Molecular Mimicry of Human Endothelial Cell Antigen by Autoantibodies to Nonstructural Protein 1 of Dengue Virus

Abstract

The pathogenesis of dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS), both serious complications of dengue virus (DV) infection, remains unclear. In this study, we found that anti-DV NS1 (nonstructural protein 1) polyclonal antibodies cross-reacted with human umbilical vein endothelial cells (HUVECs). We further identified a complex-specific mAb, DB16-1, which could recognize DV NS1 and cross-react with HUVECs and human blood vessels. The target protein of DB16-1 was further purified by immunoaffinity chromatography. LC-MS/MS analysis and co-immunoprecipitation revealed that the target protein of DB16-1 was human LYRIC (lysine-rich CEACAM1 co-isolated). Our newly generated anti-LYRIC mAbs bound to HUVECs in a pattern similar to that of DB16-1. The B-cell epitope of DB16-1 displayed a consensus motif, Lys-X-Trp-Gly (KXWG), which corresponded to amino acid residues 116 -119 of DV NS1 and mimicked amino acid residues 334 -337 in LYRIC. Moreover, the binding activity of DB16-1 in NS1 of DV-2 and in LYRIC disappeared after the KXWG epitope was deleted in each. In conclusion, DB16-1 targeted the same epitope in DV NS1 and LYRIC protein on human endothelial cells, suggesting that it might play a role in the pathogenesis of DHF/DSS. Future studies on the role of the anti-NS1 antibody in causing vascular permeability will undoubtedly be performed on sera collected from individuals before, during, and after the endothelial cell malfunction phase of a dengue illness.Dengue virus (DV), 2 a flaviviridae, causes diseases ranging from mild dengue fever to severe syndromes, such as DHF and DSS (1, 2). Primary DV infection often leads to a painful but nonfatal dengue fever and protects patients from reinfection of DV of the same serotype. However, secondary infection with DV of a different serotype can trigger the more severe and potentially fatal DHF or DSS (1, 3). The clinical presentations of DHF/DSS include thrombocytopenia, vascular leakage, hemorrhage, and complement activation. Because little is known about the pathogenic mechanisms underlying these disorders, no effective strategy has been developed to prevent their occurrence (4, 5).Several theories have been proposed to explain the pathogenesis of the DHF/DSS. One of them is antibody-dependent enhancement. It is theorized that upon the second infection by DV of different serotype, monocytes and/or macrophages enhance uptake of complexes of virus with non-neutralizing antibodies, subneutralizing cross-reactive antibodies, or low titer neutralizing antibodies through the Fc receptor (1, 6). Hence, the increased viral load induces the plasma leakage or hemorrhage in DHF/DSS. It has been proposed that host immune reactions, including complement activation, immune cell activation, cytokine production, and immune deviation, are involved in the initiation of DHF/DSS (7-10). Others suggest that viral virulence may play a role in the pathogenesis of DHF/ DSS (11, 12). However, although many theories have been put forward, the main mechanism underlying the developmen...

Predicting Zika virus structural biology: Challenges and opportunities for intervention

“…Linear epitopes containing this sequence have been previously reported to generate polyclonal antibodies that cross-react with proteins expressed by human umbilical vein endothelial cells. 25 Comparison between ZIKV strains reveals only similar mutations (E52D, K69R, A194V, V236I, and V264M) in the b ladder and wing domains far from oligomeric interfaces. Eighty C-terminal residues are responsible for platelet dysfunction and pathogenesis in DENV.…”

Molecular Mimicry between Dengue Virus and Coagulation Factors Induces Antibodies To Inhibit Thrombin Activity and Enhance Fibrinolysis

“…Because there are many regions of DENV proteins that share sequence homology with various coagulation factors, molecular mimicry has been proposed to explain the induction of coagulation factor cross-reactive antibodies during DENV infection (32,39,40). To test this hypothesis, we purified DENV from DENVinfected C6/36 cell supernatants to immunize mice and rabbits.…”

Неугодная Иммунология

“…Секретируемый неструктур-ный гликопротеин NS1 играет свою роль в патогенезе DENV. Антитела к NS1 способны связываться с клет-ками эндотелия и вызывать их апоптоз [78,80].…”