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Cell-Type-Dependent Role for nsP3 Macrodomain ADP-Ribose Binding and Hydrolase Activity during Chikungunya Virus

Taewoo Kim1, Rachy Abraham1, Lisa Pieterse1

  • 1W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.

Viruses
|December 23, 2022
PubMed

Insights

Chikungunya virus (CHIKV) virulence depends on its nsP3 protein

Area of Science:

  • Virology
  • Molecular Biology
  • Neuroscience

Background:

  • Chikungunya virus (CHIKV) causes febrile illness, rash, and arthritis, with potential neurologic complications.
  • Astrocytes are preferentially infected by CHIKV, and the nonstructural protein 3 (nsP3) macrodomain (MD) is a key virulence factor.
  • The nsP3 MD regulates stress granule dynamics by binding and removing ADP-ribose (ADPr) from substrates.

Purpose of the Study:

  • To investigate the role of CHIKV nsP3 macrodomain's ADP-ribose binding and hydrolase activities in viral replication and pathogenesis.
  • To compare the effects of wild-type (WT) CHIKV and nsP3 macrodomain mutants on astrocytic and neuronal cells.

Main Methods:

  • Compared replication of WT CHIKV 181/25, a decreased ADPr binding/hydrolase mutant (G32S), and an increased ADPr binding/decreased hydrolase mutant (Y114A).
  • Utilized C8-D1A astrocytic and NSC-34 neuronal cell lines to assess viral replication, nsP synthesis, host protein shut-off, and infectious virus production.
  • Analyzed cell-type-specific effects on structural protein (E2) synthesis and assembly into viral particles.

Main Results:

  • WT CHIKV replicated faster in astrocytes than neurons, with earlier nsP synthesis.
  • The G32S mutant showed less efficient infection, replication complex amplification, and host protein shut-off, producing less infectious virus compared to WT and Y114A.
  • G32S mutation differentially affected E2 synthesis: decreased in neurons but increased in astrocytes, leading to less infectious virus production in the latter.

Conclusions:

  • The nsP3 macrodomain's ADP-ribose hydrolase activity is crucial for efficient CHIKV replication and pathogenesis.
  • Differential regulation of host protein synthesis by the nsP3 MD contributes to cell-type-specific viral outcomes.
  • Understanding nsP3 MD function provides insights into CHIKV neurotropism and potential therapeutic targets.
Keywords:
ADP ribosylationalphavirusastrocyteschikungunya virushost-virus interactionmacrodomainneuronsneurovirulencereplication complexesviral replication

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