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TitleprM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 120, Issue 3, Page e2218899120, Year 2023
Publish dateJan 17, 2023
AuthorsKimberly A Dowd / Devika Sirohi / Scott D Speer / Laura A VanBlargan / Rita E Chen / Swati Mukherjee / Bradley M Whitener / Jennifer Govero / Maya Aleshnick / Bridget Larman / Soila Sukupolvi-Petty / Madhumati Sevvana / Andrew S Miller / Thomas Klose / Aihua Zheng / Scott Koenig / Margaret Kielian / Richard J Kuhn / Michael S Diamond / Theodore C Pierson /
PubMed AbstractCleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis ...Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis during primary infection is unknown. To investigate this question, we characterized the functional properties of newly-generated dengue virus (DENV) prM-reactive monoclonal antibodies (mAbs) in vitro and using a mouse model of DENV disease. Anti-prM mAbs neutralized DENV infection in a virion maturation state-dependent manner. Alanine scanning mutagenesis and cryoelectron microscopy of anti-prM mAbs in complex with immature DENV defined two modes of attachment to a single antigenic site. In vivo, passive transfer of intact anti-prM mAbs resulted in an antibody-dependent enhancement of disease. However, protection against DENV-induced lethality was observed when the transferred mAbs were genetically modified to inhibit their ability to interact with Fcγ receptors. These data establish that in addition to mature forms of the virus, partially mature infectious prM virions can also contribute to pathogenesis during primary DENV infections.
External linksProc Natl Acad Sci U S A / PubMed:36638211 / PubMed Central
MethodsEM (single particle)
Resolution9.8 - 10.2 Å
Structure data

EMDB-29020, PDB-8fe3:
Structure of dengue virus (DENV2) in complex with prM12, an anti-PrM monoclonal antibody
Method: EM (single particle) / Resolution: 10.2 Å

EMDB-29021, PDB-8fe4:
Structure of dengue virus (DENV2) in complex with prM13, an anti-PrM monoclonal antibody
Method: EM (single particle) / Resolution: 9.8 Å

Source
  • mus musculus (house mouse)
  • dengue virus type 2
KeywordsVIRUS/IMMUNE SYSTEM / DENV / flavivirus / prM antibody / prM12 / VIRUS-IMMUNE SYSTEM complex / prM13

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