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Severe fever with thrombocytopenia syndrome phlebovirus non-structural protein activates TPL2 signalling pathway for

Younho Choi1, Su-Jin Park2, Yinyan Sun3

  • 1Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Zilkha Neurogenetic Institute, Los Angeles, CA, USA.

Nature Microbiology
|January 9, 2019
PubMed

Insights

Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV) non-structural protein (NSs) hijacks the TPL2-ABIN2-p105 complex to induce IL-10, promoting viral pathogenesis. Blocking this pathway offers a potential therapeutic target for SFTSV infection.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV) is a high-fatality emerging pathogen.
  • SFTSV non-structural protein (NSs) is crucial for viral pathogenesis, notably by inhibiting type I interferon induction.
  • Understanding SFTSV pathogenesis is critical due to the lack of effective therapies and vaccines.

Purpose of the Study:

  • To elucidate the molecular mechanism by which SFTSV NSs contributes to viral pathogenesis.
  • To investigate the interaction of SFTSV NSs with host cellular components.
  • To identify host pathways targeted by SFTSV NSs for immune evasion and disease progression.

Main Methods:

  • Reverse genetics was employed to study SFTSV NSs function.
  • A TPL2 kinase inhibitor and Tpl2 knockout mice were used to assess the role of the TPL2 pathway.
  • Interleukin-10 (IL-10) expression levels were measured in infected cells and mice.
  • Mutant SFTSV strains (NSs P102A, NSs K211R) were generated and analyzed for pathogenicity.
  • Recombinant IL-10 was administered to assess its effect on viral pathogenesis.

Main Results:

  • SFTSV NSs interacts with A20-binding inhibitor of NF-κB activation 2 (ABIN2) and promotes the formation and signaling activity of the tumour progression locus 2 (TPL2)-ABIN2-p105 complex.
  • This interaction leads to the significant upregulation of interleukin-10 (IL-10) expression.
  • Tpl2 knockout or IL-10 knockout mice exhibited resistance to SFTSV infection, while wild-type mice succumbed rapidly.
  • SFTSV mutants lacking the ability to induce TPL2 signaling and IL-10 production showed reduced pathogenicity.
  • Exogenous IL-10 administration restored the pathogenicity of these attenuated mutants.

Conclusions:

  • SFTSV NSs targets the TPL2 signaling pathway to induce immunosuppressive IL-10 production.
  • This mechanism serves to dampen host immune defense, thereby promoting viral pathogenesis.
  • The TPL2-IL-10 axis represents a critical host pathway exploited by SFTSV for survival and disease progression.
  • Targeting the TPL2-IL-10 pathway could be a potential therapeutic strategy against SFTSV.

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