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1. Genetic Variation between Dengue Virus Type 4 Strains Impacts Human Antibody Binding and Neutralization.

Author

Gallichotte EN, Baric TJ, Nivarthi U, Delacruz MJ, Graham R, Widman DG, Yount BL, Durbin AP, Whitehead SS, de Silva AM, and Baric RS

Subjects
Animals, Antibodies, Monoclonal metabolism, Cell Line, Chlorocebus aethiops, Cross Reactions immunology, Genotype, Glycosylation, Humans, Immune Sera metabolism, Kinetics, Neutralization Tests, Phylogeny, Serogroup, Temperature, Vaccination, Vero Cells, Antibodies, Neutralizing metabolism, Antibodies, Viral metabolism, Dengue Virus genetics, Genetic Variation
Abstract

There are four distinct DENV serotypes, and within DENV4, there are five distinct genotypes. The impact of genotypic diversity is not known, nor is it clear whether infection with one DENV4 genotype results in protective immunity against the other genotypes. To measure the impact of DENV4 genetic diversity, we generated an isogenic panel of viruses containing the envelope protein from the different genotypes. We characterized many properties of these viruses and find that a small number of amino acids changes within the envelope have disproportionate impacts on virus biology. Additionally, we observe large differences in the ability of DENV4 antibodies, immune sera, and vaccine sera to neutralize the panel, suggesting that DENV4 immunity might not be equally protective against all DENV4s. Our results support the monitoring of changing or emerging DENV genotypes and their role in escaping pre-existing neutralizing antibodies in people who have been vaccinated or exposed to natural DENV4 infections., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2018
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2. The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy.

Author

Lei Y, Wen H, Yu Y, Taxman DJ, Zhang L, Widman DG, Swanson KV, Wen KW, Damania B, Moore CB, Giguère PM, Siderovski DP, Hiscott J, Razani B, Semenkovich CF, Chen X, and Ting JP

Subjects
Adaptor Proteins, Signal Transducing physiology, Amino Acid Sequence, Animals, Autophagy-Related Protein 12, Autophagy-Related Protein 5, Autophagy-Related Proteins, Carrier Proteins physiology, Cytokines biosynthesis, Cytokines genetics, DEAD Box Protein 58, DEAD-box RNA Helicases physiology, Fibroblasts metabolism, Gene Expression Regulation immunology, HEK293 Cells, Humans, Interferon Type I genetics, Macrophages, Peritoneal cytology, Macrophages, Peritoneal immunology, Mice, Microtubule-Associated Proteins deficiency, Microtubule-Associated Proteins physiology, Mitochondrial Proteins chemistry, Mitochondrial Proteins deficiency, Mitochondrial Proteins genetics, Molecular Sequence Data, Multiprotein Complexes physiology, Peptide Elongation Factor Tu chemistry, Protein Interaction Mapping, Proteins physiology, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins physiology, Sequence Alignment, Sequence Homology, Amino Acid, Specific Pathogen-Free Organisms, Vesiculovirus physiology, Autophagy physiology, Interferon Type I biosynthesis, Mitochondrial Proteins physiology, Peptide Elongation Factor Tu physiology
Abstract

The mitochondrial protein MAVS (also known as IPS-1, VISA, and CARDIF) interacts with RIG-I-like receptors (RLRs) to induce type I interferon (IFN-I). NLRX1 is a mitochondrial nucleotide-binding, leucine-rich repeats (NLR)-containing protein that attenuates MAVS-RLR signaling. Using Nlrx1(-/-) cells, we confirmed that NLRX1 attenuated IFN-I production, but additionally promoted autophagy during viral infection. This dual function of NLRX1 paralleled the previously described functions of the autophagy-related proteins Atg5-Atg12, but NLRX1 did not associate with Atg5-Atg12. High-throughput quantitative mass spectrometry and endogenous protein-protein interaction revealed an NLRX1-interacting partner, mitochondrial Tu translation elongation factor (TUFM). TUFM interacted with Atg5-Atg12 and Atg16L1 and has similar functions as NLRX1 by inhibiting RLR-induced IFN-I but promoting autophagy. In the absence of NLRX1, increased IFN-I and decreased autophagy provide an advantage for host defense against vesicular stomatitis virus. This study establishes a link between an NLR protein and the viral-induced autophagic machinery via an intermediary partner, TUFM., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Published
2012
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