Role of Oxidative and Nitrosative Stress in Dengue Pathogenesis: A Mini-Review
Raimundo Castro-Orozco1* and Nelson Rafael Alvis-Guzmán2
1University of San Buenaventura, University of Cartagena, Cartagena, Colombia
2University of Cartagena, Children´s Hospital Foundation Napoleon Franco Pareja, Cartagena, Colombia
- *Corresponding Author:
- Raimundo Castro-Orozco
University of San
University of Cartagena
Received Date: August 26, 2016; Accepted Date: October 15, 2016; Published Date: October 18,
Citation: Castro-Orozco R, Alvis-Guzmán NR (2016) Role of Oxidative and
Nitrosative Stress in Dengue Pathogenesis: A Mini-Review. J Mol Genet Med 10:229 doi: 10.4172/1747-0862.1000229
Copyright: © 2016 Castro-Orozco R, et al. This is an open-access article
distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided
the original author and source are credited.
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Dengue is a mosquito–borne acute viral disease with ubiquitous distribution in tropical and subtropical areas of the world. Dengue virus (DENV) infection is transmitted by the bite of a female Aedes aegypti mosquito (the most important vector) infected with DENV. Clinical presentation of this typical arboviral disease varies along a wide spectrum of clinical symptoms. During the course of DENV infection, some individuals develop severe manifestations relates to plasma leakage into tissues caused by increased vascular permeability. The severity of dengue disease may vary considerably according to age, ethnicity, genetic factors, immune status and underlying disease. It may also depend on the co-circulation of DENV serotypes and sequential (secondary) infections with different DENV serotypes. While the exact mechanism of pathogenesis of dengue remains elusive, several lines of evidence demonstrating that DENV infection-derived oxidative stress may trigger the release of proinflammatory cytokines, including TNF-alpha, participating in collective action in dengue disease pathogenesis. In conclusion, we review these findings and discuss about the recent advances that propose a major role of oxidative-nitrosative stress on dengue pathogenesis.
Dengue; Dengue virus; Severe dengue; Oxidative stress;
Nitrosative stress; Endothelial dysfunction
Dengue is a mosquito–borne acute disease with ubiquitous
distribution in tropical and subtropical areas of the world. One example
of the importance of this viral disease can be seen in the results of a recent
multicentric study, which estimates 390 million dengue infections per
year (95% credible interval 284-528 million), of which approximately
25% (95% credible interval 67-136 million) manifest clinically (with
any severity of disease) . Dengue is caused by Dengue virus (DENV),
a single stranded RNA positive-strand virus of the family Flaviviridae.
There are four antigenically different serotypes of the virus (DENV-1
to -4) [2,3].
Clinical presentation of this typical arboviral disease varies along
a wide spectrum of clinical symptoms. During the course of DENV
infection, some individuals develop severe manifestations relates to
plasma leakage into tissues caused by increased vascular permeability.
The severity of dengue disease may vary considerably according to age,
ethnicity, genetic factors, immune status and underlying disease. It may
also depend on the co-circulation of DENV serotypes and sequential
(secondary) infections with different DENV serotypes [4-8]. In this
respect, it has been proposed the involvement of DENV infectionderived
oxidative stress on the severity of dengue .
By definition, oxidative stress is a disturbance in the balance between
the production of reactive oxygen species (ROS) and antioxidants
defenses in favour of the pro-oxidants [10,11]. A parallel process is
nitrosative stress which is defined as an indiscriminate nitrosilation of
biological molecules . Under these stress conditions, the activation
of several stress-sensitive intracellular signaling pathways have been
reported. This activation involves the production of gene products that
can lead to cell death and/or pathophysiological conditions [12-15].
Plasma leakage is the most important characteristic and the best
indicator of severity in dengue virus infection. The structural basis of
altered vascular permeability is more related to endothelial dysfunction
that destruction of endothelial cells (ECs) [16-19]. In this regard, Yacoub and coworkers  have recently reported association between
endothelial dysfunction and dengue severity in children and adults.
Many lines of independent empirical evidence explain the
relationship between endothelial dysfunction and oxidative stress [21- 31]. Endothelial dysfunction can be defined as the partial or complete
loss of balance between vasoconstrictor and vasodilators, growth
promoting and inhibiting factors, pro-atherogenic and anti-atherogenic
factors, and pro-coagulant and anti-coagulant factors. The earliest
manifestation of endothelial dysfunction is impaired endotheliumdependent
vasodilatation produced by diminished nitric oxide (NO)
bioactivity, mainly due to accelerated NO radical degradation by
reactive oxygen species (ROS) [32,33]. Consequently, this free radical
and messenger molecule is associated with inflammation and oxidative
Multiple studies have established that oxidative stress as a
determinant of vascular homeostasis [34-37], and is involved in the
pathogenesis of various infectious diseases, such as chronic hepatitis C
, Japanese encephalitis , leptospirosis , respiratory syncytial
virus-induced acute lung inflammation , malaria , chagas
cardiomyopathy , schistosomiasis , sepsis , acute herpes
simplex virus type 1, measles subacute sclerosing panencephalitis ,
and dengue .
For the latter example, Soundravally and coworkers suggest that
DENV infection-induced oxidative stress can trigger the release of proinflammatory cytokines, including TNF-alpha, participating
collectively in pathogenesis of severe dengue . This is consistent with
studies indicating that DENV virulent strains have a strong influence
on gene expression of a variety of proinflammatory cytokines [48-51].
Nwariaku and coworkers have reported that TNF-mediated
junctional dissociation and intercellular gap formation are associated
with tyrosine phosphorylation of vascular endothelial cadherin (VEcadherin)
. Interestingly, a growing body of evidence demonstrates
increased DENV-infected human ECs permeability in conjunction
with a downregulation of VE-cadherin by phosphorylation [52-56].
Additionally, there is evidence that an excess circulating
angiopoietin-2 (ang-2) may contribute with endothelial barrier
disruption caused by intercellular gap formation and downregulation of
VE-cadherin . It is important to note that ang-2 has been associated
with transient systemic vascular leak in DENV infection [58,59].
Moreover, Thakur et al.,  reported elevated levels of vascular
endothelial growth factor (VEGF) in adults with severe dengue in
comparison with patients with non-severe dengue with and without
warning signs. Considering that VEGF induces VE-cadherin tyrosine
phosphorylation in ECs , it is important note that VEGF induction
by NADPH oxidase-derived ROS [62,63], and DENV infectioninduced
intracellular ROS/RNS production have been reported [64,65].
A related study showed that profile of VEGF upregulated expression
was associated with DENV infection in human endothelial cells .
These data together provide direct evidence for role of oxidativenitrosative
stress in DENV-induced vascular leakage.
Survey of recent studies suggest important role of oxidativenitrosative
stress in pathogenesis of dengue [67,68]. These evidences
shows that oxidative/nitrosative stress may be associated with
production of dengue pathogenesis-related protein, increased
susceptibility of mice to DENV infection with higher replication,
hemorrhage development in experimental animal model, and
induction of apoptosis in various human and animal cell lines .
Also, changes in plasma levels of reactive nitrogen species (nitric oxide
radicals), endogenous antioxidants enzymes, lipid peroxidation and
protein oxidation markers has been observed in patients with dengue
In this context, we are now executing a study evaluating the
potential use of plasma levels of protein carbonyls, lipid hydroperoxides
and manganese-dependent superoxide dismutase, as prognostics
biomarkers for dengue infection severity in pediatric patients, in order
to early identification of patients who risk developing severe dengue,
and to focus treatment in these group of patients.
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