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Advances and new insights in the neuropathogenesis of dengue infection

Avanços e novos aspectos na neuropatogênese da dengue

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 countries1.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)2.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)1.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 clear1.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 organ failure are considered severe dengue3.Hadinegoro SRS. The revised WHO dengue case classification: does the system need to be modified? Paediatr Int Child Health. 2012;32(s1):33-8. http://dx.doi.org/10.1179/2046904712Z.00000000052
https://doi.org/10.1179/2046904712Z.0000...
,4.World Health Organization. Dengue: guidelines for diagnosis, treatment, prevention and control. Geneva: World Health Organization;2009.,5.Whitehorn J, Simmons CP. The pathogenesis of dengue. Vaccine. 2011;29(42):7221-8. http://dx.doi.org/10.1016/j.vaccine.2011.07.022
https://doi.org/10.1016/j.vaccine.2011.0...
. Neurological complications can also occur in dengue infection6.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...
. 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 myelitis7.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...
,8.Soares CN, Cabral-Castro MJ, Peralta JM, Freitas MRG, Puccioni-Sohler M. Meningitis determined by oligosymptomatic dengue virus type 3 infection: report of a case. Int J Infect Dis. 2010;14(2):e150-2. http://dx.doi.org/10.1016/j.ijid.2009.03.016
https://doi.org/10.1016/j.ijid.2009.03.0...
. However, DENV-1 and DENV-4 are also identified in cases of encephalitis9.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...
. Although neurological manifestation is consider uncommon, recent studies showed that it is becoming more frequent in both DF and DHF2.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...
,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...
. About 1-21% of individuals with dengue present neurological abnormalities7.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...
,1111 .Thisyakorn U, Thisyakorn C, Limpitikul W, Nisalak A. Dengue infection with central nervous system manifestations. Southeast Asian J Trop Med Public Health. 1999;30(3):504-6.. When evaluating the suspected cases of CNS infection, dengue was observed in 4-13%1212 .Solomon T, Dung NM, Vaughn DW, Kneen R, Thao LT, Taengsakulrach B et al. Neurological manifestations of dengue infection. Lancet. 2000;355(9209):1053-9. http://dx.doi.org/10.1016/S0140-6736(00)02036-5
https://doi.org/10.1016/S0140-6736(00)02...
,1313 .Jackson ST, Mullings A, Bennett F, Khan C, Gordon-Strachan G, Rhoden T. Dengue infection in patients presenting with neurological manifestations in a dengue endemic population. West Indian Med J. 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 etiology of encephalitis in children in southern Vietnam: results of a one-year prospective descriptive study. PLoS Negl Trop Dis. 2010;4(10):e854. http://dx.doi.org/10.1371/journal.pntd.0000854
https://doi.org/10.1371/journal.pntd.000...
,1515 .Tan L Van, Thai LH, Phu NH, Nghia HD, Chuong LV, Sinh DX et al. Viral aetiology of central nervous system infections in adults admitted to a tertiary referral hospital in southern Vietnam over 12 years. PLoS Negl Trop Dis. 2014;8(8):e3127. http://dx.doi.org/10.1371/journal.pntd.0003127
https://doi.org/10.1371/journal.pntd.000...
, 15% in India1616 .Kumar R, Tripathi P, Tripathi S, Kanodia A, Pant S, Venkatesh V. Prevalence and clinical differentiation of dengue fever in children in northern India. Infection. 2008;36(5):444-9. http://dx.doi.org/10.1007/s15010-008-7172-6
https://doi.org/10.1007/s15010-008-7172-...
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. Pediatr Infect Dis J. 2001;20(2):216-8. http://dx.doi.org/10.1097/00006454-200102000-00020
https://doi.org/10.1097/00006454-2001020...
. 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, Puccioni-Sohler M. Review of the etiologies of viral meningitis and encephalitis in a dengue endemic region. J Neurol Sci. 2011;303(1-2):75-9. http://dx.doi.org/10.1016/j.jns.2011.01.012
https://doi.org/10.1016/j.jns.2011.01.01...
. 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. http://dx.doi.org/10.1590/0004-282X20130222
https://doi.org/10.1590/0004-282X2013022...
. 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..

Figure 1
Antibody-dependent enhancement (ADE) in dengue virus infection.

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 virus6.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. http://dx.doi.org/10.4081/ni.2012.e15
https://doi.org/10.4081/ni.2012.e15...
,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
https://doi.org/10.1590/0004-282X2013014...
. 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
https://doi.org/10.1016/j.jinf.2014.05.0...
. 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
https://doi.org/10.1016/j.jinf.2014.05.0...
,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...
,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
https://doi.org/10.1007/s004410051130...
. 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...
.

Figure 2
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. http://dx.doi.org/10.1007/s00428-003-0785-3
https://doi.org/10.1007/s00428-003-0785-...
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 hypothesis7.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 tissue9.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. 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...
. DENV RNA was also detected in brain tissue and in CSF of infected individuals7.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...
,9.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...
,3636 .Bastos MS, Lessa N, Naveca FG, Monte RL, Braga WS, Figueiredo LT et al. Detection of Herpesvirus, Enterovirus, and Arbovirus infection in patients with suspected central nervous system viral infection in the Western Brazilian Amazon. J Med Virol. 2014;86(9):1522-7. http://dx.doi.org/10.1002/jmv.23953
https://doi.org/10.1002/jmv.23953...
,3737 .Araújo F, Nogueira R, Araújo MS, Perdigão A, Cavalcanti L, Brilhante R et al. Dengue in patients with central nervous system manifestations, Brazil. Emerg Infect Dis. 2012;18(4):677-9. http://dx.doi.org/10.3201/eid1804.111522
https://doi.org/10.3201/eid1804.111522...
,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 reaction6.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...
,9.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 colleagues2.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 examination2.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 mice2.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 E2.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.

References

  • 1
    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
  • 2
    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
  • 3
    Hadinegoro SRS. The revised WHO dengue case classification: does the system need to be modified? Paediatr Int Child Health. 2012;32(s1):33-8. http://dx.doi.org/10.1179/2046904712Z.00000000052
    » https://doi.org/10.1179/2046904712Z.00000000052
  • 4
    World Health Organization. Dengue: guidelines for diagnosis, treatment, prevention and control. Geneva: World Health Organization;2009.
  • 5
    Whitehorn J, Simmons CP. The pathogenesis of dengue. Vaccine. 2011;29(42):7221-8. http://dx.doi.org/10.1016/j.vaccine.2011.07.022
    » https://doi.org/10.1016/j.vaccine.2011.07.022
  • 6
    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)70150-9
  • 7
    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.2007.09.040
  • 8
    Soares CN, Cabral-Castro MJ, Peralta JM, Freitas MRG, Puccioni-Sohler M. Meningitis determined by oligosymptomatic dengue virus type 3 infection: report of a case. Int J Infect Dis. 2010;14(2):e150-2. http://dx.doi.org/10.1016/j.ijid.2009.03.016
    » https://doi.org/10.1016/j.ijid.2009.03.016
  • 9
    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/10.3109/13550289809114548
  • 10
    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.2012.12.021
  • 11
    Thisyakorn U, Thisyakorn C, Limpitikul W, Nisalak A. Dengue infection with central nervous system manifestations. Southeast Asian J Trop Med Public Health. 1999;30(3):504-6.
  • 12
    Solomon T, Dung NM, Vaughn DW, Kneen R, Thao LT, Taengsakulrach B et al. Neurological manifestations of dengue infection. Lancet. 2000;355(9209):1053-9. http://dx.doi.org/10.1016/S0140-6736(00)02036-5
    » https://doi.org/10.1016/S0140-6736(00)02036-5
  • 13
    Jackson ST, Mullings A, Bennett F, Khan C, Gordon-Strachan G, Rhoden T. Dengue infection in patients presenting with neurological manifestations in a dengue endemic population. West Indian Med J. 2008;57(4):373-6.
  • 14
    Le VT, Phan TQ, Do QH, Nguyen BH, Lam QB, Bach V et al. Viral etiology of encephalitis in children in southern Vietnam: results of a one-year prospective descriptive study. PLoS Negl Trop Dis. 2010;4(10):e854. http://dx.doi.org/10.1371/journal.pntd.0000854
    » https://doi.org/10.1371/journal.pntd.0000854
  • 15
    Tan L Van, Thai LH, Phu NH, Nghia HD, Chuong LV, Sinh DX et al. Viral aetiology of central nervous system infections in adults admitted to a tertiary referral hospital in southern Vietnam over 12 years. PLoS Negl Trop Dis. 2014;8(8):e3127. http://dx.doi.org/10.1371/journal.pntd.0003127
    » https://doi.org/10.1371/journal.pntd.0003127
  • 16
    Kumar R, Tripathi P, Tripathi S, Kanodia A, Pant S, Venkatesh V. Prevalence and clinical differentiation of dengue fever in children in northern India. Infection. 2008;36(5):444-9. http://dx.doi.org/10.1007/s15010-008-7172-6
    » https://doi.org/10.1007/s15010-008-7172-6
  • 17
    Chokephaibulkit K, Kankirawatana P, Apintanapong S, Pongthapisit V, Yoksan S, Kositanont U et al. Viral etiologies of encephalitis in Thai children. Pediatr Infect Dis J. 2001;20(2):216-8. http://dx.doi.org/10.1097/00006454-200102000-00020
    » https://doi.org/10.1097/00006454-200102000-00020
  • 18
    Soares CN, Cabral-Castro MJ, Peralta JM, Freitas MRG, Zalis M, Puccioni-Sohler M. Review of the etiologies of viral meningitis and encephalitis in a dengue endemic region. J Neurol Sci. 2011;303(1-2):75-9. http://dx.doi.org/10.1016/j.jns.2011.01.012
    » https://doi.org/10.1016/j.jns.2011.01.012
  • 19
    Wiwanitkit S, Wiwanitkit V. Neurological complications in dengue infection. Arq Neuropsiquiatr. 2014;72(3):259. http://dx.doi.org/10.1590/0004-282X20130222
    » https://doi.org/10.1590/0004-282X20130222
  • 20
    Whitehorn J, Simmons CP. The pathogenesis of dengue. Vaccine. 2011;29:7221-8. Duplicata da 1.
  • 21
    Puccioni-Sohler M, Orsini M, Soares CN. Dengue: a new challenge for neurology. Neurol Int. 2012;4(3):e15. http://dx.doi.org/10.4081/ni.2012.e15
    » https://doi.org/10.4081/ni.2012.e15
  • 22
    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
    » https://doi.org/10.1590/0004-282X20130147
  • 23
    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
    » https://doi.org/10.1016/j.jinf.2014.05.010
  • 24
    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/10.1099/0022-1317-72-4-859
  • 25
    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-y
  • 26
    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
  • 27
    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
    » https://doi.org/10.1007/s004410051130
  • 28
    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.
  • 29
    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/10.1080/13550280802339643
  • 30
    Fishman R. Cerebrospinal fluid. Philadelphia: W. B. Saunders; 1992.
  • 31
    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/s00428-003-0785-3
  • 32
    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.
  • 33
    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.
  • 34
    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/S0074-02762006000300015
  • 35
    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.0b013e31824b94e9
  • 36
    Bastos MS, Lessa N, Naveca FG, Monte RL, Braga WS, Figueiredo LT et al. Detection of Herpesvirus, Enterovirus, and Arbovirus infection in patients with suspected central nervous system viral infection in the Western Brazilian Amazon. J Med Virol. 2014;86(9):1522-7. http://dx.doi.org/10.1002/jmv.23953
    » https://doi.org/10.1002/jmv.23953
  • 37
    Araújo F, Nogueira R, Araújo MS, Perdigão A, Cavalcanti L, Brilhante R et al. Dengue in patients with central nervous system manifestations, Brazil. Emerg Infect Dis. 2012;18(4):677-9. http://dx.doi.org/10.3201/eid1804.111522
    » https://doi.org/10.3201/eid1804.111522
  • 38
    Pancharoen C, Thisyakorn U. Neurological manifestations in dengue patients. Southeast Asian J Trop Med Public Health. 2001;32(2):341-5.
  • 39
    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
  • 40
    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.79.8.4557-4567.2005
  • 41
    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/10.3109/13550289709031189
  • 42
    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.0001147
  • 43
    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.2011.07.003
  • 44
    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.0b013e3181bd8258
  • 45
    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.
  • 46
    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.
  • 47
    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
  • 48
    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.
  • 49
    Nimmannitya S, Thisyakorn U, Hemsrichart V. Dengue haemorrhagic fever with unusual manifestations. Southeast Asian J Trop Med Public Health. 1987;18(3):398-406.
  • 50
    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
  • 51
    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.0044984
  • 52
    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.
  • 53
    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.
  • 54
    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/10.1099/0022-1317-77-10-2541
  • 55
    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.
  • 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
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