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Acta Médica Costarricense
On-line version ISSN 0001-6002Print version ISSN 0001-6012
Acta méd. costarric vol.54 n.2 San José Apr./Jun. 2012
Review
New
Perspectives on Dengue Pathogenesis
Eugenia
Corrales-Aguilar y Laya Hun-Opfer
Abbreviations: ADE,
Antibody dependent enhancement; DC, dendritric
cell;
EC, endothelial cell; DENV, dengue virus; DF, dengue fever; DHF, dengue
hemorrhagic fever; HLA, human leukocyte antigen; IFN, interferon; IL,
interleukin; CNS, central nervous system; DSS, dengue shock syndrome.
Abstract
Dengue
viral infections represent a major concern for
public health. Yet, the mechanisms of dengue virus (DENV) pathogenesis
are not
understood very well yet, since there are no suitable animal models for
studying the course of disease. The only source of knowledge is limited
to
clinical studies involving patients, which vary a lot and do not allow
for the
accurate understanding of the pathological events that occur during
viral
infection. Nevertheless, several factors seem to be related to DENV
pathogenesis:
i) viral factors, such as virulence and
virus
transmissibility and ii) host determinants like the immune response,
immune
status and genetic characteristics.
In this
review we describe the factors that play an
important role in dengue pathogenesis in order to have a better
understanding
of the disease and to allow for a more suitable therapeutic management
of
patients. Since the current disease classification used for determining
risk
factors during the course of a dengue infection is no longer congruent
with the
clinical studies performed, the use of the new dengue disease
classification
dictated by the World Health Organization (WHO) is suggested.
Keywords: dengue,
virus, pathogenesis, severe dengue
The dengue
virus (DENV) has a worldwide distribution
in tropical and subtropical regions.1 it is endemic in many
urban or
city centers and its presence increases because of housing development
in rural
areas, which creates the ideal conditions for the reproduction of the
main
transmitter mosquito, the Aedes aegypti.2
Worldwide, more than 50 million people are infected each year and 2500
million
are at risk of being infected.3 The DENV belongs to the Flaviviridae and four different serotypes have
been defined
(DENV-1, DENV-2, DENV-3 and DENV-4). The majority of the infections are
subclinical. The most frequent clinical manifestation is classic dengue
or
dengue fever, which subsides spontaneously. The most severe forms are
frequently related to an heterologous
inmunopathologic response, or other host or
viral
factors.
The
mechanisms of DENV pathogenesis are not well
defined, because of the lack of appropriate animal models to study the
course
of the disease. Available only is patient data, which are very diverse
and do
not allow understanding of the pathologic phenomena that occur in the
course of
the infection. However, various factors4 are related to DENV
pathogenesis: 1) viral factors, such as virulence and viral
transmissibility,
and 2) host factors, such as immune response, immunologic conditions
and its
genetic characteristics.
During mid
70´s the World Health Organization
(WHO) proposed a dengue severity classification with the purpose of
aiding the
diagnosis, patient management and monitoring of the disease.5
The following concepts were defined:
1) Dengue
fever (DF) or classic dengue: benign
disease with an acute phase of 3-7 days of unspecific symptoms, such as
high
fever, headache, myalgias, arthralgias,
maculopapular rash and, in some cases,
moderate
hemorrhage;
2) Hemorrhagic
dengue (DHF/DSS): severe
disease, with increase in vascular permeability and hemoconcentration,
with an increase up to 20% of the normal hematocrit
value and a count of less than 100 thousand platelets/mm3.
It was
classified in four grades of severity: 1 and 2, without symptoms of
circulatory
failure, and 3 and 4, characterized by circulatory failure and hypovolemic shock or dengue shock syndrome
(DSS). DSS can
be fatal in 5-15% of the cases.5 This definition has been
questioned
thoroughly, because in most countries that have dengue cases and
hemorrhagic
dengue, the clinical symptoms and the laboratory findings do not agree
with the
ones defined by the WHO and also, patients present variations due to
the infection
of different serotypes.6
In the
present review the factors that could play a
fundamental role in the dengue pathogenesis are exposed. Also, the new
clinical
classification of dengue dictated by the OMS is emphatically presented.
This
classification will help health professionals have a better
understanding of
the course of the disease, which will allow an adequate therapeutic
approach of
patients, and fewer deaths by the more severe forms of the disease.
Current
hypothesis about dengue pathogenesis
Antibody
dependent enhancement (ADE)
In vitro
essays and epidemiologic studies link the
secondary infection due to to DENV heterologous serotype (different to the one of
the first
infection) with severe disease.7-11 In studies performed in
Thailand incidence of DHF/DSS was observed to present mostly in two
groups of children:8-12
the first group constituted by neonates between 6-9 months of age,
infected by
a different serotype than the one that infected their mothers, and
those in
which the maternal antibodies had descended to subneutralizing
levels; and the other group formed by children that were previously
infected by
a DENV serotype and then by a different one. These observations allowed
to
conclude that a subsequent infection in preimmunized
people with a heterologous serotype could,
through
preexisting antibodies, exacerbate, instead of mitigating the disease.
This
phenomena is called antibody dependant enhancement (ADE),8
based on the fact that in a primary infection neutralizing antibodies
against
the infective serotype are generated, but non neutralizing antibodies
that
react against heterologous serotypes are
generated as
well. The latter antibodies maximize a subsequent infection with an heterologous serotype, by enhancing the entry of
the virus
with Fc-γ receptors
in monocytes
and macrophages, achieving not only a larger number of infected cells,
but also
an increase in the viral replication in its target cell and, as a
consequence,
increasing vascular permeability.11, 13-18
An
alternate or complementary hypothesis states that
the viral entry to its target cell by means of Fc-γ receptors
inhibits the antiviral immune response through the production of IL-6
and
IL-10, and the transcriptional inhibition of the production of IL-12,
TNF-α and IFN-γ, and as a
consequence, an ideal environment that promotes viral replication is
created.19-20
Despite the clinical studies related to the ADE phenomenon, evidence is
still
circumstantial. Evidence that proofs otherwise has been observed in
other
dengue outbreaks. In
It is
proposed that, as well as most infections, DENV
behaves epidemiologically under the “concept of the iceberg”,6 that states that the presentation
can go from
an asymptomatic infection or a mild disease, in most of the cases,
being this
the base of the iceberg, to a severe disease and in some occasions a
fatal
disease, in a much lower percentage, being this the tip of the iceberg (figure
1). Similarly, it is postulated that the hemorrhage and the shock
syndrome are
not necessarily linked to the same pathogenic mechanism.22
Another
study that refutes the ADE phenomenon was made in
The study
of viral structure and the immunogenicity of
DENV has demonstrated a relationship between the maturation state of
the virion, the infectivity and the
recognition by the
antibodies.25;26 It is suggested that various populations of
functionally different virus coexist: a) a population of virions
with high density of membrane precursor protein (PrMEM,
viral protein that contains a precursor peptide, which needs to be
sliced for
the virion to mature appropriately), that
represents
immature viral particles and non-infectious, except if they are opsonized by anti-PrMEM
antibodies, b) a population with intermediate density of this protein,
which is
infectious, but can be neutralized by anti-PrMEM
antibodies, and c) a population of mature virions
which can´t be neutralized with anti-PrMEM antibodies, but can be neutralized with
antibodies
against the viral envelope (E).27 The study suggests that
viral immature
particles also play an important part in the enhancement and can also
contribute to the possible development of the severe forms, because in
a
secondary infection they are capable of infecting target cells in the
presence
of non neutralizing antibodies.
Deviant
lymphocyte T response
The
reactivation of memory T cells that react with heterologous
serotypes, can
provide partial immunity. Nevertheless, it also may be the cause of
immunopathology.28 The pathologic finding of tissue damage
as a
result of cytolysis or inflammation, induced by an elevated number of effector T cells, is possible in DENV infections.29-30
During the acute phase of a secondary infection by an heterologous
serotype, hyperactive CD8+ clones activate, which can produce an
elevated concentration
of pro and anti-inflammatory cytokines, like IFN-γ, TNF-α and IL-13
with low levels of IL-10.31-32 a prolonged activation of CD8+ cells is
maintained with elevated production of TNF- α, IL-6 and
other soluble factors that affect the vascular permeability (read ahead
in
tropism and endothelial cells). These T cells react differently against
heterologous serotypes and against
homologous epitopes.33
Also, they lose their cytolytic
capacity, which would explain the delay in the viral elimination during
a
secondary infection. Nevertheless, it is possible that during a DENV heterologous infection, only a small
subpopulation of T
cells are sero-crossed, and this combined
with the
fact that every human being has a repertoire of T cell specific
receptors,
could explain la great variability in the presentation of the disease
after a
secondary infection.4
Little is
known about the response of CD4+ T cells
during a DENV infection and the involvement of HIV coinfection.
It has been reported that during an acute dengue infection, the HIV
viral load
in an infected patient decreases.34 This obeys to the
expression of
NS5 (one of the non structural proteins of dengue virus), that
decreases the
expression of CD4 on T cell surface, hence, inhibits the infection and
replication of HIV.35,36 The decrease of CD4 on the T cell
surface
could also damage the helper function of this cells and, potentially,
delay or
avoid the development of an effective adaptative
response.
Similarly, HIV triggered pathogenesis could be diminished, decreasing
the
signal necessary to activate the T cell receptor and inhibiting cell
proliferation.36 Also, during a sequential infection with
different
DENV serotypes, there is evidence of alteration in the response of CD4+
produced cytokines that sero-cross,
inducing high
levels of proinflamatory cytokines,37
which jointly with CD8+ cell cytokine response, can cause adverse
effects in
the immune response.
DENV
Tropism
Target
cells and DENV tropism play an important part
in the outcome of dengue infection. There is no concluding data about
which are
the target organs in vivo. However, in vitro data and some autopsies
suggest
that three systems have a fundamental role in DHF/DSS:
a) Immune
system: DENV infection occurs because
of the bite of a mosquito through the epidermis and dermis. In this
way,
infected cells are immature Langerhans
cells
(epidermal dendritic cells) and
keratinocytes.38,39 Infected
cells migrate from the infection site to
the lymph nodes, were macrophages and monocytes
are
recruited, both becoming the target of the infection. The virus spreads
through
the lymphatic system. As a result of the first viremia,
a population of mononuclear descent cells are
obtained,
such as monocytes, myeloid dendritic
cells (DC) and infected liver and spleen macrophages.40-44
Furthermore, during secondary infections with heterologous
DENV, a high concentration of a complex between the new virus and
immunoglobulin G (IgG) is observed. These immunocomplexes are phagocytized
by mononuclear cells. Most of these cells die by apoptosis,45-46
while the nearest DC are stimulated and produce most of the mediators
related
with the inflamatory44,45,47-49 and hemostatic50-52
host
response. The quantity of infected cells and, therefore, the viremia level, could be the determinants of
pro-inflammatory and anti-inflammatory cytokine relation, as well as
the level
of chemokines and other mediators.41
b) Liver:
cases of hepatitis with necrosis, steatosis
and Councilman bodies (probably apoptotic cells)
have been reported in association with DENV.53,54
Also, the tendency towards graveness because of DENV has been related
to the
elevation of liver enzymes.55,56 Although DENV has been
detected in a
significant population of hepatocytes and Kupffer cells, there is no evidence of
inflammation in the
liver. This suggests that the apoptosis and necrosis observed are
caused
directly by the virus and not by inflammatory mediators. The prevalence
of
apoptosis is higher than necrosis and this could explain la small
amount of
inflammation observed in the area. Nevertheless, the role of the
hepatic damage
in regard to the coagulopathy and the
severity of the
disease, has yet to be well established.
c) Endothelial
cells (EC) that line capillary
vessels: the integrity of cellular epithelium is regulated by many
factors that
also play an important role in the coagulation response in cases of
severe
inflammation. Tropism of DENV towards EC in vivo is still very
controversial. Some
preliminary studies of skin biopsies indicate that the microvasculature
of the
dermis is the most affected site, although no DENV antigen has been
detected in
the EC that surround the microvasculature.57,58 On the
contrary,
there is evidence of DENV antigen in the lung´s
endothelial vasculature,43 despite that this does not
necessarily
means active viral replication. Contrary to mononuclear cells, EC do
not have Fc-γ
receptors and immune complexes are not internalized. And so, the
presence of
virus in these cells could only be explained by pinocytosis.
Replication of the four DENV serotypes has been demonstrated in vitro
in EC,
and the consequence of this infection tends to generate more functional
damage
than morphologic damage.59,60 There is no evidence that
viral
susceptibility varies between vascular systems, but it is proposed that
the
coagulation response in a severe EC inflammation varies in different
parts of
the organism.61 Similarly, DENV´s
infection pattern in microvasculature cells is different, which
suggests that
different tissues have different activation patterns.62 It
has been
demonstrated that the increase in peripheral microvasculature
permeability
occurs in patients with DHF as well as DSS.63 Therefore,
pulmonary
and abdominal EC could react specifically to a DENV infection,64
explaining the vascular effusion syndrome characteristic of DHF/DSS.
Studies
suggest that the damage or vascular dysfunction is fundamental in the
pathogenesis of these severe forms of DENV infection.65-68
There is
selective apoptosis of endothelial cells of the microvasculature in
lung and
abdominal tissue, especially in the fatal cases,69
explaining the intense vascular effusion in the pleura and peritoneal
cavities.
It is interesting to emphasize that the non-structural protein 1 (NS1)
of DENV
unites preferably to EC in the lung and liver.70 The
union of NS1 to its specific antibody could contribute to the selective
effusion in the lung.
Lack of an
animal model that mimics completely the
severe disease of dengue, has allowed the physiopathology to be
inferred mostly
from in vitro studies, using mostly endothelial cell lines, like the
HUVEC.71
These cells can be infected by the dengue virus, but in culture their
trans-endothelial barrier function is compromised, making them an
inappropriate
model to study vascular permeability induced by the virus. HMEC-1
cells,
derived from human dermic
microvasculature, have been
used for this purpose because they maintain their endothelial functions
and
barrier functions in culture, because of the stability of the proteic complexes that form their tight
junctions.72
During infection with dengue virus, a loss of continuity in the
localization of
occludine (protein of tight junctions),
which
coincides with an increase of permeability to diverse molecules of
different
sizes. Also, the interaction of the actin
cytoskeleton with the components of the tight junctions
works as a significant modulator of endothelial permeability.73
During dengue infection, disorganization and fragmentation of the actin fibers is observed, increasing the
endothelial
permeability. On the other hand, cytokines modulate the organization of
the
cytoskeleton and of the proteins that form intercellular unions. Dengue
produces IL-8 secretion in HMEC-1, which agonistically united to other
factors,
causes the reorganization of the cytoskeleton. In summary, the direct
effect of
the dengue virus on the tight junctions and the cytoskeleton, together
with
IL-8 release, induce enough structural modifications that could be
important in
the alteration of the endothelial permeability72 and
responsible of
the plasmatic extravasation.
Virulence
During the
70´s, Rosen and Gubler
performed epidemiologic and entomologic studies in the Asian South
Pacific, and
described for the first time differences in the virulence of dengue.74,75 They noticed that some outbreaks on
this region
had less or no cases of DHF, considering the virus transmitted as a low
virulence virus. Other outbreaks observed had many cases of DHF after a
primary
infection, and so these viruses were considered highly virulent. The
development of DNA sequencing methods leading to copying of viral RNA
and the
generation of phylogenetic trees, has
demonstrated
that some groups of variants or genotypes are related more frequently
with more
severe disease.76-80
The most
important reason for this genetic variability
and its clinical outcome is exemplified by the American genotype of
DENV-2 (for
example the strain Trinidad/53), that is not associated to the severe
forms of
the disease.81 These facts imply that it constitutes a low
virulence
genotype.80 For example, during the 1995 epidemic in Iquitos
(Peru),
close to 50000 secondary infections presented. Based on previous
projections
(with projection models of severe clinical presentations of the disease
in
Thailand), the severe cases in Iquitos should have been from 900 to
10000,
however, no severe case was reported.82 On the other hand,
the first
epidemic of DHF in America occurred in
Analysis
of genotype or individual populations has not
confirmed that the viral isolates from patients with the severe form of
the
disease are different from the ones taken of patients with dengue fever.88,89
However, genotype IV of DENV-3 has been associated with moderate forms
of the
disease;90 certain strains associated with severe forms have
demonstrated higher infectivity in monocytes91 and also,
certain
strains of DENV-2 differ in their capacity of infecting different types
of
human cells.92
It has
also been proposed that during the 1981 Cuban
epidemic, the virus evolved to more virulent genotypes responsible for
the
severe disease with the transmission between hosts, and for this
reason, the
mortality rate increased at the end of the epidemic.83 A
similar
situation occurred in 1992 during a DENV epidemic in Australia,93and
again in Cuba in 1997.14,94 Analysis of genomes of DENV
genotypes
have demonstrated that these could evolve during an epidemic,95,96
but more studies are needed to prove that some virus evolve to more
virulent
forms.
The
sequence of infection with the different serotypes
has been proposed as an important factor in the severity of the disease
by
dengue virus. Epidemics with a high incidence of DHF have been related
with a
primary DENV infection, followed by an infection of DENV-2 or DENV-3.97,98
Such studies also proved that the longer the time interval between a
primary and
the secondary infection, the higher the risk of developing the severe
disease.
Age has
also been postulated as a risk factor in a
secondary infection with heterologous DENV.15
It has been demonstrated that DENV in different geographic areas varies
in its
ability to infect different types of cells in vitro, or causing severe
disease
in humans.18,92 Despite this, the observation that DHF/DSS
presents
in a relatively low percentage in secondary infections and much less in
primary
infections (although the infection is because of virulent strains),
suggests
that the host factors are determinant and critical in the development
of the
severe disease.
Activation
of the complement system
One of the
fundamental components of the innate immune
humoral response is the complement system,
which
interacts with the homeostatic system to provide the first line of
defense
against pathogen infection. In DENV infection it has been reported that
during
the period of fever decline, when vascular permeability increases,
elevated
plasma levels of products of complement activation (C3a and C5a) are
detected,
followed by hypocomplememtemia in patients
with DF
and DSS.99,100 Therefore, it is postulated that complement
activation has a fundamental role in the pathogenesis of dengue. Also,
studies
about genic expression in mononuclear
cells of
peripheral blood (of patients with DF and DHF/DSS) suggest their
connection
with the severity of the disease.101 During DENV´s
RNA replication, one of the non-structural proteins encoded by the
virus is
released: NS1. It is postulated that this protein not only activates
directly
the complement system,102 but
also
activates the immune complexes formed between NS1 protein and the non-homotypic antibodies, that activate the
classical pathway
of the complement.103 Complement activation produces the
complex
C5b-C9, that triggers cellular reactions and stimulates
pro-inflammatory
cytokine production, associated to the development of DHF/DSS. This
attack
membrane complex can activate other local and systemic mechanisms
involved with
disseminated intravascular coagulation (DIC).104
Temporary
autoimmunity
It has
been shown that during a DENV infection, there
is production of antibodies that can sero-cross
with
some host antigens. Although, it is not clear if this phenomenon occurs
only
during a secondary infection or also during the primary infection. Some
antibodies that recognize a linear epitope
in the
viral E protein of the envelope can also unite to human plasminogen
and inhibit plasmin activity.105-107
Anti-NS1 antibodies that sero-cross with
EC can
trigger nitric oxide (NO) production and hence induce apoptosis.108
Although it has been demonstrated that NO inhibits DENV replication,109
its excessive production causes cellular damage. Anti-NS1 antibodies
can also
stimulate expression of IL-6, IL-8 and intracellular adhesion molecule
1
(ICAM-1).110 More studies are necessary to prove that the
crossed
reaction between anti-NS1 with EC leads to an increase in vascular
permeability, characteristic of DSS. Also, it was reported that
anti-NS1 can sero-cross with platelets and
cause temporary
thrombocytopenia and hemorrhage,111
which
demonstrates that these anti-platelets antibodies are pathogenic.
Host
genetic factors
Significant
differences have been observed,
individually and among populations, with the gravity of a DENV
infection. Epidemiologic
research indicates that some genetic factors can be important
components of
infection susceptibility. Some human alleles of HLA class I and II112-116
have been related with the development of DHF as well as polymorphism
in genes
that encode for TNF-α,117 Fc-γ
receptors118, vitamin D receptor,118 amongst
others. Some
variants of glucose-6-phosphate dehydrogenase
(G6PD)
also contribute to an enhanced monocyte
replication.119
The risk of developing a more severe disease could be determined,
however, by a
combination of host genetic factors and not by individual polymorphisms.120
Studies in patients that develop DHF or DSS, could help to identify
more
polymorphisms or defects in unique genes that could predispose to the
development of more severe diseases.
Modulation
of the interpheron´s response
Dengue
virus is detected by cells with Toll-like
receptors (TLR) and the intracellular receptors, producing a response
mediated
by INF-α
and INF-γ.44,121 IFN works with infected and
non-infected cells
stimulating JAK-STAT signaling cascade, causing the activation of
specific
genes that establish an antiviral status.
Some
non-structural viral proteins are capable of
modulating interpheron response122
against
dengue virus. The importance of this process lies in that the
modulating of the
response translates to elevated viremia
levels or
exacerbated viral propagation, despite the existence of a proper early
immune rersponse.
New
criteria for the classification of dengue caused disease
Independently
of the classification of the disease
caused by dengue virus, severe dengue associates to certain
manifestations that
include hemorrhage or,123-126 hepatic alterations,127,128
CNS manifestations128,129 and shock syndrome.123,124,126
Although hypovolemic shock associated to
an increase
in vascular permeability is an obvious manifestation of severe disease,
this
phenomenon can occur without thrombocytopenia and hemorrhage.123,126
Many studies show that the clinical determination of plasma leakage
during the
acute phase of the disease is very difficult, when symptoms of effusion
are
absent and the value of hematocrit is
normal.125
As a consequence and using the previous classification by the WHO,
clinicians
tend to classify all severe cases as DHF. This leads to confusing
estimates of
the incidence and even erroneous concepts about the pathogenesis of the
disease. For these reasons it is suggested that the previous
definitions by the
WHO for DF and DHF are both inadequate and disorientating.130,131 It is suggested that an alternative
approach for
the classification of the cases could be “severe” vs
“not severe”, and that the severe cases
should include the whole range of manifestations including shock with
or
without evidence of plasmatic effusion, manifestations of liver
failure, CNS,
hemorrhage and thrombocytopenia. So, the definition of shock due to
plasma loss
would be simple and practical for the diagnosis and management of the
patient,
independently from thrombocytopenia and hemorrhage, and very adequate
in
countries were dengue is endemic or epidemic.
New
clinical multicenter prospective studies have been
performed by the WHO, with the purpose of redefining the categories of
the
disease to standardize the clinical guidelines to follow.3,132
Therefore,
this disease is being classified with
levels of severity: dengue with or without the presence of alarm
signals and
severe dengue (figure 2),
based on clinical and laboratory data. It must be
remembered that even patients with dengue without alarm signals can
develop
severe symptoms. This classification with levels of severity has a high
potential to help clinicians make decisions as to where and how
intensely a
patient has to be observed and treated, and has demonstrated to be more
effective than the DF/DHF/DSS for a rapid recognition of severe disease.132
However, training is required, spreading of information and more
investigating
on the clinical manifestations of the alarm signals and the definition
of the
clinical cases in absence of laboratory data.
Consequences
for prevention and control
Although
dengue has been attempted to be controlled
and prevented via vector vigilance, better medical management, better
education
and better information; the main prevention method would be a vaccine.
However,
a secure and effective vaccine against this disease becomes difficult
because
of the important role of the immune-pathogenesis. An essential
requisite of the
vaccine would be to induce prolonged protection against the four
serotypes of
dengue, as incomplete immunity could influence the development of
severe
disease in vaccinated people. Another source of concern is the lack of
clear
protective determinants against the disease and the absence of a robust
experimental
model that mimics observed pathogenesis in humans. However, a more
appropriate
definition of the causes of dengue´s pathogenicity would assist the formulation of
effective
candidates for the vaccine and the development of antiviral agents.
Note: the
authors of the present article don’t
have any conflicts of interest.
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