Abstracts
Dengue virus (DENV) infects approximately 390 million persons every year in more than 100 countries. Reports of neurological complications are more frequently. The objective of this narrative review is to bring up the advances in the dengue neuropathogenesis. DENV can access the nervous system through blood-brain barrier disturbance mediated by cytokine. The blood-cerebrospinal fluid (CSF) barrier seems to be also involved, considering the presence of the virus in the CSF of patients with neurological manifestations. As for neurotropism, several studies showed the presence of RNA and viral antigens in brain tissue and CSF in humans. In murine model, different virus mutations were associated to neurovirulence. Despite the advances in the dengue neuropathogenesis, it is still necessary to determine a more appropriate animal model and increase the number of cases of autopsy. The detection of neurovirulence markers may contribute to establish a prognosis, the disease control and vaccine development.
dengue; neuropathogenesis; neurotropism; neurovirulence
O vírus da dengue (DENV) infecta anualmente cerca de 390 milhões de indivíduos em mais de 100 países. Complicações neurológicas estão se tornando frequentes. O objetivo desta revisão narrativa é abordar os avanços sobre neuropatogênese na dengue. O DENV invade o sistema nervoso central através do distúrbio da barreira hemato-encefálica, mediado por citocina. A barreira hemato-liquórica (LCR) parece também estar envolvida, considerando a presença do vírus no LCR. Estudos demonstraram RNA e antígenos virais no tecido cerebral e LCR de indivíduos infectados pelo DENV, confirmando o neurotropismo viral. Em modelo murino, diferentes mutações virais foram associadas a neurovirulência. Apesar dos avanços no conhecimento da neuropatogênese da dengue, ainda são necessários a determinação de um modelo animal mais adequado e aumento do número de casos de autopsia. A determinação de marcadores de neurovirulência pode contribuir para o estabelecimento de prognóstico, controle da doença e no desenvolvimento de vacina.
dengue; neuropatogenese; neurotropismo; neurovirulência
Dengue virus (DENV) is an arbovirus transmitted mainly by two species of mosquitoes:
Aedes aegypti and A. albopictus. This RNA virus
belongs to Flavivirus genus of Flaviviridae family and
infects approximately 390 million persons every year in more than 100 countries11 .Grange L, Simon-Loriere E, Sakuntabhai A, Gresh L, Paul R, Harris
E. Epidemiological risk factors associated with high global frequency of
inapparent dengue virus infections. Front Immunol. 2014;5:280.
http://dx.doi.org/10.3389/fimmu.2014.00280
https://doi.org/10.3389/fimmu.2014.00280...
. It genomes comprises a ~11kb long
single strand positive-sense RNA that encodes a polyprotein precursor that is cleaved by
virus and host cell proteases. Thus, this polyprotein yields the structural proteins (E,
M and C) as also the non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and
NS5)22 .Bordignon J, Strottmann DM, Mosimann ALP, Probst CM, Stella V,
Noronha L et al. Dengue neurovirulence in mice: identification of molecular
signatures in the E and NS3 helicase domains. J Med Virol. 2007;79(10):1506-17.
http://dx.doi.org/10.1002/jmv.20958
https://doi.org/10.1002/jmv.20958...
. There are four different
DENV genotypes described (DENV1, DENV2, DENV3 and DENV4)11 .Grange L, Simon-Loriere E, Sakuntabhai A, Gresh L, Paul R, Harris
E. Epidemiological risk factors associated with high global frequency of
inapparent dengue virus infections. Front Immunol. 2014;5:280.
http://dx.doi.org/10.3389/fimmu.2014.00280
https://doi.org/10.3389/fimmu.2014.00280...
. All of them can cause disease in humans. A possible fifth
serotype has recently been detected, but it importance as disease agent is not
clear11 .Grange L, Simon-Loriere E, Sakuntabhai A, Gresh L, Paul R, Harris
E. Epidemiological risk factors associated with high global frequency of
inapparent dengue virus infections. Front Immunol. 2014;5:280.
http://dx.doi.org/10.3389/fimmu.2014.00280
https://doi.org/10.3389/fimmu.2014.00280...
.
DENV can cause a wide spectrum of clinical manifestation, ranging from a self-limiting
febrile syndrome (dengue fever, DF), severe hemorrhagic syndrome (DHF) and severe shock
syndrome (DSS). In 2009, WHO proposed a new criteria for dengue classification according
to levels of severity: dengue without warning signs; dengue with warning signs and
severe dengue. Abdominal pain, liver enlargement, lethargy, persistent vomiting, fluid
accumulation, mucosal bleeding as also as increasing hematocrit with concomitant
decreasing platelets are considered warning signs. Plasma leakage, bleeding, and/or
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.
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. Severe dengue includes central nervous system (CNS)
impairment.
The neurological manifestations in dengue infection are caused mainly by DENV-2 and
DENV-3. These serotypes are associated with cases of encephalitis, meningitis and
myelitis77 .Domingues RB, Kuster GW, Onuki-Castro FL, Souza VA, Levi JE,
Pannuti CS. Involvement of the central nervous system in patients with dengue
virus infection. J Neurol Sci. 2008;267(1-2):36-40.
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. However, DENV-1 and DENV-4 are also
identified in cases of encephalitis99 .Ramos C, Sánchez G, Pando RH, Baquera J, Hernández D, Mota J et al.
Dengue virus in the brain of a fatal case of hemorrhagic dengue fever. J
Neurovirol. 1998;4(4):465-8.
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.
Although neurological manifestation is consider uncommon, recent studies showed that it
is becoming more frequent in both DF and DHF22 .Bordignon J, Strottmann DM, Mosimann ALP, Probst CM, Stella V,
Noronha L et al. Dengue neurovirulence in mice: identification of molecular
signatures in the E and NS3 helicase domains. J Med Virol. 2007;79(10):1506-17.
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,1010 .Hapuarachchi HC, Oh HML, Thein TL, Pok KY, Lai YL, Tan LK et al.
Clinico-genetic characterisation of an encephalitic Dengue virus 4 associated
with multi-organ involvement. J Clin Virol. 2013;57(1):91-4.
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. About 1-21% of individuals with dengue present neurological
abnormalities77 .Domingues RB, Kuster GW, Onuki-Castro FL, Souza VA, Levi JE,
Pannuti CS. Involvement of the central nervous system in patients with dengue
virus infection. J Neurol Sci. 2008;267(1-2):36-40.
http://dx.doi.org/10.1016/j.jns.2007.09.040
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of CNS infection, dengue was observed in 4-13%1212 .Solomon T, Dung NM, Vaughn DW, Kneen R, Thao LT, Taengsakulrach B
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2008;57(4):373-6.. The prevalence of DENV among viral infections in CNS is
reported to be 5% and 6% in Vietnam1414 .Le VT, Phan TQ, Do QH, Nguyen BH, Lam QB, Bach V et al. Viral
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, 15% in India1616 .Kumar R, Tripathi P, Tripathi S, Kanodia A, Pant S, Venkatesh V.
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and 20% in Thailand1717 .Chokephaibulkit K, Kankirawatana P, Apintanapong S, Pongthapisit V,
Yoksan S, Kositanont U et al. Viral etiologies of encephalitis in Thai children.
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. Our group also demonstrated that in a dengue endemic
region (Rio de Janeiro, Brazil), DENV infection was the leading cause of viral acute
encephalitis (47%) and was the etiologic agent of 10% of viral meningitis cases1818 .Soares CN, Cabral-Castro MJ, Peralta JM, Freitas MRG, Zalis M,
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in a dengue endemic region. J Neurol Sci. 2011;303(1-2):75-9.
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. Therefore, it seems that
neurological complications in dengue infection is becoming increasingly common and is
not a rare observation. This fact can be related to the increased concern of the
practitioners1919 .Wiwanitkit S, Wiwanitkit V. Neurological complications in dengue
infection. Arq Neuropsiquiatr. 2014;72(3):259.
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. However, it is
known that in a secondary dengue infection associated with a different serotype, an
antibody dependent enhanced (ADE) mechanism can occur. In those cases, the heterotypic
non-neutralizing antibodies interact with dengue virus, favoring the infection of host
cell. As consequence, the viral replication is increased, as well the chances of dengue
hemorrhagic fever. By hypothesis, the high replication rate may also contribute to the
development of neurological disorders (Figure
1)2020 .Whitehorn J, Simmons CP. The pathogenesis of dengue. Vaccine.
2011;29:7221-8. Duplicata da 1..
The neuropathogenesis of DENV infection needs to be clarified. The CNS damage can be a
result of four distinct mechanisms: (a) metabolic imbalance; (b) hemorrhagic disturbance
(thrombocytopenia); (c) post-infectious autoimmune reaction; (d) CNS infection by dengue
virus66 .Carod-Artal FJ, Wichmann O, Farrar J, Gascón J. Neurological
complications of dengue virus infection. Lancet Neurol. 2013;12(9):906-9.
http://dx.doi.org/10.1016/S1474-4422(13)70150-9
https://doi.org/10.1016/S1474-4422(13)70...
,2121 .Puccioni-Sohler M, Orsini M, Soares CN. Dengue: a new challenge for
neurology. Neurol Int. 2012;4(3):e15.
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,2222 .Puccioni-Sohler M, Rosadas C, Cabral-Castro MJ. Neurological
complications in dengue infection: a review for clinical practice. Arq
Neuropsiquiatr. 2013;71(9B):667-71.
http://dx.doi.org/10.1590/0004-282X20130147
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. The present narrative review summarizes the advances
in the neuropathogenesis studies, in sense of to improve the understanding regarding the
neuroinvasivess, neurotropism and neurovirulence of DENV. Although these themes remain
elusive, new knowledge has emerged in recent years.
NEUROINVASION: HOW DENV ACCESS THE NERVOUS SYSTEM
The ability of a microorganism to invade the nervous system is known as
neuroinvasion. Hematological seems to be the most important route used by DENV to
get into the nervous system. It is preceded by a viremia. The virus can disseminate
as a free particle or inside of an infected cell (using a Trojan-horse mechanism of
entry)2323 .Neal JW. Flaviviruses are neurotropic, but how do they invade the
CNS? J Infect. 2014;69(3):203-15.
http://dx.doi.org/10.1016/j.jinf.2014.05.010
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. A study developed in
mice showed that DENV can breakdown the blood-brain barrier (BBB). The BBB is
composed by endothelial cells of brain microvessels. During the infection, there is
an over-expression of cytokines, that alter the permeability of the endothelium
through the disturbance of the tight junctions2323 .Neal JW. Flaviviruses are neurotropic, but how do they invade the
CNS? J Infect. 2014;69(3):203-15.
http://dx.doi.org/10.1016/j.jinf.2014.05.010
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,2424 .Chaturvedi UC, Dhawan R, Khanna M, Mathur A. Breakdown of the
blood-brain barrier during dengue virus infection of mice. J Gen Virol.
1991;72(4):859-66. http://dx.doi.org/10.1099/0022-1317-72-4-859
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,2525 .Velandia-Romero ML, Acosta-Losada O, Castellanos JE. In vivo
infection by a neuroinvasive neurovirulent dengue virus. J Neurovirol.
2012;18(5):374-87. http://dx.doi.org/10.1007/s13365-012-0117-y
https://doi.org/10.1007/s13365-012-0117-...
. In fact, the break of BBB in dengue infection was
associated with high levels of plasmatic metalloproteinase 9 (MMP-9)2424 .Chaturvedi UC, Dhawan R, Khanna M, Mathur A. Breakdown of the
blood-brain barrier during dengue virus infection of mice. J Gen Virol.
1991;72(4):859-66. http://dx.doi.org/10.1099/0022-1317-72-4-859
https://doi.org/10.1099/0022-1317-72-4-8...
. MMP digests the basal lamina of
neurovascular units, weakening the tight interactions between the endothelial cells
and other elements of neurovascular units. Thus, this enzyme facilitate the entry of
both free viral particle and infected leucocyte into cerebral tissue2424 .Chaturvedi UC, Dhawan R, Khanna M, Mathur A. Breakdown of the
blood-brain barrier during dengue virus infection of mice. J Gen Virol.
1991;72(4):859-66. http://dx.doi.org/10.1099/0022-1317-72-4-859
https://doi.org/10.1099/0022-1317-72-4-8...
. Moreover, DENV-2-infected
monocytes express monocyte chemoattractant protein-1 (MCP-1). In
vitro, this protein is able to increase the permeability and disrupt
tight junctions of human vascular endothelium cells. In fact, a high expression of
MCP-1 was detected in DHF patient’s plasma2626 .Lee YR, Liu MT, Lei HY, Liu CC, Wu JM, Tung YC et al. MCP-1, a
highly expressed chemokine in dengue haemorrhagic fever/dengue shock syndrome
patients, may cause permeability change, possibly through reduced tight
junctions of vascular endothelium cells. J Gen Virol. 2006;87(12):3623-30.
http://dx.doi.org/10.1099/vir.0.82093-0
https://doi.org/10.1099/vir.0.82093-0...
. Therefore, DENV is able to enter in the CNS. Another
hypothesis is that dengue virus can access the nervous system, crossing the
endothelial cells through transcytosis. This entry mechanism has been demonstrated
in West Nile virus (WNV) infection2727 .Liou ML, Hsu CY. Japanese encephalitis virus is transported across
the cerebral blood vessels by endocytosis in mouse brain. Cell Tissue Res.
1998;293(3):389-94. http://dx.doi.org/10.1007/s004410051130
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. The ability of DENV to infect endothelial cells allows
viral replication and may facilitate the subsequent entry into the brain parenchyma
similar to what happens to other flavivirus infections2828 .Avirutnan P, Malasit P, Seliger B, Bhakdi S, Husmann M. Dengue
virus infection of human endothelial cells leads to chemokine production,
complement activation, and apoptosis. J Immunol.
1998;161(11):6338-46.,2929 .Liu TH, Liang LC, Wang CC, Liu HC, Chen WJ. The blood-brain barrier
in the cerebrum is the initial site for the Japanese encephalitis virus entering
the central nervous system. J Neurovirol. 2008;14(6):514-21.
http://dx.doi.org/10.1080/13550280802339643
https://doi.org/10.1080/1355028080233964...
. For hypothesis, it could be the same mechanism that
the virus access the cerebrospinal fluid (CSF) cross the blood-CSF barrier. It
contain fenestrated vascular endothelial cells on the choroid plexus, which may
facilitate the neuroinvasion (Figure 2)3030 .Fishman R. Cerebrospinal fluid. Philadelphia: W. B. Saunders;
1992.. Moreover, the genetic
characterization of DENV-4 obtained in a patient with encephalitis showed 99.99% of
similarity between serum and CSF-derived viruses1010 .Hapuarachchi HC, Oh HML, Thein TL, Pok KY, Lai YL, Tan LK et al.
Clinico-genetic characterisation of an encephalitic Dengue virus 4 associated
with multi-organ involvement. J Clin Virol. 2013;57(1):91-4.
http://dx.doi.org/10.1016/j.jcv.2012.12.021
https://doi.org/10.1016/j.jcv.2012.12.02...
.
Neuroinvasivess of DENV in central nervous system. A. Viral invasion cross the skin after mosquito bite. It is followed by viral replication in lymph nodes, muscles and fibroblasts. The free particles or especially the infected monocyte disseminate the virus from the blood (viremia) to the visceral organ, inclusive the nervous system. B. Blood-brain barrier invasion. C. Blood-CSF barrier invasion.
It has been suggested the route of retrograde axonal transport as an alternative
neuroinvasive mechanism. An et al.3131 .An J, Zhou DS, Kawasaki K, Yasui K. The pathogenesis of spinal cord
involvement in dengue virus infection. Virchows Arch. 2003;442(5):472-81.
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showed, using transmission electron microscopy, that DENV
is able to penetrate and infect both CNS and peripheral nervous system neurons
(motor neurons, axons and ependymal cells) in murine model. In the same study, the
authors observed virion-containing vesicles that appeared to be fused to
presynapse’s membranes, reinforcing the ability of DENV to use the axonal
transport2929 .Liu TH, Liang LC, Wang CC, Liu HC, Chen WJ. The blood-brain barrier
in the cerebrum is the initial site for the Japanese encephalitis virus entering
the central nervous system. J Neurovirol. 2008;14(6):514-21.
http://dx.doi.org/10.1080/13550280802339643
https://doi.org/10.1080/1355028080233964...
. Based on this
study, the axonal transport could also be used for virus dissemination throughout
the nervous system. A negative serum with positive CSF (both collected in same day)
DENV detected by polymerase chain reaction (PCR) reinforced this hypothesis77 .Domingues RB, Kuster GW, Onuki-Castro FL, Souza VA, Levi JE,
Pannuti CS. Involvement of the central nervous system in patients with dengue
virus infection. J Neurol Sci. 2008;267(1-2):36-40.
http://dx.doi.org/10.1016/j.jns.2007.09.040
https://doi.org/10.1016/j.jns.2007.09.04...
. Although, the presence of virus in
CNS may be only the consequence of a passive crossing through the blood-brain and/or
blood-CSF barriers. The virus was past in peripheral blood, before crossing the
barriers into the brain. Therefore it could not be found in blood anymore.
DENV NEUROTROPISM
There are several evidences that dengue virus is able to infect and replicate in
neural cells. This ability is called neurotropism. Viral antigens were detected by
immunohistochemistry in human cerebral tissue99 .Ramos C, Sánchez G, Pando RH, Baquera J, Hernández D, Mota J et al.
Dengue virus in the brain of a fatal case of hemorrhagic dengue fever. J
Neurovirol. 1998;4(4):465-8.
http://dx.doi.org/10.3109/13550289809114548
https://doi.org/10.3109/1355028980911454...
,3232 .Bhoopat L, Bhamarapravati N, Attasiri C, Yoksarn S, Chaiwun B,
Khunamornpong S et al. Immunohistochemical characterization of a new monoclonal
antibody reactive with dengue virus-infected cells in frozen tissue using
immunoperoxidase technique. Asian Pac J Allergy Immunol.
1996;14(2):107-13.,3333 .Miagostovich MP, Ramos RG, Nicol AF, Nogueira RM, Cuzzi-Maya T,
Oliveira AV et al. Retrospective study on dengue fatal cases. Clin Neuropathol.
1997;16(4):204-8.,3434 .Miagostovich MP, Barreto F, Fumian TM, et al. Complete genetic
characterization of a Brazilian dengue virus type 3 strain isolated from a fatal
outcome. Mem Inst Oswaldo Cruz. 2006;101(3):307-13.
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,3535 .Araújo FMC, Araújo MS, Nogueira RMR, Brilhante RS, Oliveira DN,
Rocha MF et al. Central nervous system involvement in dengue: a study in fatal
cases from a dengue endemic area. Neurology. 2012;78(10):736-42.
http://dx.doi.org/10.1212/WNL.0b013e31824b94e9
https://doi.org/10.1212/WNL.0b013e31824b...
. DENV RNA was also detected in brain tissue and in CSF
of infected individuals77 .Domingues RB, Kuster GW, Onuki-Castro FL, Souza VA, Levi JE,
Pannuti CS. Involvement of the central nervous system in patients with dengue
virus infection. J Neurol Sci. 2008;267(1-2):36-40.
http://dx.doi.org/10.1016/j.jns.2007.09.040
https://doi.org/10.1016/j.jns.2007.09.04...
,99 .Ramos C, Sánchez G, Pando RH, Baquera J, Hernández D, Mota J et al.
Dengue virus in the brain of a fatal case of hemorrhagic dengue fever. J
Neurovirol. 1998;4(4):465-8.
http://dx.doi.org/10.3109/13550289809114548
https://doi.org/10.3109/1355028980911454...
,3434 .Miagostovich MP, Barreto F, Fumian TM, et al. Complete genetic
characterization of a Brazilian dengue virus type 3 strain isolated from a fatal
outcome. Mem Inst Oswaldo Cruz. 2006;101(3):307-13.
http://dx.doi.org/10.1590/S0074-02762006000300015
https://doi.org/10.1590/S0074-0276200600...
,3535 .Araújo FMC, Araújo MS, Nogueira RMR, Brilhante RS, Oliveira DN,
Rocha MF et al. Central nervous system involvement in dengue: a study in fatal
cases from a dengue endemic area. Neurology. 2012;78(10):736-42.
http://dx.doi.org/10.1212/WNL.0b013e31824b94e9
https://doi.org/10.1212/WNL.0b013e31824b...
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al. Detection of Herpesvirus, Enterovirus, and Arbovirus infection in patients
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Brilhante R et al. Dengue in patients with central nervous system
manifestations, Brazil. Emerg Infect Dis. 2012;18(4):677-9.
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,3838 .Pancharoen C, Thisyakorn U. Neurological manifestations in dengue
patients. Southeast Asian J Trop Med Public Health.
2001;32(2):341-5.. Human and animal neurons, astrocytes, microglia and
Purkinje cells can be infected by DENV. Moreover, plexus choroid and endothelial
cells were also infected in animal and human2525 .Velandia-Romero ML, Acosta-Losada O, Castellanos JE. In vivo
infection by a neuroinvasive neurovirulent dengue virus. J Neurovirol.
2012;18(5):374-87. http://dx.doi.org/10.1007/s13365-012-0117-y
https://doi.org/10.1007/s13365-012-0117-...
,3232 .Bhoopat L, Bhamarapravati N, Attasiri C, Yoksarn S, Chaiwun B,
Khunamornpong S et al. Immunohistochemical characterization of a new monoclonal
antibody reactive with dengue virus-infected cells in frozen tissue using
immunoperoxidase technique. Asian Pac J Allergy Immunol.
1996;14(2):107-13.,3333 .Miagostovich MP, Ramos RG, Nicol AF, Nogueira RM, Cuzzi-Maya T,
Oliveira AV et al. Retrospective study on dengue fatal cases. Clin Neuropathol.
1997;16(4):204-8..
The proteins Hsp70 and Hsp90, seems to form a candidate receptor complex to DENV
entry in both human monocytes and neuroblastoma cells3939 .Salazar MI, Pérez-García M, Terreros-Tinoco M, Castro-Mussot ME,
Diegopérez-Ramírez, Ramírez-Reyes AG et al. Dengue virus type 2: protein binding
and active replication in human central nervous system cells. Sci World J.
2013;2013:ID904067. http://dx.doi.org/10.1155/2013/904067
https://doi.org/10.1155/2013/904067...
,4040 .Reyes-Del Valle J, Chávez-Salinas S, Medina F, Del Angel RM. Heat
shock protein 90 and heat shock protein 70 are components of dengue virus
receptor complex in human cells. J Virol. 2005;79(8):4557-67.
http://dx.doi.org/10.1128/JVI.79.8.4557-4567.2005
https://doi.org/10.1128/JVI.79.8.4557-45...
. Another possible DENV receptor in neuroblastoma cells
is the Mr 65,000 protein4141 .Ramos-Castañeda J, Imbert JL, Barrón BL, Ramos C. A 65-kDa
trypsin-sensible membrane cell protein as a possible receptor for dengue virus
in cultured neuroblastoma cells. J Neurovirol. 1997;3(6):435-40.
http://dx.doi.org/10.3109/13550289709031189
https://doi.org/10.3109/1355028970903118...
.
Salazar and colleagues demonstrated that dengue virus can bind to different host
cell proteins that are present in both white and grey matter3939 .Salazar MI, Pérez-García M, Terreros-Tinoco M, Castro-Mussot ME,
Diegopérez-Ramírez, Ramírez-Reyes AG et al. Dengue virus type 2: protein binding
and active replication in human central nervous system cells. Sci World J.
2013;2013:ID904067. http://dx.doi.org/10.1155/2013/904067
https://doi.org/10.1155/2013/904067...
. NS1 dengue antigen was also detected in brain
and in CSF of infected individuals4242 .Lima MRQ, Nogueira RMR, Schatzmayr HG, Filippis AMB, Limonta D, dos
Santos FB. A new approach to dengue fatal cases diagnosis: NS1 antigen capture
in tissues. PLoS Negl Trop Dis. 2011;5(5):e1147.
http://dx.doi.org/10.1371/journal.pntd.0001147
https://doi.org/10.1371/journal.pntd.000...
,4343 .Araújo FMC, Brilhante RSN, Cavalcanti LPG, Rocha MF, Cordiero RA,
Perdigão AC et al. Detection of the dengue non-structural 1 antigen in cerebral
spinal fluid samples using a commercially available enzyme-linked immunosorbent
assay. J Virol Methods. 2011;177(1):128-31.
http://dx.doi.org/10.1016/j.jviromet.2011.07.003
https://doi.org/10.1016/j.jviromet.2011....
. In animal model, previous studies showed that at early
stages of the infection, only a few virions were present in the cytoplasm of
ependymal cells. However, with the progression of the infection, virions were
observed in the lumen of the rough endoplasmic reticulum (RER), as also as
RER-derived vesicles and the Golgi region of infected neurons3131 .An J, Zhou DS, Kawasaki K, Yasui K. The pathogenesis of spinal cord
involvement in dengue virus infection. Virchows Arch. 2003;442(5):472-81.
http://dx.doi.org/10.1007/s00428-003-0785-3
https://doi.org/10.1007/s00428-003-0785-...
. This data demonstrates the DENV neurotropism.
Another evidence of CNS infection is the viral detection of DENV-2, -3 and -4 in the
CSF in cases of encephalitis, meningitis and myelitis. Additionally, intrathecal
synthesis of specific antibodies (calculated by antibody index) was observed in DENV
infected patients with myelitis. Therefore, the antibody index for DENV may be used
as a marker of myelitis associated with dengue, and it seems to be associated to the
pathogenesis of spinal cord disease due to direct viral invasion4444 .Puccioni-Sohler M, Soares CN, Papaiz-Alvarenga R, Castro MJC, Faria
LC, Peralta JM. Neurologic dengue manifestations associated with intrathecal
specific immune response. Neurology. 2009;73(17):1413-7.
http://dx.doi.org/10.1212/WNL.0b013e3181bd8258
https://doi.org/10.1212/WNL.0b013e3181bd...
.
DENV NEUROVIRULENCE
Neurovirulence can be defined as the ability of the virus to induce neurologic
disease. It is important to note that neurotropism is not a synonym for
neurovirulence. However, in some cases, they may be associated. In fact, DENV
infection of neuron induced apoptotic cell death in mouse model4545 .Desprès P, Frenkiel MP, Ceccaldi PE, Duarte Dos Santos C, Deubel V.
Apoptosis in the mouse central nervous system in response to infection with
mouse-neurovirulent dengue viruses. J Virol. 1998;72(1):823-9.,4646 .Desprès P, Flamand M, Ceccaldi PE, Deubel V. Human isolates of
dengue type 1 virus induce apoptosis in mouse neuroblastoma cells. J Virol.
1996;70(6):4090-6.,4747 .Santos CND, Frenkiel MP, Courageot MP, Rocha CF, Vazeille-Falcoz
MC, Wien MW et al. Determinants in the envelope E protein and viral RNA helicase
NS3 that influence the induction of apoptosis in response to infection with
dengue type 1 virus. Virology. 2000;274(2):292-308.
http://dx.doi.org/10.1006/viro.2000.0457
https://doi.org/10.1006/viro.2000.0457...
. The apoptosis may be induced by a cellular stress
caused by an accumulation of viral proteins in cell membrane. For example, the
neuroadapted BR/90 strain presents some mutations that prevent the maturation of the
E protein. So, it results in an abortive virus assembly with an increased
accumulation of viral proteins in cell membranes, which, in turn, seems to
deflagrate apoptosis4646 .Desprès P, Flamand M, Ceccaldi PE, Deubel V. Human isolates of
dengue type 1 virus induce apoptosis in mouse neuroblastoma cells. J Virol.
1996;70(6):4090-6.. Moreover,
the viral infection may trigger the host immune response, which can contribute to
neurologic damage. In this context, nitric oxide synthase expression correlates with
death in dengue infection in murine model.
In some cases, the virus does not cause neurological disorder, even when infecting
the central nervous system. Indeed, in some neuropathological autopsy studies,
dengue virus or antigen have been detected in brain tissue without histopathological
features of inflammatory reaction66 .Carod-Artal FJ, Wichmann O, Farrar J, Gascón J. Neurological
complications of dengue virus infection. Lancet Neurol. 2013;12(9):906-9.
http://dx.doi.org/10.1016/S1474-4422(13)70150-9
https://doi.org/10.1016/S1474-4422(13)70...
,99 .Ramos C, Sánchez G, Pando RH, Baquera J, Hernández D, Mota J et al.
Dengue virus in the brain of a fatal case of hemorrhagic dengue fever. J
Neurovirol. 1998;4(4):465-8.
http://dx.doi.org/10.3109/13550289809114548
https://doi.org/10.3109/1355028980911454...
,4848 .Nogueira RMR, Filippis AMB, Coelho JMO, Sequeira PC, Schatzmayr HG,
Paiva FG et al. Dengue virus infection of the central nervous system (CNS): a
case report from Brazil. Southeast Asian J Trop Med Public Health.
2002;33(1):68-71.,4949 .Nimmannitya S, Thisyakorn U, Hemsrichart V. Dengue haemorrhagic
fever with unusual manifestations. Southeast Asian J Trop Med Public Health.
1987;18(3):398-406.,5050 .Souza KP, Silva EG, Rocha ESO, Figueiredo LB, Almeida-Leite CM,
Arantes RM et al. Nitric oxide synthase expression correlates with death in an
experimental mouse model of dengue with CNS involvement. Virol J. 2013;10:267.
http://dx.doi.org/10.1186/1743-422X-10-267
https://doi.org/10.1186/1743-422X-10-267...
.
In this context, Bordignon and colleagues22 .Bordignon J, Strottmann DM, Mosimann ALP, Probst CM, Stella V,
Noronha L et al. Dengue neurovirulence in mice: identification of molecular
signatures in the E and NS3 helicase domains. J Med Virol. 2007;79(10):1506-17.
http://dx.doi.org/10.1002/jmv.20958
https://doi.org/10.1002/jmv.20958...
, using a mice model, showed that infection with a
neurovirulent strain of DENV (FGA/NA) resulted in a higher viral load and progeny in
CNS than the infection of the non-neurovirulent strain (FGA/89). Although the FGA/89
can efficiently infect CNS cells, it does not produce neurological disorder neither
death of infected animals. In contrast, the neuroadapted virus FGA/NA can replicate
more efficiently in CNS, causing extensive inflammatory process characterized by
encephalitis and leptomeningitis as observed in histopathological examination22 .Bordignon J, Strottmann DM, Mosimann ALP, Probst CM, Stella V,
Noronha L et al. Dengue neurovirulence in mice: identification of molecular
signatures in the E and NS3 helicase domains. J Med Virol. 2007;79(10):1506-17.
http://dx.doi.org/10.1002/jmv.20958
https://doi.org/10.1002/jmv.20958...
. The genetic analysis of these
viral strains showed three amino acid substitutions: one in E (structural) protein,
and two in NS3 (non-structural) protein.
Interestingly, the genomic sequencing during the neuroadaptation process revealed
that the mutations were concomitant with the appearance of signs of encephalitis in
mice22 .Bordignon J, Strottmann DM, Mosimann ALP, Probst CM, Stella V,
Noronha L et al. Dengue neurovirulence in mice: identification of molecular
signatures in the E and NS3 helicase domains. J Med Virol. 2007;79(10):1506-17.
http://dx.doi.org/10.1002/jmv.20958
https://doi.org/10.1002/jmv.20958...
. Genetic analysis of
others neuroadapted strains reveals mutations that mapped to the same viral domain.
While mutations in the E protein could enhance the neuropathogenicity of dengue
infections by changing the virus binding or entrance into neuronal cells, the
mutations in NS3 protein may increase the replicative capacity of DENV, which could
explain the higher viral load observed in FGA/NA infection. These data together
suggest that both E and NS3 protein are associated with neurovirulence in dengue
infection in mice. The identification of molecular signatures associated with
neurovirulence of DENV is extremely important as they can serve as molecular markers
of neurovirulence. Nevertheless, when evaluating natural human infections, those
findings were not observed. Complete genome characterization of DENV-4 did not
reveal any of the described mutations associated with neurological strains. The same
study observed that the majority mutations were in non-structural proteins encoding
genes 1010 .Hapuarachchi HC, Oh HML, Thein TL, Pok KY, Lai YL, Tan LK et al.
Clinico-genetic characterisation of an encephalitic Dengue virus 4 associated
with multi-organ involvement. J Clin Virol. 2013;57(1):91-4.
http://dx.doi.org/10.1016/j.jcv.2012.12.021
https://doi.org/10.1016/j.jcv.2012.12.02...
.
FROM MOUSE MODEL TO HUMAN INFECTION
Non-human primates are not suitable models for neurological dengue once they present
only a transient viremia, with no clinical signs5151 .Amorim JH, Pereira Bizerra RS, Alves RPS, Sbrogio-Almeida ME, Levi
JE, Capurro ML et al. A genetic and pathologic study of a DENV2 clinical isolate
capable of inducing encephalitis and hematological disturbances in
immunocompetent mice. PLoS One. 2012;7(9):e44984.
http://dx.doi.org/10.1371/journal.pone.0044984
https://doi.org/10.1371/journal.pone.004...
. Murine model is the most commonly used. Nevertheless,
wild type DENV strains are not able to infect nor to induce mice death. So, the
researchers have to use immunocompromised animals and/or DENV has to be adapted to
this new host. In this adaptation process, which consists of several in vivo
or in vitro virus passages, different mutations occur.
These mutations take place throughout the genome, but are primarily observed in
viral glycoprotein E22 .Bordignon J, Strottmann DM, Mosimann ALP, Probst CM, Stella V,
Noronha L et al. Dengue neurovirulence in mice: identification of molecular
signatures in the E and NS3 helicase domains. J Med Virol. 2007;79(10):1506-17.
http://dx.doi.org/10.1002/jmv.20958
https://doi.org/10.1002/jmv.20958...
,4646 .Desprès P, Flamand M, Ceccaldi PE, Deubel V. Human isolates of
dengue type 1 virus induce apoptosis in mouse neuroblastoma cells. J Virol.
1996;70(6):4090-6.,4747 .Santos CND, Frenkiel MP, Courageot MP, Rocha CF, Vazeille-Falcoz
MC, Wien MW et al. Determinants in the envelope E protein and viral RNA helicase
NS3 that influence the induction of apoptosis in response to infection with
dengue type 1 virus. Virology. 2000;274(2):292-308.
http://dx.doi.org/10.1006/viro.2000.0457
https://doi.org/10.1006/viro.2000.0457...
,5252 .Gualano RC, Pryor MJ, Cauchi MR, Wright PJ, Davidson AD.
Identification of a major determinant of mouse neurovirulence of dengue virus
type 2 using stably cloned genomic-length cDNA. J Gen Virol.
1998;79(3):437-46.,5353 .Bray M, Men R, Tokimatsu I, Lai CJ. Genetic determinants
responsible for acquisition of dengue type 2 virus mouse neurovirulence. J
Virol. 1998;72(2):1647-51.,5454 .Sánchez IJ, Ruiz BH. A single nucleotide change in the E protein
gene of dengue virus 2 Mexican strain affects neurovirulence in mice. J Gen
Virol. 1996;77(10):2541-5.
http://dx.doi.org/10.1099/0022-1317-77-10-2541
https://doi.org/10.1099/0022-1317-77-10-...
,5555 .Kawano H, Rostapshov V, Rosen L, Lai CJ. Genetic determinants of
dengue type 4 virus neurovirulence for mice. J Virol.
1993;67(11):6567-75.. In respect to the pathogenesis of neurological dengue,
these mutations detected in neuroadapted virus, may cause significant differences
between what occurs in human infections to what happens in animal models. Indeed,
those mutations were not observed in neurovirulent humans DENV. Moreover, several
studies showed that the neurovirulent mutants selected by serial intracerebral
passage in mice exhibited significant attenuation for human infection. In the past,
this technique was even used to obtain attenuated virus for vaccine development5353 .Bray M, Men R, Tokimatsu I, Lai CJ. Genetic determinants
responsible for acquisition of dengue type 2 virus mouse neurovirulence. J
Virol. 1998;72(2):1647-51.. Therefore, this fact may
generate an important bias regarding those studies. Another important issue is that
in the majority studies regarding neurovirulence in mouse model, the virus was
inoculated through the intra cranial route5151 .Amorim JH, Pereira Bizerra RS, Alves RPS, Sbrogio-Almeida ME, Levi
JE, Capurro ML et al. A genetic and pathologic study of a DENV2 clinical isolate
capable of inducing encephalitis and hematological disturbances in
immunocompetent mice. PLoS One. 2012;7(9):e44984.
http://dx.doi.org/10.1371/journal.pone.0044984
https://doi.org/10.1371/journal.pone.004...
. As the immune response varies according to the
penetration route this can also cause discrepancies between what really happens in
humans and what is induced in mice.
In murine model, neuroinfection was observed only in immune or neurological immature
mice2525 .Velandia-Romero ML, Acosta-Losada O, Castellanos JE. In vivo
infection by a neuroinvasive neurovirulent dengue virus. J Neurovirol.
2012;18(5):374-87. http://dx.doi.org/10.1007/s13365-012-0117-y
https://doi.org/10.1007/s13365-012-0117-...
. However, cases of
neurological complications due to dengue infection are observed in adult patients
without any sign of immune impairment.
In conclusion, neurological complications in dengue infections are becoming more frequent. Neuroinvasion is not always associated with neurological disease. The demonstration of viral tropism and invasion in human nervous system are well established. Although, the role of viral factors (neurovirulence) still need to be clarified in humans. In addition, the identification of brain damage and viral markers are extremely important to understand the dengue neuropathogenesis. They can also help, in the future, to the establishment of a prognosis, disease control and vaccine development. The intrathecal synthesis of specific antibodies to dengue virus seems to be a good marker of neurovirulence. Genetic analysis, mainly regarding E and NS3 protein, searching for specific mutations, can also be used as a potential neurovirulence marker in dengue infection. The current knowledge concerning neuropathogenesis of dengue virus has been hampered by the lack of an appropriate animal model of disease as also as limited autopsy data from fatal human cases. Although the available evidence is still preliminary, it suggests a direction to follow in future studies.
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Support: Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) for the support. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil, for the PhD fellowship to C.R.
Publication Dates
-
Publication in this collection
Aug 2015
History
-
Received
28 Jan 2015 -
Reviewed
24 Mar 2015 -
Accepted
13 Apr 2015