Melissa Wirawan, Guntur Fibriansah, Jan K. Marzinek, Xin Xiang Lim, Thiam-Seng Ng, Adelene Y.L. Sim, Qian Zhang, Victor A. Kostyuchenko, Jian Shi, Scott A. Smith, Chandra S. Verma, Ganesh Anand, James E. Crowe, Peter J. Bond, Shee-Mei Lok, Mechanism of Enhanced Immature Dengue Virus Attachment to Endosomal Membrane Induced by prM Antibody, Structure, Volume 27, Issue 2, 2019, Pages 253-267.e8, ISSN 0969-2126, https://doi.org/10.1016/j.str.2018.10.009.
Abstract:
Dengue virus particles are released from cells in different maturation states. Fully immature DENV (immDENV) is generally non-infectious, but can become infectious when complexed with anti-precursor membrane (prM) protein antibodies. It is unknown how anti-prM antibody-coated particles can undergo membrane fusion since the prM caps the Envelope (E) protein fusion loop. Here, we determined cryoEM maps of the immDENV:anti-prM complex at different pH mimicking the extracellular (pH 8.0) or endosomal (pH 5.0) environments. At pH 5.0, there are two structural classes with fewer antibodies bound than at pH 8.0. These classes may represent different maturation states. Molecular simulations, together with the measured high affinity pr:antibody interaction (versus the weak pr:E interaction) and also the low pH cryoEM structures, suggest how antibody:pr complex can dislodge from the E protein at low pH. This exposes the E protein fusion loop enhancing virus interaction with endosomes.
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Funding Info:
This study has been supported by the following grants awarded to S.-M.L., National Research Foundation Singapore Investigatorship ( NRF-NRFI2016-01 ); to J.E.C., United States National Institutes of Health grant U54 AI057157 (the Region IV Southeast Regional Center of Excellence in Emerging Infections and Biodefense); and to S.A.S., United States National Institutes of Health grant K08 AI103038 . S.-M.L., P.J.B., C.S.V., and G.A. thank Ministry of Education , Singapore, ( MOE2012-T3-008 ) for support. The DENV2 and 3 strains were kindly provided by Eng-Eong Ooi (Duke-NUS Medical School). The HMAb 4.8A used in the THP-1 infection assay was kindly provided by John Schieffelin. We thank the NSCC and BMSI (A∗STAR) for computing facilities. We thank Aravinda M. de Silva (The University of North Carolina at Chapel Hill) for helpful discussions and Jiaqi Wang, Xin-Ni Lim, and Valerie S.Y. Chew (Duke-NUS Medical School) for help with fusion assay experiments.
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The full paper can be downloaded from the publishers URL: https://doi.org/10.1016/j.str.2018.10.009