Dataset Information

Asymmetric competitive suppression between strains of dengue virus.

ABSTRACT:

Background

Within-host competition between strains of a vector-borne pathogen can affect strain frequencies in both the host and vector, thereby affecting viral population dynamics. However little is known about inter-strain competition in one of the most genetically diverse and epidemiologically important mosquito-borne RNA virus: dengue virus (DENV). To assess the strength and symmetry of intra-host competition among different strains of DENV, the effect of mixed infection of two DENV serotypes, DENV2 and DENV4, on the replication of each in cultured mosquito cells was tested. The number of infectious particles produced by each DENV strain in mixed infections was compared to that in single infections to determine whether replication of each strain was decreased in the presence of the other strain (i.e., competition). The two DENV strains were added to cells either simultaneously (coinfection) or with a 1 or 6-hour time lag between first and second serotype (superinfection).

Results

DENV2 and DENV4 showed significantly reduced replication in mixed infection relative to single infection treatments. In superinfection treatments, replication was suppressed to a greater extent when the interval between addition of each strain was longer, and when a strain was added second. Additionally, competitive effects were asymmetric: although both strains replicated to similar peak population sizes in single infections, DENV2 was more suppressed than DENV4 in mixed infections. Superinfection treatments yielded significantly lower combined virus titers than coinfection or single infection treatments.

Conclusion

Competition between DENV strains in cultured mosquito cells can cause a significant decrease in peak viral population sizes, which could translate to decreased transmission by the vector. Effects of competition were asymmetric between DENV2 and DENV4, probably reflecting significant variation in the competitive ability of DENV strains in nature. Competition was strongest in superinfection treatments, suggesting that colonization of new DENV strains could be impeded in areas where numerous mosquitoes are infected with endemic DENV strains.

SUBMITTER: Pepin KM

PROVIDER: S-EPMC2259308 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Publications

Asymmetric competitive suppression between strains of dengue virus.

Pepin Kim M KM Lambeth Kalli K Hanley Kathryn A KA

BMC microbiology 20080208

<h4>Background</h4>Within-host competition between strains of a vector-borne pathogen can affect strain frequencies in both the host and vector, thereby affecting viral population dynamics. However little is known about inter-strain competition in one of the most genetically diverse and epidemiologically important mosquito-borne RNA virus: dengue virus (DENV). To assess the strength and symmetry of intra-host competition among different strains of DENV, the effect of mixed infection of two DENV ...[more]

PMID: 18261207

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Project description:Flaviviral infections including dengue virus are an increasing clinical problem worldwide. Dengue infection triggers host production of the type 1 IFN, IFN alpha, one of the strongest and broadest acting antivirals known. However, dengue virus subverts host IFN signaling at early steps of IFN signal transduction. This subversion allows unbridled viral replication which subsequently triggers ongoing production of IFN which, again, is subverted. Identification of downstream IFN antiviral effectors will provide targets which could be activated to restore broad acting antiviral activity, stopping the signal to produce endogenous IFN at toxic levels. To this end, we performed a targeted functional genomic screen for IFN antiviral effector genes (IEGs), identifying 56 IEGs required for antiviral effects of IFN against fully infectious dengue virus. Dengue IEGs were enriched for genes encoding nuclear receptor interacting proteins, including HELZ2, MAP2K4, SLC27A2, HSP90AA1, and HSP90AB1. We focused on HELZ2 (Helicase With Zinc Finger 2), an IFN stimulated gene and IEG which encodes a promiscuous nuclear factor coactivator that exists in two isoforms. The two unique HELZ2 isoforms are both IFN responsive, contain ISRE elements, and gene products increase in the nucleus upon IFN stimulation. Chromatin immunoprecipitation-sequencing revealed that the HELZ2 complex interacts with triglyceride-regulator LMF1. Mass spectrometry revealed that HELZ2 knockdown cells are depleted of triglyceride subsets. We thus sought to determine whether HELZ2 interacts with a nuclear receptor known to regulate immune response and lipid metabolism, AHR, and identified HELZ2:AHR interactions via co-immunoprecipitation, found that AHR is a dengue IEG, and that an AHR ligand, FICZ, exhibits anti-dengue activity. Primary bone marrow derived macrophages from HELZ2 knockout mice, compared to wild type controls, exhibit enhanced dengue infectivity. Overall, these findings reveal that IFN antiviral response is mediated by HELZ2 transcriptional upregulation, enrichment of HELZ2 protein levels in the nucleus, and activation of a transcriptional program that appears to modulate intracellular lipid state. IEGs identified in this study may serve as both (1) potential targets for host directed antiviral design, downstream of the common flaviviral subversion point, as well as (2) possible biomarkers, whose variation, natural, or iatrogenic, could affect host response to viral infections.

Project description:Any potential dengue virus (DENV) vaccine needs to elicit protective immunity against strains from all four serotypes to avoid potential antibody-dependent enhancement (ADE). In this study, four independent DENV envelope (E) glycoproteins were generated using wild-type E sequences from viruses isolated between 1943 and 2006 using computationally optimized broadly reactive antigen (COBRA) methodology. COBRA and wild-type E antigens were expressed on the surface of subvirion viral particles (SVPs). Four separate wild-type E antigens were used for each serotype. Mice vaccinated with wild-type DENV SVPs had anti-E IgG antibodies that neutralized serotype-specific viruses. COBRA DENV SVPs elicited a broader breadth of antibodies that neutralized strains across all four serotypes. Two COBRA DENV vaccine candidates that elicited the broadest breadth of neutralizing antibodies in mice were used to vaccinate rhesus macaques (Macaca mulatta) that either were immunologically naive to any DENV serotype or had preexisting antibodies to DENV. Antibodies elicited by COBRA DENV E immunogens neutralized all 12 strains of DENV in vitro, which was comparable to antibodies elicited by a tetravalent wild-type E SVP vaccination mixture. Therefore, using a single DENV COBRA E protein can elicit neutralizing antibodies against strains representing all four serotypes of DENV in both naive and dengue virus-preimmune populations.IMPORTANCE Dengue virus infects millions of people living in tropical areas of the world. Dengue virus-induced diseases can range from mild to severe with death. An effective vaccine will need to neutralize viruses from all four serotypes of dengue virus without inducing enhanced disease. A dengue virus E vaccine candidate generated by computationally optimized broadly reactive antigen algorithms elicits broadly neutralizing protection for currently circulating strains from all four serotypes regardless of immune status. Most dengue vaccines in development formulate four separate components based on prM-E from a wild-type strain representing each serotype. Designing a monovalent vaccine that elicits protective immunity against all four serotypes is an effective and economical strategy.

Dataset Information

Asymmetric competitive suppression between strains of dengue virus.

Background

Results

Conclusion

Publications

Asymmetric competitive suppression between strains of dengue virus.

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