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

doi:10.1073/pnas.2218899120

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

Cell Biology

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

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 language	English (US)
Article number	e2218899120
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	120
Issue number	3
DOIs	https://doi.org/10.1073/pnas.2218899120
State	Published - Jan 17 2023

Keywords

antibody-dependent enhancement
dengue virus
prM antibody
virion maturation

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1073/pnas.2218899120

Cite this

Dowd, K. A., Sirohi, D., Speer, S. D., VanBlargan, L. A., Chen, R. E., Mukherjee, S., Whitener, B. M., Govero, J., Aleshnick, M., Larman, B., Sukupolvi-Petty, S., Sevvana, M., Miller, A. S., Klose, T., Zheng, A., Koenig, S., Kielian, M., Kuhn, R. J., Diamond, M. S., & Pierson, T. C. (2023). prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis. Proceedings of the National Academy of Sciences of the United States of America, 120(3), Article e2218899120. https://doi.org/10.1073/pnas.2218899120

Dowd, KA, Sirohi, D, Speer, SD, VanBlargan, LA, Chen, RE, Mukherjee, S, Whitener, BM, Govero, J, Aleshnick, M, Larman, B, Sukupolvi-Petty, S, Sevvana, M, Miller, AS, Klose, T, Zheng, A, Koenig, S, Kielian, M, Kuhn, RJ, Diamond, MS & Pierson, TC 2023, 'prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis', Proceedings of the National Academy of Sciences of the United States of America, vol. 120, no. 3, e2218899120. https://doi.org/10.1073/pnas.2218899120

@article{26005d94caab41ec9e811f583ea0177d,

title = "prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis",

abstract = "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.",

keywords = "antibody-dependent enhancement, dengue virus, prM antibody, virion maturation",

author = "Dowd, {Kimberly A.} and Devika Sirohi and Speer, {Scott D.} and VanBlargan, {Laura A.} and Chen, {Rita E.} and Swati Mukherjee and Whitener, {Bradley M.} and Jennifer Govero and Maya Aleshnick and Bridget Larman and Soila Sukupolvi-Petty and Madhumati Sevvana and Miller, {Andrew S.} and Thomas Klose and Aihua Zheng and Scott Koenig and Margaret Kielian and Kuhn, {Richard J.} and Diamond, {Michael S.} and Pierson, {Theodore C.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 the Author(s). Published by PNAS.",

year = "2023",

month = jan,

day = "17",

doi = "10.1073/pnas.2218899120",

language = "English (US)",

volume = "120",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "3",

}

TY - JOUR

T1 - prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis

AU - Dowd, Kimberly A.

AU - Sirohi, Devika

AU - Speer, Scott D.

AU - VanBlargan, Laura A.

AU - Chen, Rita E.

AU - Mukherjee, Swati

AU - Whitener, Bradley M.

AU - Govero, Jennifer

AU - Aleshnick, Maya

AU - Larman, Bridget

AU - Sukupolvi-Petty, Soila

AU - Sevvana, Madhumati

AU - Miller, Andrew S.

AU - Klose, Thomas

AU - Zheng, Aihua

AU - Koenig, Scott

AU - Kielian, Margaret

AU - Kuhn, Richard J.

AU - Diamond, Michael S.

AU - Pierson, Theodore C.

PY - 2023/1/17

Y1 - 2023/1/17

N2 - 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.

AB - 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.

KW - antibody-dependent enhancement

KW - dengue virus

KW - prM antibody

KW - virion maturation

UR - http://www.scopus.com/inward/record.url?scp=85146363723&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85146363723&partnerID=8YFLogxK

U2 - 10.1073/pnas.2218899120

DO - 10.1073/pnas.2218899120

M3 - Article

C2 - 36638211

AN - SCOPUS:85146363723

SN - 0027-8424

VL - 120

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 3

M1 - e2218899120

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this