Sweeping analysis of transcript profile in Dengue virus serotype 3 infection and Antibody-Dependent Enhancement of Infection

Dengue virus (DENV) is the most common vector-borne viral disease with nearly 400 million worldwide infections each year concentrated in the tropical and subtropical regions of the world. Severe dengue complications are often associated with a secondary heterotypic infection of one of the four circulating serotypes. In this scenario, humoral immune responses targeting cross-reactive, poorly-neutralizing epitopes can lead to increased infectivity of susceptible cells via antibody-dependent enhancement (ADE). In this way, antibodies produced in response to infection or vaccination are capable of contributing to enhanced disease in subsequent infections. Currently, there are no available therapeutics to combat DENV disease, and there is an urgent need for a safe and efficacious vaccine. Here, we developed a nucleotide-modified mRNA vaccine encoding for the membrane and envelope structural proteins from DENV serotype 1 encapsulated into lipid nanoparticles (prM/E mRNA-LNP). Vaccination of mice elicited robust antiviral immune responses comparable to viral infection with high levels of neutralizing antibody titers and antiviral CD4+ and CD8+ T cells. Immunocompromised AG129 mice vaccinated with the prM/E mRNA-LNP vaccine were protected from a lethal DENV challenge. Vaccination with either a wild-type vaccine, or a vaccine with mutations in the immunodominant fusion-loop epitope, elicited equivalent humoral and cell mediated immune responses. Neutralizing antibodies elicited by the vaccine were sufficient to protect against a lethal challenge. Both vaccine constructs demonstrated serotype specific immunity with minimal serum cross-reactivity and reduced ADE compared to a live DENV1 viral infection. IMPORTANCE With 400 million worldwide infections each year, dengue is the most common vector-born viral disease. 40% of the world's population is at risk with dengue experiencing consistent geographic spread over the years. With no therapeutics available and vaccines performing sub optimally, the need for an effective dengue vaccine is urgent. Here we develop and characterize a novel mRNA vaccine encoding for the dengue serotype 1 envelope and premembrane structural proteins that is delivered via a lipid nanoparticle. Our DENV1 prM/E mRNA-LNP vaccine induces neutralizing antibody and cellular immune responses in immunocompetent mice and protects an immunocompromised mouse from a lethal DENV challenge. Existing antibodies against dengue can enhance subsequent infections via antibody-dependent enhancement. Importantly our vaccine only induced serotype specific immune responses and did not induce ADE.

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Faculty Opinions recommendation of Dengue virus (DENV) antibody-dependent enhancement of infection upregulates the production of anti-inflammatory cytokines, but suppresses anti-DENV free radical and pro-inflammatory cytokine production, in THP-1 cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1090961.544319 ◽

2007 ◽

Author(s):

Scott Halstead

Keyword(s):

Free Radical ◽

Dengue Virus ◽

Inflammatory Cytokines ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Inflammatory Cytokine Production ◽

Antibody Dependent Enhancement ◽

Anti Inflammatory

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Faculty Opinions recommendation of Functional Transplant of a Dengue Virus Serotype 3 (DENV3)-Specific Human Monoclonal Antibody Epitope into DENV1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726209844.793524581 ◽

2016 ◽

Author(s):

Scott Halstead

Keyword(s):

Monoclonal Antibody ◽

Dengue Virus ◽

Human Monoclonal Antibody ◽

Antibody Epitope ◽

Virus Serotype

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Structural perspectives of antibody-dependent enhancement of infection of dengue virus

Current Opinion in Virology ◽

10.1016/j.coviro.2019.02.002 ◽

2019 ◽

Vol 36 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Seamus R Morrone ◽

Shee-Mei Lok

Keyword(s):

Dengue Virus ◽

Antibody Dependent Enhancement

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Micafungin Inhibits Dengue Virus Infection through the Disruption of Virus Binding, Entry, and Stability

Pharmaceuticals ◽

10.3390/ph14040338 ◽

2021 ◽

Vol 14 (4) ◽

pp. 338

Author(s):

Yen-Chen Chen ◽

Jeng-Wei Lu ◽

Chia-Tsui Yeh ◽

Te-Yu Lin ◽

Feng-Cheng Liu ◽

...

Keyword(s):

Dengue Virus ◽

Dengue Fever ◽

Early Stage ◽

Quantitative Polymerase Chain Reaction ◽

Enterovirus 71 ◽

Denv Infection ◽

Immunofluorescence Assay ◽

Dependent Manner ◽

Virus Binding ◽

Virus Serotype

Dengue fever is an arbovirus disease caused by infection with the dengue virus (DENV). Half of the world’s population lives under the threat of dengue fever, however, researchers have yet to develop any drugs that are clinically applicable to this infection. Micafungin is a member of the echinocandins family of anti-fungal drugs, capable of blocking the synthesis of β-1,3-D-glucan in the walls of fungal cells. Previous studies have demonstrated the effectiveness of Micafungin against infections of enterovirus 71 (EV71) and chikungunya virus (CHIKV). This is the first study demonstrating the effectiveness of micafungin in inhibiting the cytopathic effects of dengue virus serotype 2 (DENV-2) in a dose-dependent manner. Time-of-addition assays verified the inhibitory effects of micafungin in pre-treated, co-treated, and full-treatment groups. Binding and entry assays also demonstrated the effectiveness of micafungin in the early stage of DENV-2 infection. The virucidal efficacy of micafungin appears to lie in its ability to destroy the virion. Molecular docking assays revealed the binding of micafungin to the envelope protein of DENV-2, thereby revealing the mechanism by which micafungin affects the early stage of DENV infection and the stability of DENV. Two other micafungin analogs, caspofungin and anidulafungin, were also shown to have the antiviral effects on DENV-2. Finally, immunofluorescence assay (IFA) and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) confirmed the broad anti-DENV ability of micafungin against dengue virus serotypes 1, 3, and 4 (DENV-1, DENV-3, and DENV-4). Taken together, these results demonstrate the potential of micafungin and its analogs as candidates for the development of broad-spectrum treatments for DENV infection.

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