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Active Human Complement Reduces the Zika Virus Load via Formation of the Membrane-Attack Complex.

ABSTRACT: Although neglected in the past, the interest on Zika virus (ZIKV) raised dramatically in the last several years. The rapid spread of the virus in Latin America and the association of the infection with microcephaly in newborns or Guillain-Barré Syndrome in adults prompted the WHO to declare the ZIKV epidemic to be an international public health emergency in 2016. As the virus gained only limited attention in the past, investigations on interactions of ZIKV with human complement are limited. This prompted us to investigate the stability of the virus to human complement. At low serum concentrations (10%) which refers to complement concentrations found on mucosal surfaces, the virus was relatively stable at 37°C, while at high complement levels (50% serum concentration) ZIKV titers were dramatically reduced, although the virus remained infectious for about 4-5 min under these conditions. The classical pathway was identified as the main actor of complement activation driven by IgM antibodies. In addition, direct binding of C1q to both envelope and NS1 proteins was observed. Formation of the MAC on the viral surface and thus complement-mediated lysis and not opsonization seems to be essential for the reduction of viral titers.

SUBMITTER: Schiela B

PROVIDER: S-EPMC6199351 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Active Human Complement Reduces the Zika Virus Load via Formation of the Membrane-Attack Complex.

Schiela Britta B Bernklau Sarah S Malekshahi Zahra Z Deutschmann Daniela D Koske Iris I Banki Zoltan Z Thielens Nicole M NM Würzner Reinhard R Speth Cornelia C Weiss Guenter G Stiasny Karin K Steinmann Eike E Stoiber Heribert H

Frontiers in immunology 20181017

Although neglected in the past, the interest on Zika virus (ZIKV) raised dramatically in the last several years. The rapid spread of the virus in Latin America and the association of the infection with microcephaly in newborns or Guillain-Barré Syndrome in adults prompted the WHO to declare the ZIKV epidemic to be an international public health emergency in 2016. As the virus gained only limited attention in the past, investigations on interactions of ZIKV with human complement are limited. This ...[more]

PMID: 30386325

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Project description:BackgroundThe complement system functions primarily as a first-line host defense against invading microbes, including viruses. However, the interaction of Hepatitis B virus (HBV) with the complement-components during chronic HBV infection remains largely unknown. We investigated the mechanism by which HBV inhibits the formation of cytolytic complement membrane-attack complex (MAC) and studied its impact on MAC-mediated microbicidal activity and disease pathogenesis.MethodsBlood/liver tissues were collected from chronically HBV-infected patients and controls. HepG2hNTCP cells were infected with HBV particles and Huh7 cells were transfected with full-length linear HBV-monomer or plasmids containing different HBV-ORFs and expression of complement components or other host genes were evaluated. Additionally, ELISA, Real-time PCR, Western blot, bioinformatics analysis, gene overexpression/knock-down, mutagenesis, chromatin immunoprecipitation, epigenetic studies, immunofluorescence, and quantification of serum HBV-DNA, bacterial-DNA and endotoxin were performed.ResultsAmong the MAC components (C5b-C9), significant reduction was noted in the expression of C9, the major constituent of MAC, in HBV-infected HepG2hNTCP cells and in Huh7 cells transfected with full-length HBV as well as HBX. C9 level was also marked low in sera/liver of chronic hepatitis B (CHB) and Immune-tolerant (IT) patients than inactive carriers and healthy controls. HBX strongly repressed C9-promoter activity in Huh7 cells but CpG-island was not detected in C9-promoter. We identified USF-1 as the key transcription factor that drives C9 expression and demonstrated that HBX-induced hypermethylation of USF-1-promoter is the leading cause of USF-1 downregulation that in turn diminished C9 transcription. Reduced MAC formation and impaired lysis of HBV-transfected Huh7 and bacterial cells were observed following incubation of these cells with C9-deficient CHB sera but was reversed upon C9 supplementation. Significant inverse correlation was noted between C9 concentration and HBV-DNA, bacterial-DNA and endotoxin content in HBV-infected patients. One-year Tenofovir therapy resulted in improvement in C9 level and decline in viral/bacterial/endotoxin load in CHB patients.ConclusionCollectively, HBX suppressed C9 transcription by restricting the availability of USF-1 through hypermethylation of USF-1-promoter and consequently hinder the formation and lytic functions of MAC. Early therapy is needed for both CHB and IT to normalize the aberrant complement profile and contain viral and bacterial infection and limit disease progression.

Dataset Information

Active Human Complement Reduces the Zika Virus Load via Formation of the Membrane-Attack Complex.

Publications

Active Human Complement Reduces the Zika Virus Load via Formation of the Membrane-Attack Complex.

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