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Host genetics and dengue fever

Article  in  Infection, Genetics and Evolution: Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases · November 2017
DOI: 10.1016/j.meegid.2017.11.009

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 Infection, Genetics and Evolution 56 (2017) 99–110

Contents lists available at ScienceDirect

Infection, Genetics and Evolution

journal homepage: www.elsevier.com/locate/meegid

Review

Host genetics and dengue fever T

a b a
Caroline Xavier-Carvalho , Cynthia Chester Cardoso , Fernanda de Souza Kehdy ,
⁎
Antonio Guilherme Pachecoc, Milton Ozório Moraesa,
a
Laboratório de Hanseníase, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ, Brazil
b
Laboratório de Virologia Molecular, Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, RJ, Brazil
c
Programa de Computação Científica (PROCC) – FIOCRUZ, Rio de Janeiro, RJ, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: Dengue is a major worldwide problem in tropical and subtropical areas; it is caused by four different viral
Dengue serotypes, and it can manifest as asymptomatic, mild, or severe. Many factors interact to determine the severity
Polymorphisms of the disease, including the genetic profile of the infected patient. However, the mechanisms that lead to severe
Cytokines disease and eventually death have not been determined, and a great challenge is the early identification of
SNPs
patients who are more likely to progress to a worse health condition. Studies performed in regions with cyclic
GWAS
CD209
outbreaks such as Cuba, Brazil, and Colombia have demonstrated that African ancestry confers protection
against severe dengue. Highlighting the host genetics as an important factor in infectious diseases, a large
number of association studies between genetic polymorphisms and dengue outcomes have been published in the
last two decades. The most widely used approach involves case-control studies with candidate genes, such as the
HLA locus and genes for receptors, cytokines, and other immune mediators. Additionally, a Genome-Wide
Association Study (GWAS) identified SNPs associated with African ethnicity that had not previously been
identified in case-control studies. Despite the increasing number of publications in America, Africa, and Asia, the
results are quite controversial, and a meta-analysis is needed to assess the consensus among the studies. SNPs in
the MICB, TNF, CD209, FcγRIIA, TPSAB1, CLEC5A, IL10 and PLCE1 genes are associated with the risk or pro-
tection of severe dengue, and the findings have been replicated in different populations. A thorough under-
standing of the viral, human genetic, and immunological mechanisms of dengue and how they interact is es-
sential for effectively preventing dengue, but also managing and treating patients.

1. Introduction
Tropical and subtropical countries are prone to dengue epidemics
caused by four viral serotypes circulating around the world: DENV-1, 2,
3 and 4 (Messina et al., 2014; WHO, 2009). The Asian and American
tropical regions have the highest incidence of dengue due to their cli-
mate conditions (Bhatt et al., 2013; Guzman et al., 2016; Messina et al.,
2014; WHO, 2009). The recent emergence of other arboviruses, such as
Zika and Chikungunya (Lucas et al., 2016; Roberto et al., 2015) in Latin
American countries including Brazil, has brought new challenges—-
mainly due to the similarities among these diseases—that can hamper
the correct diagnosis and management of patients.
Dengue is a multifactorial disease, in which both viral and human
genetic factors contribute to the pathogenesis and disease outcomes.
The spectrum of dengue can range from asymptomatic (the majority of
the cases) to mild or more severe disease with bleeding, plasma leakage,
and the involvement of organs such as the heart and nervous system.
The mechanisms that can lead to more severe disease and eventually
death have not yet been described. One of the most challenging aspects
of the disease is the early identification of patients who are prone to a
worse prognosis (WHO, 2009). The critical phase occurs around the
fourth to sixth day; a cytokine storm seems to be the cause of the se-
verity observed during this time. However, the intrinsic reasons for this
unbalanced cytokine production, as well as which mediators regulate
the progression towards a more severe disease, are unknown.
The most commonly accepted hypothesis for the occurrence of se-
vere dengue is a secondary infection by a distinct DENV serotype. An
infection with a specific serotype - for example, DENV-1 - confers long-
term immunity against it but can trigger nonspecific responses against
all the other types (i.e., DENV-2, 3, or 4). In this case, it is suggested
that the memory T cells produced during a primary infection can react
more readily but with less effectiveness than naïve cells during a sec-
ondary nonspecific infection, resulting in an inefficient immune re-
sponse with the deregulated production of cytokines. This theory is

⁎
Corresponding author.
E-mail address: milton.moraes@fiocruz.br (M.O. Moraes).

https://doi.org/10.1016/j.meegid.2017.11.009
Received 17 July 2017; Received in revised form 7 November 2017; Accepted 9 November 2017
Available online 10 November 2017
1567-1348/ © 2017 Elsevier B.V. All rights reserved.
C. Xavier-Carvalho et al.
known as “original antigenic sin” (Halstead et al., 1983;
Mongkolsapaya et al., 2006). A similar assumption is the antibody-de-
pendent enhancement hypothesis, in which the nonspecific antibodies
produced during a secondary infection with a heterologous serotype
lead to higher viral uptake and replication in target cells, such as
monocytes, through Fc receptors (Guzman and Vazquez, 2010;
Halstead, 1979).
Despite the clear evidence for both theories, the majority of in-
dividuals living in endemic dengue areas have antibodies against the
dengue virus and do not develop severe forms of the disease. In con-
trast, several epidemiological studies have demonstrated the occurrence
of severe dengue during primary infections in children and adults
(Balmaseda et al., 2006; Halstead et al., 2002; Hung et al., 2004;
Khurram et al., 2014; Lin et al., 2010; Soo et al., 2016). These data
reinforce the multifactorial nature of dengue fever and suggest that
additional immunological or genetic factors are associated with more
severe disease outcomes. Consequently, the small number of severe
cases among dengue patients during a single epidemic and the low
frequency of symptomatic dengue patients—considering the high
number of exposed and infected individuals—suggest that host genetics
play a role in dengue. All of these issues will be discussed in this review.
2. Study design and genetic association studies in dengue
There are different approaches to investigating genetic associations
with infectious diseases, and published reviews have discussed the
strategies for performing this type of genetic analysis (Pacheco and
Moraes, 2009; Reid-Lombardo and Petersen, 2017). Thus, we will not
present those strategies here. Nevertheless, it is important to mention
that the most popular approach to identifying associations using genetic
variables involves case-control studies that test candidate genes, where
single nucleotide polymorphisms (SNPs) are the markers of choice.
Their features include being biallelic, having a wide distribution in the
genome, being easy to genotype, and having the ability to be tested on a
large scale. According to this approach, the allele for one SNP will be
the exposure factor, while the disease and its different forms will be the
outcome. Nowadays, there are several databases with tools enabling the
location of tag SNPs in different population, providing information
about linkage disequilibrium analysis and the relevant functional ef-
fects (Adzhubei et al., 2010; Xu and Taylor, 2009). Thus, case-control
studies have been widely used in research on dengue.
The influence of host genetics on dengue was first suggested by
comparisons among the occurrence frequencies of severe cases in eth-
nically distinct populations. As demonstrated by Halstead (2001) and
reviewed by Sierra et al. (2006), both dengue hemorrhagic fever (DHF)
and dengue syndrome shock (DSS) have a low incidence among Afro-
descendants. Accordingly, a study conducted among Brazilians from the
state of Bahia showed an association between African ancestry and
protection against severe dengue (Blanton et al., 2008). Similar results
were obtained from two studies involving Colombian subjects (Chacón-
Duque et al., 2014; Rojas Palacios et al., 2016). The subsequent de-
velopment of association studies, mostly using candidate genes related
to the immune response, has helped to better explain the role of genetic
variations in dengue.
3. Genome-wide association studies
The first genome-wide association study (GWAS) conducted on
dengue enrolled 2008 pediatric DSS cases from Vietnam and 2018 cord
blood controls and the results were replicated in an independent
Vietnamese cohort (Khor et al., 2011). The results obtained from this
study showed an association among the major histocompatibility
complex class I polypeptide-related sequence B (MICB) and phospho-
lipase C, epsilon 1 (PLCE), and DSS. The most significant SNPs asso-
ciated with DSS were rs3132468 where the allele C; showed Odds Ratio
(OR) = 1.41 and rs3134899 (allele G; OR = 1.31) at MICB and
100
Infection, Genetics and Evolution 56 (2017) 99–110
rs3765524 at PLCE1 (allele T; OR = 0.77) (Khor et al., 2011). The same
genes were investigated in another replication study among Thai people
(Dang et al., 2014) and the results of the MICB analysis were similar to
those obtained in the GWAS. However, the PLCE1 SNP rs3765524 was
associated with an increased risk of DSS (allele C; OR = 1.49; Dang
et al., 2014). It is important to note that the alleles associated with
protection and risk (T and C) are different, which confirms an asso-
ciation in the same direction.
Later, the same group responsible for the GWAS extended the ana-
lysis to determine possible associations between MICB and PLCE1 and
less severe dengue outcomes (Whitehorn et al., 2013). The study in-
cluded 7 cohorts (4 pediatric and 3 adult), with a total of 3961 dengue
cases with different clinical outcomes and 5968 cord blood controls.
The pooled ORs indicated an association between the SNPs MICB
rs3132468 and PLCE1 rs3740360 and dengue cases without shock.
However, in both cases, the OR values were close to null (allele C for
both; OR = 1.15 for rs3132468 and OR = 0.92 for rs3740360), sug-
gesting a subtler effect in comparison to the GWAS. Additionally, an in
silico analysis showed that the SNPs at MICB and PLCE previously as-
sociated with DSS in the above-cited GWAS deleteriously affected DNA-
protein interactions (Taqi et al., 2016).
A more recent and very interesting GWAS analyzed 2.5 million SNPs
in a cohort of 274 dengue patients from Cuba recruited during the 2006
epidemic. The major breakthrough of this study was the employment of
ancestry analysis to identify SNPs associated with protection among
African descendants. The authors confirmed that African ancestry was
associated with protection against DHF and identified haplotypes in
oxysterol binding protein-like 10 (OSBPL10) and SNPs at the retinoid X
receptor alpha (RXRA) genes associated genetically and functionally
with DHF protection in Africans (Sierra et al., 2017). OSBPL and RXRA
are genes related to steroid metabolism, and lipid profile alterations are
already known to be associated with severe dengue (Durán et al.,
2015).
4. Classical HLA alleles
Long-term host-pathogen interactions have shaped the human
genome, and infectious agents are probably some of the most important
recent evolutionary forces. It has been suggested that in highly endemic
areas where humans and deadly pathogens coexist, the human popu-
lations exhibit genetic variations indicative of selective pressure.
Infectious agents, whether viruses, bacteria, or parasites, have been
shaping the human genome towards adaptive responses that can be
detected through the emergence of resistant genotypes in different
human genes associated with diseases.
The set of genes involved in the innate immune responses clearly
shows a high nucleotide diversity and strong positive selection
(Ferwerda et al., 2007; Fornarino et al., 2011; Manry et al., 2011;
Mukherjee et al., 2013) and the human leukocyte antigen (HLA) com-
plex, located at the 6p21 chromosome region, is the most polymorphic
human gene family. HLA class I (A, B, and C) and class II (DR, DQ, and
DP) alleles were the first candidates for dengue association studies in
different ethnicities including Indians, Cubans, Vietnamese, Filipinos,
Brazilians, Sri Lankans, Mexicans, and Malays. A previous study per-
formed a wide review of HLA case controls for dengue (Stephens,
2010). Despite the great number of studies, the results remain highly
discrepant, and no replication has been observed in different studies.
Furthermore, there is a lack of functional data to corroborated genetic
findings. The alleles for the HLA locus associated with dengue outcomes
are summarized in Table 1.
5. Non-HLA immune-response genes associated with dengue
outcomes
Upon infection, the innate immune system is capable of recognizing
pathogenic structures through several receptors on the cell surface.
C. Xavier-Carvalho et al. Infection, Genetics and Evolution 56 (2017) 99–110

Table 1 populations showed an association between the allele -336G and DHF
Association studies between HLA locus and dengue. (Sakuntabhai et al., 2005; Wang et al., 2011). Later, a study including
the promoter SNPs at the − 871 (rs735239), −336 (rs4804803), and
Allele Region Association Reference
− 139 (rs2287886) positions showed an association between allele G
HLA-DR4 Mexico Protection against LaFleur et al., 2002 and genotype GG at − 139 (rs2287886) as well as the A/A/G haplotype
DHF and an increased risk of developing DF among Indians (Alagarasu et al.,
HLA-DRB1*07 India Risk of DHF Alagarasu et al.,
2013a, 2013b, 2013c). In addition, the AA genotype at − 871
HLA-DRB1*07/ 2013a, 2013b,
15 2013c (rs735239) was associated with thrombocytopenia, and no association
HLA-DRB1*09:01 Vietnam Protection against Lan et al., 2008 was found for the − 336 SNP (Alagarasu et al., 2013a, 2013b, 2013c).
HLA-A*24 DSS Similarly, another case-control study conducted among Thais and in-
Risk of DSS cluding an appropriate number of subjects did not confirm the pre-
HLA-B*35 Mexico Protection against or Falcón-Lezama
viously reported association between the − 336 SNP and DHF (Dang
HLA-DQB1*0302 dengue fever (DF) et al., 2009
HLA-DQB1*0202 Risk of DHF et al., 2016).
Risk of DF The association between the CD209 gene and dengue outcomes has
HLA-B*48 Thailand Risk of DHF Vejbaesya et al., also been investigated in American populations. The − 336 promoter
HLA-B*57 2009
variation (rs4804803) was investigated in Mexicans, and a borderline
HLA-DPB1*0501
HLA-A*0207 Thailand Risk of DHF Stephens et al., association (p = 0.08) between allele G and dengue fever risk was
HLA-B*51 Risk of DHF 2002 observed when patients with uncomplicated symptoms were compared
HLA-B*52 Risk of DF with asymptomatic individuals (Noecker et al., 2014). Studies con-
HLA A*31 Cuba Risk of DHF Sierra et al., 2007 ducted among Brazilians showed a protective association between the
HLA-B*15 Risk of DHF
GG genotype or G carriers and dengue severity (Silva et al., 2010b;
DRB1*07 Protection against
DF/DHF Xavier-Carvalho et al., 2013).
HLA-A*33:01 Philippines Risk of DHF and DSS Mercado et al., 2015 The conflicting results have encouraged the development of a meta-
HLA-B*53 Malaysia Risk of DHF Appanna et al., analysis to define consensus estimates for the effect of the − 336 SNP in
HLA-A*03 Protection against 2010
dengue infection. A total of 5 studies were included (Alagarasu et al.,
HLA-B*18 DHF
HLA-A*31 DRB1*08 Sri Lanka Risk of DSS Malavige et al.,
2013a, 2013b, 2013c; Sakuntabhai et al., 2005; Silva et al., 2010a;
2011 Wang et al., 2011; Xavier-Carvalho et al., 2013), and no association was
HLA-B*44 Brazil Risk of DHF Xavier Eurico de observed. However, when populations were stratified into Asian and
HLA-B*07 Protection against Alencar et al., 2013 Brazilian subjects and pooled ORs were defined, the results showed
HLA-DR*13 DHF
opposite associations with risk and protection (Xavier-Carvalho et al.,
Protection against
DHF 2013).
HLA-A*01 Brazil Risk of DHF Monteiro et al., The SNP at − 336 affects the SP1 transcription site and, therefore,
2012 may influence promoter activity (Liu et al., 2003; Sakuntabhai et al.,
HLA-DQ1 Brazil Risk of DF Polizel et al., 2004
2005). Cells from individuals with the AG genotype expressed higher
HLA-DR1
DC-SIGN levels, producing more TNF and IP-10 and lower viral re-
plication than cells from individuals with the AA genotype (Wang et al.,
After pathogen binding—in this case, the binding of the dengue vir- 2011). In contrast, Lozach et al. (2005) found a positive correlation
us—there is uptake of the virus and consequent increase in replication. between the DC-SIGN expression levels on cell surfaces and viral re-
At the same time, the virus-receptor interaction activates downstream plication (Lozach et al., 2005).
pathways, resulting in the production of inflammatory and antiviral In spite of the relevant functional effects for − 336 at the CD209
mediators. These mediators can contribute to the resolution of a disease promoter, the result for this SNP should be carefully considered. Even
or lead to more severe symptoms. though the meta-analysis indicates an ethnic influence, few studies
Several immune mediators and their receptors are present at in- were analyzed to obtain a pooled OR, and the studies had weaknesses
creased levels in patient's serum with dengue and severe dengue. It has such as a small number of patients and different disease classifications.
been reported that tumor necrosis factor (TNF), interferon-gamma Furthermore, other SNPs also located in the promoter region may have
(IFNγ), macrophage migration inhibitory factor (MIF), different inter- an additive effect either independently or through haplotype combi-
leukins (IL)-1β, -4, -6, -8, -10, and chemokines are upregulated during nations with −336 SNP.
the first days of infection (Bozza et al., 2008; Braga et al., 2001; Cui While DC-SIGN seems to play a central role in viral uptake, CLEC5A
et al., 2016; Ferreira et al., 2015; Mustafa et al., 2001; Singla et al., (C-type lectin domain containing 5A) has an important role in signaling
2016). Many of the genes for these mediators have been analyzed to test pathways, mainly those resulting in the release of proinflammatory
the frequency of SNPs in cases as compared to controls that are dis- cytokines (Chen et al., 2008; Cheng et al., 2016; Cheung et al., 2011;
cussed below. Paradowska-Gorycka and Jurkowska, 2013; Turnbull and Colonna,
2007). The CLEC5A gene encodes the receptor, which is expressed in
myeloid cells (Bakker et al., 1999). An association between a SNP at the
6. Innate immune genes 3′ near-gene region (rs1285933, T > C) and severe dengue among
Brazilians was previously shown (Xavier-Carvalho et al., 2013). More
6.1. DC-SIGN and CLEC5A specifically, TT carriers were associated with severe dengue, and
functional analyses have shown higher TNF levels among patients with
The CD209 gene encodes the dendritic cell-specific intercellular TT and TC genotypes.
adhesion molecule 3 grabbing nonintegrin (DC-SIGN), which is con- More recently, our group replicated this result using an independent
sidered to be the main receptor for the dengue virus in dendritic cells cohort from another region in Brazil while functional analysis con-
and macrophages (Tassaneetrithep et al., 2003). Therefore, the CD209 firmed the relationship between CLEC5A and TNF also indicating a
gene has been extensively studied in dengue, and the promoter SNP possible connection with other pathways (Xavier-Carvalho et al., 2017)
− 336 G/A (rs4804803) has been the most common candidate in these highlighting the important role of CLEC5A in dengue im-
studies. However, the role of CD209 variations in dengue susceptibility munopathogenesis.
is still controversial. The results of studies of Taiwanese and Thai

101
C. Xavier-Carvalho et al.
6.2. FCγRIIA receptor
FCγRIIA gene codes for one of the Fc receptors (Nimmerjahn and
Ravetch, 2008), which are expressed in antigen-presenting cells such as
macrophages and dendritic cells and bind to antigen-antibody com-
plexes. Fc receptors play a central role in dengue immunopathogenesis
due to their putative activity in antibody-dependent enhancement,
which is associated with disease severity in dengue (Guzman and
Vazquez, 2010; Littaua et al., 1990).
The uptake of antigen-antibody complexes may vary according to
the Fc receptor. More specifically, it has been shown that FcγRIA binds
only to neutralizing antibodies, being more efficient than FcγRIIA in
neutralizing activity (Chawla et al., 2013). A recent interesting study
showed that patients who develop severe dengue produce IgG anti-
bodies with a higher affinity for FcγRIIIA due to structural modifica-
tions that result in platelet reduction and thrombocytopenia, reinfor-
cing the role of these receptors in severe dengue outcomes (Wang et al.,
2017).
The nonsynonymous polymorphism Arg131His (rs1801274) at the
FCγRIIA gene was studied in different populations, and results are
discrepant. The Arg/Arg (RR) genotype was associated with protection
against DHF among Vietnamese children (Loke et al., 2002). The
homozygous HH131 genotype was significantly associated with risk to
either DF, DHF,DSS or bleedings in three different studies from Cuba
and Pakistan (Garcia et al., 2012; García et al., 2010; Mohsin et al.,
2015). On the other hand, the homozygous genotype for histidine (HH)
and the heterozygous (HR) were found associated with protection for
DF and DHF in Mexicans (Noecker et al., 2014). Among Indians, the RR
genotype was associated with thrombocytopenia but not with disease
outcomes (Alagarasu et al., 2015b, 2015c, 2015d). Although results are
not consistent so far, HH genotype appeared at least in two populations
in association with different phenotypes of severe dengue.
6.3. Toll-like receptors, TIRAP, and DDX58
Toll-like receptors (TLRs) recognize pathogen-associated molecular
patterns (PAMPs), activating innate immune cells. Among the TLRs,
there are some such as TLR3, TLR7, and TLR8 that recognize double-
and single-stranded RNA and, therefore, are directly associated with
immune responses against viral infections. Moreover, TLR2, TLR4, and
TLR6 can recognize other proteic or lipoproteic viral structures (Kumar
et al., 2009a, 2009b). TLR4 is an extracellular receptor expressed in
monocytes, macrophages, and endothelial cells. In the context of
dengue infections, this receptor can be activated by NS1(Modhiran
et al., 2017), resulting in the production of type I interferons (IFNs) and
other inflammatory cytokines (Kumar et al., 2009b). A study performed
on Indian dengue patients (DHF/DSS) and healthy controls described
an increased susceptibility to dengue infections (DF + DHF/DSS)
among heterozygotes for the SNPs Asp299Gly (rs4986790) and
Thr399IIe (rs4986791) in TLR4 (Sharma et al., 2016a). The same SNPs
were also investigated in a study from Indonesia, including in children
with DHF and healthy controls, but no association was observed
(Djamiatun et al., 2011).
Polymorphisms in the TLRs expressed in intracellular compartments
have also been associated with dengue outcomes. The polymorphism
rs3775291 (Phe/Leu), at the TLR3 gene, is associated with altered NF-
κB activation (Zhou et al., 2011), and genotypes carrying allele
rs3775291T (coding for phenylalanine) are associated with protection
against DHF as compared to DF. Meanwhile, the haplotypes
rs3764879C and rs3764880A, at TLR8, are associated with the risk of
DF among males, while the G/G haplotype is associated with DHF
(Alagarasu et al., 2015b, 2015c, 2015d). Additionally, other SNPs in
genes of the TLR family (toll interleukin-1 receptor domain containing
adapter protein, or TIRAP) and RNA cytoplasmic receptors such as re-
tinoic acid inducible gene I (DDX58) have been tested. The rs8177374
CT and rs669260 TC genotypes at TIRAP and DDX58, respectively,
102
Infection, Genetics and Evolution 56 (2017) 99–110
were associated with DHF (Alagarasu et al., 2015b; Alagarasu and
Memane, 2015a).
6.4. Proinflammatory cytokines and related receptors
Tumor necrosis factor is considered to be the major proin-
flammatory cytokine in infectious disease pathogenesis. TNF is im-
portant in the early elimination of the dengue virus, but high yields of
this cytokine can contribute to an exacerbated inflammation and a
worse prognosis. Indeed, in the serum of severe dengue patients, high
TNF have been detected (Braga et al., 2001; Singla et al., 2016), al-
though others did not find any differences when classic and severe
forms were compared (Priyadarshini et al., 2010). TNF has been studied
in dengue infection experimental models corroborating its role in in-
flammation during DENV infection (Assunção-Miranda et al., 2010;
Chen et al., 2008; Chuang et al., 2011; Rothman, 2011).
Many genetic studies have shown associations between SNPs in the
TNF and dengue outcomes. SNPs at the −308 (rs1800629) and − 238
(rs1799964) positions are the most common candidates tested. A study
of Venezuelan subjects associated allele −308A carriers with an in-
creased risk of DHF compared to DF (Fernández-Mestre et al., 2004).
Similarly, Perez et al. (2010) found an association between the haplo-
types containing − 308A and DHF in a cohort of patients from Cuba
with a secondary infection after a previous exposure to DENV-1/2
(Perez et al., 2010). According to the data from Alagarasu et al. (2013a,
2013b, 2013c), the A allele for the −308 SNP showed a higher fre-
quency in DHF compared to DF and controls, but this difference was not
significant, although heterozygosity (GA) was associated with DHF
among Indians (Alagarasu et al., 2013a, 2013b, 2013c).
In parallel, − 308 homozygosity (GG) was associated with risk of
severe dengue in studies performed in Sri Lanka and Malaysia
(Fernando et al., 2015; Sam et al., 2015). A case-control study con-
ducted by our group that included subjects from southern Brazil did not
show an association between the − 308 SNP and dengue (Xavier-
Carvalho et al., 2013). In the same study, we performed a meta-analysis
to define consensus estimates for the effect of the -308 SNP in dengue. A
pooled OR was obtained from four studies, but no significant associa-
tion was found (Xavier-Carvalho et al., 2013). Later, the meta-analysis
was updated to include eight studies (dos Santos et al., 2017), and a
consensus estimate indicating an association between the -308GG
genotype and susceptibility to symptomatic dengue was found, how-
ever, no association was found between DHF and DF. On the other hand
(in the same meta analysis) the GA genotype and the − 308A allele
were associated with protection symptomatic dengue, with p values
between 0.03 and 0.05 (dos Santos et al., 2017). It has been suggested
that − 308A is associated with higher TNF levels (Bayley et al., 2004).
Therefore, it could be speculated that higher production early during
infection may contain virus replication and protect against dengue
fever.
For the −238 SNP, allele A was also associated with risk of DHF/
DSS among Malaysian people (Sam et al., 2015); in the same way,
haplotypes containing this allele were also associated with risk of DHF
in Thai people (Vejbaesya et al., 2009) and were associated with pro-
tection against DF/DHF in Mexican people (Garcia-Trejo et al., 2011).
In addition to TNF, polymorphisms in other cytokines, chemokines,
and their receptors, such as IL1B, IL6, IL10, and IL1RA, have been in-
vestigated in dengue outcomes, but results are not conclusive
(Cansanção et al., 2016; Sa-ngasang et al., 2014).
6.5. IFNs and related genes: OASs, JAK, STING
Viral components such as dsRNA and ssRNA can trigger the secre-
tion of IFNs, which bind to the receptor on infected cells and induce
interferon-stimulated genes (ISGs), leading to antiviral status (Sadler
and Williams, 2008). The type I response in dengue is well character-
ized, and it is notable that IFN-deficient mice are highly susceptible to
C. Xavier-Carvalho et al.
infection (Muller et al., 1994). Even so, the dengue virus has developed
numerous strategies to escape from the host immune response (Aguirre
et al., 2012; Muñoz-Jordan et al., 2003).
IFNγ is a classic cytokine inducing granuloma formation and in-
tracellular bacterial killing. However, it is also an antiviral mediator
with important role in the activation of macrophages. Unlike IFNα and
β, which are more important for controlling an infection during its early
stages, IFNγ appears to be important during the later stages of an in-
fection (Shresta et al., 2004). Yet, its effects during dengue infection are
still controversial, and IFNγ has already been associated with severe
dengue and a higher viral load (Pal et al., 2017; Pandey et al., 2015). A
case-control study performed on Brazilians found the rs243056 SNP AA
genotype to be associated with DF, compared to other febrile diseases
and healthy controls (Feitosa et al., 2016).
The oligoadenylate synthetases (OASs) belong to the group of ISGs,
and their induction contributes to the antiviral response (Lin et al.,
2009; Samuel, 2001). The key role of these molecules was shown in a
study with mutant mice that were highly susceptible to a flavivirus
infection (Mashimo et al., 2002). A genetic association study conducted
by Alagarasu et al. (2013a, 2013b, 2013c) detected no association after
the analysis of single SNPs at OAS genes. Other studies also failed to
consistently find association (Thamizhmani and Vijayachari, 2014).
Nevertheless, a careful and unique study combining host with pathogen
genotype interaction found serotype-specific associations between OAS
variants and dengue severity in Thailand (Simon-Loriere et al., 2015).
The OAS3 common allele 381R was associated with protection for
DENV-2 infection (OR = 0.13) but not for DENV-1. This result suggest
that specific circulating DENV serotypes might interact differentially
with populations indicating distinct prevalence rates for severity in
Asian and Latin America(Simon-Loriere et al., 2015).
Finally, the association of SNPs at the JAK1 (Janus kinase) gene and
dengue severity was investigated in a study from Northern Brazil. JAK
is responsible for STAT (signal transducer and activator or transcrip-
tion) phosphorylation (Samuel, 2001). Five SNPs at this gene
(rs11208534, rs2780831, rs310196, rs310222, and rs310216) were
associated with DHF in this sample (Silva et al., 2010a).
6.6. Cytokines related to apoptosis and immune regulation: IL-10, TGFβ,
CTLA-4 and BAK1
Like TNF, IL-10 is a cytokine broadly studied in dengue and other
infectious diseases due to its anti-inflammatory properties and T cell
immunosuppressive effects (Adikari et al., 2016). High levels of IL-10,
but also TGF-β have been found in the serum of dengue patients,
especially in the later stages of infection (Abhishek et al., 2017; Pandey
et al., 2015). IL-10 serum levels were associated with T-cell apoptosis in
patients who developed DSS (Cecchinato et al., 2008), while TGF-β was
associated with an increase in platelet production (Malavige et al.,
2012). A study from Indonesia showed lower TGF-β levels in children
who developed DHF than in controls, but no association was found with
the platelet count (Djamiatun et al., 2011).
A large number of studies have investigated the association of the
IL10 gene with dengue. The results from Cuba showed that the haplo-
types ACC and ATA for the −1082 (G > A), − 819 (C > T), and
− 592 (C > A) SNPs were associated with DHF risk (Perez et al.,
2010). These haplotypes were previously studied and associated with
low IL-10 expression (Turner et al., 1997). From these observations, the
authors suggested that the haplotypes associated with DHF could be
responsible for inefficient immune regulation (Perez et al., 2010). In
addition, a study conducted in Sri Lanka confirmed the association
between the same haplotypes and DHF, while alternative combinations
were associated with protection against the same phenotype (Fernando
et al., 2015).
Our group has also investigated the role of the IL10 −819C > T
SNP among Brazilians, but no association was found with severe dengue
(Xavier-Carvalho et al., 2013). Among Indian people, the − 819 SNP
103
Infection, Genetics and Evolution 56 (2017) 99–110
GA genotype was associated with protection against DHF compared to
DF (Alagarasu et al., 2015b, 2015c, 2015d), and a recent meta-analysis
did not find an association between the − 819 SNP and dengue (dos
Santos et al., 2017). Nevertheless, ACC and ATA IL10 haplotypes that
are classically associated with low IL-10 production seems to contribute
towards the progression of severe forms of dengue (Fernando et al.,
2015; Perez et al., 2010), but more studies with larger sample sizes are
needed to confirm this hypothesis.
Regarding TGF-β, the CC genotype for the − 509C > T SNP was
associated with DHF compared to DF in Taiwan (Chen et al., 2009). In
addition, a combination of the TGF-β −509 CC and the CTLA4 + 49G
SNP was also associated with DHF (Chen et al., 2009). CTLA-4 is a
cytokine that can act in the regulation of Treg cells and T-cell activation
(Cecchinato et al., 2008; Jiang et al., 2007). Thus, SNPs in these genes
can play a role in control of a proinflammatory response. However, this
result lack the support of functional studies. Finally, the SNP rs5745568
(G allele), located at the gene coding region for the BCL-2 homologous
antagonist/killer (BAK1), was associated with a risk of DHF in a Thai
population (Dang et al., 2016). BAK1 is known to mediate the control of
platelet apoptosis in mice (Mason et al., 2017) and thrombocytopenia is
a hallmark of severe dengue, thus SNPs at BAK1 also can play a role in
dengue immunopathogenesis through the control of platelet survival.
6.7. MBL, CFH and VDR
The MBL2 gene encodes mannose-binding lectin (MBL), a plasmatic
glycoprotein with an important involvement in innate immune re-
sponses. MBL is produced by the liver and is capable of initiating the
complement cascade independently of antibodies, through binding to
the carbohydrates present in microorganisms (Jack et al., 2001). MBL
has a role in DENV neutralization (Fuchs et al., 2017). The mutations
for any variant at codons 52 (allele D), 54 (allele B), or 57 (allele C) at
MBL2 can result in low MBL levels in serum. Combinations of these
alleles were associated with DHF in Brazilian patients from the city of
Recife (Figueiredo et al., 2016). On the other hand, a study performed
in the same city found an association between the wild-type genotype
variant and thrombocytopenia, with a borderline p value (0.06; Acioli-
Santos et al., 2008). MBL2 polymorphisms were also investigated in
Thai patients, and no association was observed. However, the haplotype
YB is associated with low MBL levels. Y is an allele for the SNP at the
− 221 position, and allele B is referent to variant 54 (Prommalikit and
Nayok, 2015). Accordingly, Figueiredo et al. (2016) showed that hap-
lotypes containing the Y allele for SNP −221 are associated with low
MBL levels in dengue (Figueiredo et al., 2016).
Variations in the gene coding for the complement factor H (CFH)
have also been studied in dengue. The SNP genotypes and haplotypes of
the CFH gene were associated with protection against severe dengue
among Brazilians; moreover, lower levels of CFH were observed in DHF
patients (Nascimento et al., 2009). The allele T at CFH − 257
(rs3753394) was associated with higher CFH expression. Indeed, a
protective effect was detected for the SNP at the −257 site and also the
nonsynonymous variation G257A (Val/Ile, rs800292) in severe dengue
(Pastor et al., 2013).
The vitamin D receptor mediates the effects of 1,25-dihydroxy-vi-
tamin D3 and can modulate immunopathogenesis during dengue
through the regulation of several mediators such as TNF and IFNγ
(Puerta-Guardo et al., 2012; Vidyarani et al., 2007). Studies with cell
lines have shown a decrease in dengue infection and the production of
proinflammatory cytokines such as TNF and IL1β after treatment with
vitamin D (Puerta-Guardo et al., 2012; Vidyarani et al., 2007). Studies
have also shown vitamin D to regulate the expression of DC-SIGN and
FCγRIIA (Torres et al., 2010). A study performed in Vietnam described
an association between allele T for the SNP located at the 352
(rs731236) position and protection against DHF (Loke et al., 2002).
Alagarasu et al. (2012) associated allele C and the CC genotype for the
rs7975232 SNP with protection against dengue (DF + DHF). The same
C. Xavier-Carvalho et al. Infection, Genetics and Evolution 56 (2017) 99–110

Table 2
Single nucleotide polymorphisms associated with severity in dengue and replicated in at least two populations.

SNP/gene OR (p value) Allele/genotype Population Sample size Outcome Ref

MICB rs3132468 1.41 (5.39 × 10− 8) C Vietnam1 2008 casesC DSS Khor et al., 2011
2018 controlsA
1.27 (9.32 × 10− 5) C Vietnam1 1737 cases DSS Khor et al., 2011
2934 controlsA
− 11
OR meta 1.34 (4.41 × 10 ) C Vietnam 3745 casesD DSS Khor et al., 2011
4952 controlsA
1.15 (0.0014) C Vietnam 3961 casesD Severe dengue Whitehorn et al.,
5968 controlsA without shock 2013
1.58 (0.02) C Thailand 76 casesC DSS Dang et al., 2014
84 controls non DSSC
-308 TNF rs1800629 2.53 (0.04) GG Sri Lanka 107 cases DHF Fernando et al., 2015
67 controls IgG+
2.48 (0.009)/2.44 (0.007) GG/G Malaysia 196 cases DHF/DSS Sam et al., 2015
120 controls IgG −
2.5 (95% IC: 1.47–4.13) A Venezuela 25 cases DHF Fernández-Mestre
46 controls et al., 2004
1.62 (0.04)/1.62 (0.03)/ GG/G/GA/A South Americans and 384 cases Symptomatic dengue dos Santos et al., 2017
0.69(0.04)/0.64 (0.05) Asians 995 controls IgG ±
CD209 rs4804803 DF vs controls 2.34 (0.018) G carrier (GG/GA) Taiwan 135 DHF DF and DHF Wang et al., 2011
(-336) DHF vs controls 3.57 (0.001) 176 DF
DHF vs DF 2.44 (0.02) 120 controls IgG ±
DF vs controls 0.09 (0.001) G carrier (GG/GA) RA Thailand1 182 DHF DF and DHF Sakuntabhai et al.,
DFH vs DF 14.31 51 DF 2005
(2.3 × 10− 4) 296 controls
DF vs controls 0.34 (0.018) G carrier (GG/GA) SI Thailand1 167 DHF DF and DHF Sakuntabhai et al.,
DF vs DHF 3.79 (0.0024) 72 DF 2005
214 controls
DF vs controls 0.008 (0.012) G carrier (GG/GA) KK Thailand1 103 DHF DF and DHF Sakuntabhai et al.,
DHF vs DF 99.75 (0.037) 27 DF 2005
183 controls
OR meta 5.84 (1.4 × 10− 7) G carrier (GG/GA) Thailand1 452 DHF DHF Sakuntabhai et al.,
150 DF 2005
0.12 (0.04) GG Brazil 88 casesC Severe dengue Xavier-Carvalho
333 controls IgG ± et al., 2013
2
ORallele meta 2.77 (0.0001) G and G carriers South American and 616 DHF and severe Severe dengue/DHF Xavier-Carvalho
ORcarrier meta 2.99 (0.0001)2 (GG/AG) Asian countries cases et al., 2013
ORallele meta 0.66 (0.013)3 409 DF or healthy
controls IgG+
IL-10 2.54 (0.03) A/C/C or A/T/A Cuba 43 cases DHF Perez et al., 2010
-1082/-819/-592 99 controls
2.42 (0.04) A/C/C or A/T/A Sri Lanka 107 cases DHF Fernando et al., 2015
67 controls IgG+
TPSAB1 2.54 (0.0084) αα Vietnam1 107 casesC DHF Vasquez Velasquez
α tryptase 1 195 controlsC et al., 2015
3.52 (p < 0.0001) αα Vietnam1 218 casesC DSS Vasquez Velasquez
198 controlC et al., 2015
3.37 (p < 0.0001) αα Philippines 1
121 casesC DSS Vasquez Velasquez
268 controlsC et al., 2015
CLEC5A 2.25 (0.03) TT Brazil 88 casesC Severe dengue Xavier-Carvalho
rs1285933 333 controls IgG ± et al., 2013
2.11 (0.04) T carriers (TC/CC) Brazil 151 severe cases Severe dengue Xavier-Carvalho
62 mild controls et al., 2017
FcγRIIA 0.57 (0.036) Arg/Arg (RR) Vietnam 302 casesC DHF Loke et al., 2002
rs1801274 238 controlsC
4
(Arg131His) 0.67 (0.032) Allele H and Mexico 145 asymptomatic DF and DHF or severe Noecker et al., 2014
0.51(0.038)4 carriers of H (HH 67DF
0.45 (0.026)5 + HR) 37 DHF
DF vs subclinical 2.82 (0.04) Allele H and Pakistan 40 subclinical DF, DHF/DSS Mohsin et al., 2015
DHF/DSS vs subclinical carriers of H (HH 40 DF
3.90 (0.02) + HR) 30 DHF/DSS
Subclinical vs DF: 4.42 (0.03) HH Cuba 68 DF DF García et al., 2010
Subclinical vs DHF: 10.5 29 DHF or DSS DHF
(0.00)
PLCE1 rs3765524 0.77 (2.68 × 10− 7) T Vietnam1 2008 casesC DSS Khor et al., 2011
2018 controlsA
0.83 (1.60 × 10− 4) T Vietnam1 1737 cases DSS Khor et al., 2011
2934 controlsA
− 10
OR meta 0.80 (3.08 × 10 ) T Vietnam 3745 casesD DSS Khor et al., 2011
4952 controlsA
1.49 (0.02) C Thailand 76 DSS casesC DSS Dang et al., 2014
841 non DSS controlsC
(continued on next page)

104
C. Xavier-Carvalho et al.
Table 2 (continued)
SNP/gene OR (p value) Allele/genotype Population
−8
PLCE1 rs3740360 0.75 (5.84 × 10 ) C Vietnam
0.85 (0.0012) C Vietnam1
OR meta 0.80 (1.15 × 10− 9) C Vietnam
0.92 (0.018) C Vietnam
1- independent cohorts from the same study; 2- pooled OR for Asian studies; 3- pooled OR for Brazilian studies; 4- symptomatic versus assymptomatic; 5- severe dengue versus
asymptomatic; A- controls are cord blood; C- children, teenager or school age; D- children and adult; IgG +: dengue seropositive; IgG−: dengue seropositive; IgG ± : dengue seropositive
and seronegative. In the absence of C and D individuals enrolled individuals are adults. Some studies do not provide information about IgG test among controls.
study showed an association between allele T at rs2228570 SNP and
DHF (Alagarasu et al., 2012).
6.8. ICAM-1 and TPSAB1
Intercellular cell adhesion molecule-1 (ICAM-1) is a glycoprotein
present on the surface of endothelial cells and leukocytes but can also
be secreted and detected in the serum during the infectious or in-
flammatory process, including in severe dengue (Anderson et al., 1997;
Cardier et al., 2006; Gearing and Newman, 1993). ICAM-1 mediates
cell-cell adhesion and therefore has an important role in cell migration
during inflammation. Vascular adhesion cell activation triggers plasma
leakage, which can occur during severe dengue. A study performed
among Indians found that homozygous individuals (EE) for the rs5498
SNP (K469E) presented a higher risk of DHF/DSS and had higher mRNA
ICAM-1 levels (Sharma et al., 2016b).
Tryptases are storage proteins inside mast cells and together, chy-
mases and vascular endothelial cell growth factor (VEGF) can act as
markers of inflammation and the activation of mast cells, which are
important cells in the allergy process (Galli et al., 2005). Previous
studies have demonstrated the participation of mast cells in dengue
infection, due to the higher levels of VEGF, tryptase, and chymase
among patients who developed DHF/DSS (Furuta et al., 2012). TPSAB1
encodes α and β tryptase 1 proteases. Homozygosity (αα) characterized
by the deletion of 10 bp at intron 4 of the TPSAB1 gene was associated
with DHF in two cohorts from Vietnam and one cohort from Philippines
(Vasquez Velasquez et al., 2015).
7. Study limitations and conclusions
Case-control studies for dengue usually have limitations, and the
main one is choosing the ideal control group. The best-case scenario
would be test the disease severity in a study where the controls would
be IgG + people that recollect mild dengue fever cases. Asymptomatic
individuals could show IgG positive results indicating previous ex-
position and certainly no severity. However, studies have used an ap-
proach in which severe, DHF, or DSS cases were compared to a mild or
DF group, which seems a realistic strategy.
Most of the studies enrolled a low number of individuals for the
comparisons made, and very few studies were able to ascertain the virus
serotype that infected each individual. Also, functional validations of
the associated genes/SNPs are scarce. As a result, many discrepancies
can be seen among associations across different populations that, on
one hand, may highlight the ancestry differences in association studies
for infectious diseases, as discussed before; on the other hand, the
discrepancies could also be a result of spurious associations.
Another key issue is the classification of dengue, which can be
confusing across studies. The DHF and DF classifications from the WHO
(1997) are still widely used in genetic studies, but in comparison with
the WHO (2009) criteria, some patients who were previously classified
as DHF would now be identified as having mild cases, and the
105
Infection, Genetics and Evolution 56 (2017) 99–110
Sample size Outcome Ref
1 C
2008 cases DSS Khor et al., 2011
2018 controlsA
1737 cases DSS Khor et al., 2011
2934 controlsA
3745 casesD DSS Khor et al., 2011
4952 controlsA
3961 casesD Severe dengue Whitehorn et al.,
5968 controlsA without shock 2013
association with severity can be false. Furthermore, within the DHF
group, patients can be classified as degrees I, II, III, and IV, but not all
studies identified the degree of the patients enrolled, and they were
usually analyzed together, which could lead to the over- or under-
estimation of the number of severe dengue patients.
As reviewed here, even the most-studied genes have shown highly
discrepant results, such as the HLA, DC-SIGN and TNF genes, although
for DCSIGN and TNF meta-analysis helped to reach a consensus esti-
mate. The − 336GG/GA at CD209 (DC-SIGN), rs3132468C at MICB,
− 308 GG genotype at TNF, αα genotype at TPSAB1, histidine allele for
SNP Arg131His at the FcγRIIA, A/C/C or A/T/A (− 1082/− 819/
− 592) haplotype at IL-10 promoter and rs1285933 T allele at the
CLEC5A genes, were the ones associated with a risk of severe dengue
that were also replicated in at least two independent populations, while
rs3740360 C allele at PLCE1 was the one associated with protection to
severe dengue and replicated (Table 2).
From the data and genes reviewed here, and considering mainly
those with results replicated in different cohorts, several mechanisms
have a confirmed role in determining the severity of dengue fever. The
presence of polymorphisms in specific genes (Fig. 1) can disrupt these
protective mechanisms starting with innate immunity receptors, from
those resulting in viral uptake (DC-SIGN) to mechanisms related to the
activation of signaling pathways (CLEC5A). In fact, DC-SIGN and
CLEC5A can act synergistically, increasing CLEC5A signaling after
dengue binding (Lo et al., 2016). SNPs at their respective genes can
change DC-SIGN and CLEC5A functions individually or with an additive
effect, resulting in an increase or decrease in the viral load and proin-
flammatory response, considering the canonical DC-SIGN and down-
stream CLEC5A pathways, respectively.
MICB encodes a protein that is a ligand for the NKG2D type II re-
ceptor expressed in NK and CD8 + T cells; the engagement of NKG2D
after MICB protein binding results in a signaling pathway via adapters
such as DAP10 or DAP12 (Lazear et al., 2013). DAP12 is also activated
after the dengue virus binds to CLEC5A and seems to modulate cellular
activation in different ways (Cheung et al., 2011; Turnbull and
Colonna, 2007; Watson et al., 2011). Hoang et al. (2010) demonstrated
that MICB is highly expressed in cells from patients with acute dengue
and has a central role in antiviral activity (Hoang et al., 2010); thus,
SNPs at MICB can affect MICB-NKG2D binding and disrupt the antiviral
response by NK and CD8 + T cells.
After the first interaction with receptors, the change in cytokine
production is known to be crucial in dengue pathogenesis, and SNPs at
TNF and IL10 were highlighted here. Additionally, the inflammatory
mechanisms previously unknown during viral infections, such as the
engagement of mast cells, have been shown to be important for sur-
veillance against viral pathogens (King et al., 2002; St. John et al.,
2011; St et al., 2011).
Regarding associations with protection against severe dengue,
PLCE-1 is a phospholipase enzyme that catalyzes the hydrolysis of
phosphatidylinositol-4,5-bisphosphate, producing second messengers
that, in turn, regulate cell processes such as growth, differentiation, and
C. Xavier-Carvalho et al. Infection, Genetics and Evolution 56 (2017) 99–110

Fig. 1. Most important SNPs at genes and pathways that regulates host immune response and severity in dengue fever. 1- SNPs at MICB can affect levels of the protein impairing its
ligation with NKG2D. After MICB-NKG2D binds on surface of NK or CD8+ T cells, cellular activation through DAP10 and DAP12 occurs with production of pro-inflammatory cytokines
(TNF), antiviral mediators (type I IFNs), and production of perforin and granzyme leading, consequently, to T cells activation. 2 and 3- Similarly, SNPs at CLEC5A and CD209 (DC-SIGN)
can affect proteins levels changing virus uptake (DC-SIGN) or signaling pathways through DAP12 (CLEC5A). Red arrows represent virus uptake. In this case, the specific allele associated
with a higher expression of the receptors resulting in a higher virus uptake and the efficient DAP12 signaling is represented. 4- Associated SNPs at FcγRIIA are nonsynonymous can
interfere in protein structure resulting in a higher or lower antibody-virus complex uptake depending of the specified, Arg or His, amino acid. 5- SNPs at TLRs can affect dengue virus
interaction on cell surface or could also affect viral structures interaction inside the cells modulating antiviral and pro-inflammatory response. 6- SNPs at tryptase, more specifically α
allele, can contribute with pro-inflammatory process and vascular permeability.7- SNPs at genes of the type I or II IFN pathways can interfere in its production and function such as T cells
activation and antiviral response in NK and antigen presenting cells upon DENV antigen stimulation. 8- SNPs at TNF can affect its expression levels that could interfere in vascular
permeability. 9- SNP at IL10 gene can change its RNAm expression and regulate of TNF and other Th1 responses. (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)

gene expression. The authors who found the association suggested that
PLCE-1 could play a role in the regulation of blood pressure and the
maintenance of a normal vascular endothelial cell barrier (Khor et al.,
2011; Whitehorn et al., 2013).
Finally, SNPs at the OSBPL10 and RXRA genes were identified from
a GWAS in association with protection against severe dengue in people
with African ancestry. These genes participate in lipid metabolism, and
since an alteration in the lipid profile has a role in dengue and severe
dengue, allele variants for OSBPL10 and RXRA deserve more attention
for possible therapeutic models for dengue infection (Durán et al.,
2015; Suvarna and Rane, 2009; van Gorp et al., 2002; Villar-centeno
et al., 2008).
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