[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]
OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE
Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies
Ludmila Perelygina, Min-hsin Chen, Suganthi Suppiah, Adebola Adebayo, Emily Abernathy, Morna Dorsey, Lionel Bercovitch, Kenneth Paris, Kevin P. White, Alfons Krol, Julie Dhossche, Ivan Y. Torshin, Natalie Saini, [ … ], Joseph Icenogle
Published: October 28, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008080 / This is an uncorrected proof.
Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10−3 subs/site/year and 8.9 x 10−4 subs/site/year, respectively. Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies.
Primary immunodeficiency diseases (PID) are caused by genetic defects and lead to serious problems including chronic granulomas (abnormal collections (nodules) of inflammatory cells), sometimes lasting for decades and sometimes leading to severe ulcers. Initial reports (2014–2016), including our report of a blinded study using ultrasensitive virus detection in biopsies, proved the association between granuloma of the skin in PID patients and rubella virus. The viruses in these reports and the current report were derived from a widely used vaccine strain of the rubella virus. Work reported here shows that these vaccine-derived viruses are biologically different from the vaccine virus and that their genomes have changed. Genomic changes could be analyzed largely because the exact sequence of starting vaccine virus genome was known. These genomic differences are likely generated via mechanisms similar to those occurring during normal circulation of wild type rubella. We present data that newly recognized mechanisms for generation of sequence diversity in viruses (because of cellular deaminases) likely occurs in the generation of these vaccine-derived rubella viruses. Thousands of PID patients in the United States are likely shedding these vaccine-derived rubella viruses. Our work presented here characterizing viruses in diagnostic specimens highlights at least two areas where insufficient work has been done: 1) research on the properties of rubella virus (limited understanding of the antibody binding sites on the virus); 2) controlled research studies to assess the public health impact of viruses in populations with high immunity.
Citation: Perelygina L, Chen M-h, Suppiah S, Adebayo A, Abernathy E, Dorsey M, et al. (2019) Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies. PLoS Pathog 15(10): e1008080. https://doi.org/10.1371/journal.ppat.1008080
Editor: Adam S. Lauring, University of Michigan, UNITED STATES
Received: April 24, 2019; Accepted: September 13, 2019; Published: October 28, 2019
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Data Availability: All sequences of iVDRV genomes are available from the GenBank database (accession number(s) MK787188 – MK787191 and MK780807- MK780812)
Funding: This work was supported by core funding from the Centers for Disease Control and Prevention, by a grant to K.E.S. from the National Institute of Health (R21-AI130967-01A1) and by the US National Institute of Health Intramural Research Program Project Z1AES103266 to D.A.G. K.E.S. was supported by the Wallace Chair of Pediatrics. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the United States Centers for Disease Control and Prevention. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have read the journal’s policy and have the following conflicts: Andrey Zharkikh is an employee of Myriad Genetics. This company works in cancer genetics and diagnostics without any relation to pathogen studies and treatments. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials.
Keywords: Rubella; Vaccines; Rubivirus.