A measles virus collective infectious unit that caused lethal human brain disease includes many locally restricted and few widespread copy-back defective genomes

Biruhalem Taye, Iris Yousaf, Chanakha K. Navaratnarajah, Declan C. Schroeder, Christian K. Pfaller, Roberto Cattaneo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

During virus replication in cultured cells, copy-back defective viral genomes (cbDVGs) can arise. CbDVGs are powerful inducers of innate immune responses in vitro, but their occurrence and impact on natural infections of human hosts remain poorly defined. We asked whether cbDVGs were generated in the brain of a patient who succumbed to subacute sclerosing panencephalitis (SSPE) about 20 years after acute measles virus (MeV) infection. Previous analyses of 13 brain specimens of this patient indicated that a collective infectious unit (CIU) drove lethal MeV spread. In this study, we identified 276 replication-competent cbDVG species, each present in over 100 copies in the brain. Six species were detected in multiple forebrain locations, implying that they travelled long-distance with the CIU. The cbDVG to full-length genomes ratio was often close to 1 (0.6–1.74). Most cbDVGs were 324–2,000 bases in length, corresponding to 2%–12% of the full-length genome; all are predicted to have complementary terminal sequences. If improperly encapsidated, these sequences have the potential to form double-stranded structures that can induce innate immune responses. To assess this, we examined the transcriptome of all brain specimens. Several interferon and inflammatory response genes were upregulated, but upregulation levels did not correlate with cbDVG levels in the specimens. Thus, the CIU that drove MeV pathogenesis in this brain includes, in addition to two complementary full-length genome populations, many locally restricted and few widespread cbDVG species. The widespread cbDVG species may have been positively selected but how they impacted pathogenesis remains to be determined.

Original languageEnglish (US)
JournalJournal of virology
Volume98
Issue number11
DOIs
StatePublished - Nov 2024

Bibliographical note

Publisher Copyright:
Copyright © 2024 American Society for Microbiology. All Rights Reserved.

Keywords

  • brain transcriptome
  • brain tropism
  • collective infectious unit
  • copy-back defective viral genome
  • defective interfering
  • defective viral genomes
  • human brain
  • innate immune response
  • measles virus
  • subacute sclerosing panencephalitis

PubMed: MeSH publication types

  • Journal Article

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