metabolic and stress responses. At 2 days post-fluconazole exposure (a time when tolerance is measurable), surviving cells bifurcate into two major subpopulations: one characterized by the upregulation of genes encoding ribosomal proteins, rRNA processing machinery, and mitochondrial cellular respiration capacity, termed the Ribo-dominant (Rd) state; and the other enriched for genes encoding stress responses and related processes, termed the Stress-dominant (Sd) state. This bifurcation persists at 3 and 6 days post-treatment. We provide evidence that the ribosome assembly stress response (RASTR) is activated in these subpopulations and may facilitate cell survival.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Taylor J Abele, Zachary P Billman ... Edward A Miao
    Research Article

    Pyroptosis and apoptosis are two forms of regulated cell death that can defend against intracellular infection. When a cell fails to complete pyroptosis, backup pathways will initiate apoptosis. Here, we investigated the utility of apoptosis compared to pyroptosis in defense against an intracellular bacterial infection. We previously engineered Salmonella enterica serovar Typhimurium to persistently express flagellin, and thereby activate NLRC4 during systemic infection in mice. The resulting pyroptosis clears this flagellin-engineered strain. We now show that infection of caspase-1 or gasdermin D deficient macrophages by this flagellin-engineered S. Typhimurium induces apoptosis in vitro. Additionally, we engineered S. Typhimurium to translocate the pro-apoptotic BH3 domain of BID, which also triggers apoptosis in macrophages in vitro. During mouse infection, the apoptotic pathway successfully cleared these engineered S. Typhimurium from the intestinal niche but failed to clear the bacteria from the myeloid niche in the spleen or lymph nodes. In contrast, the pyroptotic pathway was beneficial in defense of both niches. To clear an infection, cells may have specific tasks that they must complete before they die; different modes of cell death could initiate these ‘bucket lists’ in either convergent or divergent ways.