Abstract
BackgroundThe C-type lectin DC-SIGN (CD209) is known to be the major dengue receptor on human dendritic cells, and a single nucleotide polymorphism (SNP) in the promoter region of CD209 (−336 A/G; rs4804803) is susceptible to many infectious diseases. We reason that variations in the DC-SIGN gene might have a broad influence on viral replication and host immune responses.Methods and FindingsWe studied whether the rs4804803 SNP was associated with a susceptibility to dengue fever (DF) and/or dengue hemorrhagic fever (DHF) through genotyping analysis in a Taiwanese cohort. We generated monocyte-derived dendritic cells (MDDCs) from individuals with AA or AG genotype of rs4804803 to study the viral replication and immune responses for functional validation. A total of 574 DNA samples were genotyped, including 176 DF, 135 DHF, 143 other non-dengue febrile illnesses (OFI) and 120 population controls. A strong association between GG/AG genotypes of rs4804803 and risk of DHF was found when compared among DF, OFI and controls (p = 0.004, 3×10−5 and 0.001, respectively). The AA genotype was associated with protection against dengue infection compared with OFI and controls (p = 0.002 and 0.020, respectively). Moreover, MDDCs from individuals with AG genotype with a higher cell surface DC-SIGN expression had a significantly higher TNFα, IL-12p40, and IP-10 production than those with AA genotype in response to dengue infection. However, the viral replication in MDDCs with AG genotype was significantly lower than those with AA genotype. With both genotypes, MDDCs revealed an increase in viral replication following the addition of anti-IP-10 neutralizing antibody.Conclusions/SignificanceThe rs4804803 SNP in the CD209 promoter contributed to susceptibility to dengue infection and complication of DHF. This SNP with AG genotype affects the cell surface DC-SIGN expression related to immune augmentation and less viral replication.
Highlights
Dengue viruses (DEN) are arthropod-borne flaviviruses that cause dengue fever (DF) with significant morbidity and mortality in tropical and subtropical regions of the world
DC-SIGN, called CD209, expresses on dendritic cells (DCs) that bind to intercellular adhesion molecule 3 (ICAM-3), which is expressed on T cells to facilitate the initial interaction between DCs and T cells
Functional studies determined that monocyte-derived DCs (MDDCs) from individuals with AG genotype had significantly higher cell surface DC-SIGN expression, associated with higher TNFa, IL-12p40, and IFNinducible protein 10 (IP-10) production, but lower viral replication than those with AA genotype
Summary
Dengue viruses (DEN) are arthropod-borne flaviviruses that cause dengue fever (DF) with significant morbidity and mortality in tropical and subtropical regions of the world. There are four serotypes of dengue viruses (DEN types 1–4). Since the 1950s, a more severe form of the disease, dengue hemorrhagic fever (DHF), has been recognized worldwide [1]. DHF pathogenesis has been attributed to viral virulence versus immune enhancement; that has been the subject of debate for many years [2,3]. The C-type lectin DC-SIGN (CD209) is known to be the major dengue receptor on human dendritic cells, and a single nucleotide polymorphism (SNP) in the promoter region of CD209 (2336 A/G; rs4804803) is susceptible to many infectious diseases. We reason that variations in the DC-SIGN gene might have a broad influence on viral replication and host immune responses
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