prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis

Kimberly 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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Article numbere2218899120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - Jan 17 2023


  • antibody-dependent enhancement
  • dengue virus
  • prM antibody
  • virion maturation

ASJC Scopus subject areas

  • General


Dive into the research topics of 'prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis'. Together they form a unique fingerprint.

Cite this