Proceedings of the National Academy of Sciences of the United States of America · 2023
prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis.
СтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод в очереди
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Dowd Kimberly A, Sirohi Devika, Speer Scott D, VanBlargan Laura A, Chen Rita E, Mukherjee Swati, Whitener Bradley M, Govero Jennifer, Aleshnick Maya, Larman Bridget, Sukupolvi-Petty Soila, Sevvana Madhumati, Miller Andrew S, Klose Thomas, Zheng Aihua, Koenig Scott, Kielian Margaret, Kuhn Richard J, Diamond Michael S, Pierson Theodore C
Аннотация
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.