Dengue Virus, Susceptibility To

A number sign (#) is used with this entry because variation in several different genes likely influences susceptibility and resistance to dengue virus, as well as disease progression and severity.

A promoter polymorphism in the CD209 gene (604672) is associated with protection from dengue fever, but not dengue hemorrhagic fever.

Description

Dengue virus is a flavivirus belonging to the family Flaviviridae. Its principal vector is Aedes aegypti, a highly urbanized, daytime-biting mosquito that breeds in stored water. There are 4 antigenetically variant serotypes of dengue virus, DEN-1 to DEN-4, and type-specific immunity against one serotype cannot block infection with another serotype. Disease manifestations following dengue infection range from subclinical infection to severe and fatal disease, with age, gender, genotype, immunologic status, and flavivirus infection history of the host all influencing disease severity. Primary infection is mainly associated with dengue fever (DF). Symptoms of DF typically appear 4 to 7 days after the mosquito bite and include high fever, headache, retroocular pain, conjunctival changes, and facial flushing. Although primary dengue infections are mostly recovered, a secondary infection with a different serotype of the virus leads to the complex condition of dengue hemorrhagic fever (DHF) with plasma leakage and thrombocytopenia or a more fatal condition, dengue shock syndrome (DSS). High fever, hemorrhagic phenomenon, hepatomegaly, and circulatory failure are mainly associated with DHF. Hemorrhages in DHF are seen in skin, subcutaneous tissues, heart, liver, and gastrointestinal tract. An estimated 50 to 100 million illnesses due to dengue infection occur annually, including 250,000 to 500,000 cases of DHF and 24,000 deaths. About 2.5 billion people are estimated to be at risk, particularly those living in tropical and subtropical areas of Asia and Latin America (reviews by Faheem et al. (2011), Whitehorn and Simmons (2011), and Guzman et al. (2010)).

Pathogenesis

Dengue virus (DV) primarily targets dendritic cells. Navarro-Sanchez et al. (2003) found that anti-DCSIGN (CD209; 604672) and the soluble tetrameric ectodomain of DCSIGN inhibited DV infection. The data indicated that DCSIGN functions as a DV-binding lectin that interacts as an attachment factor with the DV envelope glycoprotein.

Using ELISA, Chen et al. (2008) found that CLEC5A (604987), in addition to DCSIGN, interacted with DV. The DV-CLEC5A interaction promoted phosphorylation of DAP12 (TYROBP; 604142) and did not result in viral entry, but it did stimulate secretion of proinflammatory cytokines, including TNF (191160) and IL6 (147620), by macrophages. Blockade of DV-CLEC5A interaction suppressed proinflammatory cytokine secretion without affecting IFNA (147660) release. Treatment of DV-infected Stat1 (600555)-deficient mice with anti-Clec5a inhibited DV-induced plasma leakage and subcutaneous and vital organ hemorrhaging, resulting in a 50% reduction in mortality. Chen et al. (2008) proposed that CLEC5A signaling blockade offers a promising strategy for mitigating the effects of DHF and DSS.

Sessions et al. (2009) identified insect host factors required for dengue virus propagation by carrying out a genomewide RNA interference screen in D. melanogaster cells using a well established 22,632 double-stranded RNA library. This screen identified 116 candidate dengue virus host factors (DVHFs). Although some were previously associated with flaviviruses, most of the DVHFs were newly implicated in dengue virus propagation. The dipteran DVHFs had 82 readily recognizable human homologs and, using a targeted short interfering RNA screen, Sessions et al. (2009) showed that 42 of these are human DVHFs. These include NPR2 (108961), SEC61B (609214), TMEM214, TAZ (300394), EXDL2, and CNOT2 (604909). Sessions et al. (2009) concluded that this overlap indicates notable conservation of required factors between dipteran and human hosts.

Using a focused RNA interference analysis, followed by validation with pharmacologic inhibitors, Heaton et al. (2010) identified 3 cellular pathways required for DV replication: autophagy, actin polymerization, and fatty acid biosynthesis. They identified FASN (600212) as a key enzyme in the fatty acid biosynthetic pathway and showed that FASN relocalized to sites of DV replication. DV nonstructural protein-3 (NS3) colocalized with FASN and interacted with FASN in a 2-hybrid assay. Purified recombinant NS3 stimulated FASN activity in vitro. Heaton et al. (2010) proposed that DV co-opts the fatty acid biosynthesis pathway to establish replication complexes.

Dengue virus may become more virulent or show greater outbreak potential in a population exposed to new viral strains. Manokaran et al. (2015) identified a determinant of fitness in a new clade (PR-2B) of Dengue virus serotype-2 (DENV-2) that became dominant during a 1994 epidemic in Puerto Rico and replaced an endemic clade (PR-1) of DENV-2. PR-2B DENV-2 showed increased levels of subgenomic flavivirus RNA (sfRNA) compared with genomic RNA during replication. PR-2B sfRNA exhibited sequence-dependent binding to and prevention of TRIM25 (600453) deubiquitylation, which is required for sustained and amplified RIGI (DDX58; 609631)-induced type I interferon (see 147640) expression. Manokaran et al. (2015) concluded that a distinctive viral RNA-host protein interaction leads to evasion of the innate immune response, resulting in increased epidemiologic fitness of the new viral strain.

Marques et al. (2015) observed reduced replication of DENV in mouse and human monocytes treated with an antagonist of CCR5 (601373) expression. DENV induced expression of CCR5 ligands, and CCR activation was required for permissiveness to DENV replication. CCR5 did not act as a DENV receptor, but it colocalized with DENV at the macrophage membrane. Marques et al. (2015) demonstrated that antagonism of Ccr5 in mouse macrophages prevented replication of DENV. Macrophages lacking Ccr5 also showed reduced DENV replication. Ccr5 -/- mice were protected against lethal challenge from at least 2 strains of DENV, and this protection was associated with reduced viral load, lower cytokine production, and lower inflammatory responses. Mice pretreated with Ccr5 antagonists were protected from DENV infection. Marques et al. (2015) concluded that CCR5 contributes to DENV replication in vitro and to disease development in vivo.

Wang et al. (2017) noted that dengue virus infection can be exacerbated to DHF or DSS when it occurs in the presence of reactive, nonneutralizing IgG (RNNIg) through the mechanism of antibody-dependent enhancement (ADE). However, this progression to severe disease occurs in less than 15% of RNNIg-positive patients. Wang et al. (2017) found that patients with DHF/DSS produced IgG with enhanced affinity to FCGR3A (146740) due to the presence of afucosylated (i.e., lacking fucose sugar units) glycans of the IgG1 subclass. RNNIg enriched for afucosylated IgG1 triggered platelet reduction in vivo and was a significant risk factor for thrombocytopenia. Wang et al. (2017) proposed that therapeutics and vaccines that restrict afucosylated IgG1 RNNIg production during infection may prevent ADE of dengue virus disease.

Reviews

Independently, Whitehorn and Simmons (2011) and Faheem et al. (2011) reviewed dengue pathogenesis and strategies for dengue vaccine development.

Molecular Genetics

Sakuntabhai et al. (2005) found that a CD209 promoter polymorphism, -336A-G (604672.0001), was associated with severity of dengue disease. Specifically, the G allele of the variant was associated with strong protection against dengue fever, but not against dengue hemorrhagic fever. These results indicated that CD209 has a crucial role in dengue pathogenesis, which discriminates between severe dengue fever and dengue hemorrhagic fever.

By genotype analysis of 50 Brazilians with probable or possible dengue hemorrhagic fever (DHF), 236 Brazilians with dengue fever (DF), and 236 Brazilians with asymptomatic infections during the active transmission year of 2002 to 2003, Silva et al. (2010) identified SNPs in the 5-prime end of JAK1 that were significantly associated with DHF. Increased risk was associated with individuals homozygous for T at rs11208534 in intron 3 and homozygous for G at rs2780831 in intron 2, whereas protection was associated with homozygosity for T at rs310196 in intron 1. The 3 markers each showed association with African ancestry, with the susceptible genotypes having a lower frequency in these individuals. No association was observed with markers in CD209. Silva et al. (2010) concluded that association of JAK1 with DHF is in agreement with data indicating that generalized decreased type I IFN-stimulated gene expression occurs in these patients.

Khor et al. (2011) performed a genomewide association study of 2,008 pediatric cases treated for dengue shock syndrome and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at 2 loci showed genomewide significant association with dengue shock syndrome. Khor et al. (2011) identified a susceptibility locus at MICB (602436), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, p(meta) = 4.41 x 10(-11), per-allele odds ratio = 1.34, 95% confidence interval 1.23-1.46). They identified associated variants within PLCE1 (601282) on chromosome 10 (rs3765524, p(meta) = 3.08 x 10(-10), per-allele odds ratio = 0.80, 95% confidence interval 0.75-0.86).