Información del artículo
Resumen
El virus del dengue (DENV) es el agente causal de la enfermedad conocida como dengue, que es la principal enfermedad viral transmitida por artrópodos en el mundo. El DENV es un flavivirus que ingresa por endocitosis y se replica en el citoplasma de la célula infectada, originando tres proteínas estructurales y siete proteínas no estructurales, sobre las cuales se conocen sólo algunas de sus funciones en la replicación viral o en la infección. El ciclo viral que ocurre en las células infectadas hasta ahora está comenzando a aclararse y su conocimiento permitirá en el futuro próximo diseñar racionalmente moléculas que lo intervengan y eviten la replicación del virus. Durante la infección, el individuo puede presentar fiebre indiferenciada o, en otros casos, puede presentar un proceso generalizado de activación de la respuesta inmunitaria innata y adquirida, lo cual provoca la liberación de factores inflamatorios solubles que alteran la fisiología de los tejidos, principalmente el endotelio, conllevando al desarrollo de manifestaciones clínicas graves. Aunque se ha identificado un gran número de factores del individuo asociados al desarrollo de la enfermedad por DENV, queda por identificar el papel de las diferentes proteínas virales en la patogenia de la enfermedad. En la presente revisión, se presenta una breve actualización sobre la estructura y biología del DENV, de su ciclo viral intracelular y, finalmente, se introducen algunos conceptos sobre la inmunopatogenia de la enfermedad producida por este agente.
Palabras clave:
virus del dengue
estructura
ensamblaje
inmunopatogenia
Abstract
Dengue virus (DENV) is responsible for the clinical entity known as dengue that is a great concern for economy and public health of tropical countries. This flavivirus is a single strand RNA virus that after their translation and replication in host cells produces three structural and seven non-structural proteins with specific function in replication or cell binding process that we will describe here. Intracellular viral cycle has begun to be described and this knowledge will impact the rational design of new antiviral drugs. Patients suffering dengue can have an undifferentiated fever or in the severe cases, show an aberrant immunological activation process that lead to soluble inflammatory mediators secretion, affecting tissue function, mainly endothelium. This organ dysfunction is associated with plasma leakage and coagulatory imbalance. Despite it has been recently described some host factors associated with severity of infection, it remains unknown some aspects of viral biology or the role of DENV proteins in disease pathogenesis. This article pretends to make an updated revision about DENV structure, cell viral cycle and introduce some concepts about dengue immunopathogenesis.
Key words:
Dengue Virus
structure
assembly
immunopathogenesis
El Texto completo está disponible en PDF
Referencias
[1.]
B. Lindenbach, H. Thiel, C. Rice.
Flavivirus: The virus and their replication.
Fields Virology, pp. 1101-1152
[2.]
J. Kyle, E. Harris.
Global spread and persistence of dengue.
Annual Rev Microbiol, 62 (2008), pp. 71-92
[3.]
M. Tolle.
Mosquito-borne diseases.
Curr Probl Pediatr Adolesc Health Care, 39 (2009), pp. 97-140
[4.]
W. McBride, H. Bielefeldt.
Dengue viral infections; pathogenesis and epidemiology.
Microb Infect, 2 (2000), pp. 1041-1050
[5.]
H. Lei, T. Yeh, H. Liu, Y. Lin, S. Chen, C. Liu.
Immunopathogenesis of dengue virus infection.
J Biomed Sci, 8 (2001), pp. 377-388
[6.]
Ministerio de la Protección Social, Instituto Nacional de Salud.
Subdirección de Vigilancia y Control en Salud Pública.
Inf Quinc Epidemiol Nac, 15 (2010), pp. 381-384
[7.]
Instituto Nacional de Salud, Subdirección de Vigilancia y Control en Salud Pública. Boletín Epidemiológico Semanal. Semana epidemiológica 51 de 2010 (19 al 25 de diciembre de 2010). [Internet]. Diciembre de 2010. Disponible en: http://190.27.195.165:8080/index.php?idcategoria=83087#
[8.]
R. Maestre, G. Rey, A. De Las Salas, C. Vergara, L. Santacoloma, S. Goenaga, et al.
Susceptibilidad de Aedes aegypti (Diptera: Culicidae) a temefos en Atlántico-Colombia.
Rev Colomb Entomol, 35 (2009), pp. 202-205
[9.]
Ministerio de la Protección Social, Instituto Nacional de Salud, OPS/OMS.
Guía de atención clínica integral del paciente con dengue.
Ministerio de la Protección Social, (2010),
[10.]
A. Schneemann.
The structural and functional role of RNA in icosahedral virus assembly.
Annu Rev Microbiol, 60 (2006), pp. 51-67
[11.]
M. Samsa, J. Mondotte, N. Iglesias, I. Assunção, G. Barbosa, A. Da Poian, et al.
Dengue virus capsid protein usurps lipid droplets for viral particle formation.
PLoS Pathog, 10 (2005), pp. e1000632
[12.]
L. Ma, C. Jones, T. Groesch, R. Kuhn, C. Post.
Solution structure of dengue virus capsid protein reveals another fold.
Proc Natl Acad Sci USA, 101 (2004), pp. 3414-3419
[13.]
M. Urbanowski, C. Ilkow, T. Hobman.
Modulation of signaling pathways by RNA virus capsid proteins.
Cell Signal, 20 (2008), pp. 227-236
[14.]
Y. Zhang, J. Cover, P. Chipman, W. Zhang, S. Pletnev, D. Sedlak, et al.
Structures of immature flavivirus particles.
EMBO J, 22 (2003), pp. 2604-2613
[15.]
A. Catteau, O. Kalinina, M. Wagner, V. Deubel, M. Courageot, P. Despres.
Dengue virus M protein contains a proapoptotic sequence referred to as ApoptoM.
J Gen Virol, 84 (2003), pp. 2781-2793
[16.]
J. Imbert, P. Guevara, J. Ramos-Castañeda, C. Ramos, J. Sotelo.
Dengue virus infects mouse cultured neurons but not astrocytes.
J Med Virol, 42 (1994), pp. 228-233
[17.]
S. Allison, J. Schalich, K. Stiasny, C. Mandl, C. Kunz, F. Heinz.
Oligomeric rearrangement of tick-borne encephalitis virus envelope proteins induced by an acid pH.
J Virol, 69 (1995), pp. 695-700
[18.]
Y. Chem, T. Maguire, R. Hileman, J. Fromm, J. Esko, R. Linhadt, et al.
Dengue virus infectivity depends on envelope protein binding to target cell heparin sulfate.
Nat Med, 3 (1997), pp. 866-871
[19.]
S. Hung, P. Lee, H. Chen, L. Chen, C. Kao, C. King.
Analysis of the steps involved in dengue virus entry into host cells.
Virology, 257 (1999), pp. 156-167
[20.]
E. Lee, M. Lobigs.
Substitution at the putative receptor-binding site of an encephalitic flavivirus alter virulence and host cell tropism and reveal a role for glycosaminoglycans in entry.
J Virol, 74 (2000), pp. 8867-8875
[21.]
C. Lin, H. Lei, A. Shiau, H. Liu, T. Yeh, S. Chen, et al.
Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide.
J Immunol, 169 (2002), pp. 657-664
[22.]
Y. Zhang, W. Zhang, S. Ogata, D. Clements, J. Strauss, T. Baker, et al.
Conformational changes of the flavivirus E glycoprotein.
Structure, 12 (2004), pp. 1607-1618
[23.]
K. Stiasny, F. Heinz.
Flavivirus membrane fusion.
J Gen Virol, 87 (2006), pp. 2755-2766
[24.]
S. Noisakran, T. Dechtawewat, P. Avirutnan, T. Kinoshita, U. Siripanyaphinyo, C. Puttikhunt, et al.
Association of dengue virus NS1 protein with lipid rafts.
J Gen Virol, 89 (2008), pp. 2492-2500
[25.]
P. Avirutnan, N. Punyadee, S. Noisakran, C. Komoltri, S. Thiemmeca, K. Auethavornanan, et al.
Vascular leakage in severe dengue virus infections: A potential role for the nonstructural viral protein NS1 and complement.
J Infect Dis, 193 (2006), pp. 1078-1088
[26.]
P. Avirutnan, L. Zhang, N. Punyadee, A. Manuyakorn, C. Pittikhunt, W. Kasinrerk, et al.
Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E.
PLoS Pathog, 3 (2007), pp. e183
[27.]
J. Schelesinger.
Flavivirus nonstructural protein NS1: Complementary surprises.
Proc Natl Acad Sci USA, 103 (2006), pp. 18879-18880
[28.]
V.D. Krishna, M. Rangappa, V. Satchidanandam.
Virus-specific cytolytic antibodies to nonstructural protein 1 of Japanese encephalitis virus effect reduction of virus output from infected cells.
J Virol, 83 (2009), pp. 4766-4777
[29.]
B. Lindenbach, C. Rice.
Molecular biology of flavivirus.
Adv Virus Res, 59 (2003), pp. 23-61
[30.]
M. Bollati, K. Álvarez, R. Assenberg, C. Baronti, B. Canard, S. Cook, et al.
Structure and functionality in flavivirus NS-proteins: Perspectives for drug design.
Antiviral Res, 87 (2010), pp. 125-148
[31.]
J. Bazan, R. Fletterick.
Detection of a trypsin-like serine protease domain in flaviviruses and pestiviruses.
Virology, 171 (1989), pp. 637-639
[32.]
T. Chambers, R. Weir, A. Grakoui, D. McCourt, J. Bazan, R. Fletterick, et al.
Evidence that the N-terminal domain of nonstructuralprotein NS3 from yellow fever virus is a serine protease responsible for sitespecific cleavages in the viral polyprotein.
Proc Natl Acad Sci USA, 87 (1990), pp. 8898-8902
[33.]
N.S. Heaton, R. Perera, K.L. Berger, S. Khadka, D.J. Lacount, R.J. Kuhn, et al.
Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis.
Proc Natl Acad Sci U S A, 107 (2010), pp. 17345-17350
[34.]
C. Patkar, R. Kuhn.
Yellow Fever Virus NS3 plays and essential role in virus assembly independent of its enzymatic functions.
J Virol, 82 (2008), pp. 3342-3352
[35.]
C. Chiou, C. Andrew, P. Chen, C. Liao, Y. Lin, J. Wang.
Association of Japanese encephalitis virus NS3 protein with microtubules and tumor susceptibility gene 101 (TSG101) protein.
J Gen Virol, 84 (2003), pp. 2795-2805
[36.]
J.L. Muñoz-Jordan, G.G. Sánchez-Burgos, M. Laurent-Rolle, A. García- Sastre.
Inhibition of interferon signaling by dengue virus.
Proc Natl Acad Sci USA, 100 (2003), pp. 14333-14338
[37.]
B. Selisko, F.F. Peyrane, B. Canard, K. Álvarez, E. Decroly.
Biochemical characterization of the (nucleoside-2>O)-methyltransferase activity of dengue virus protein NS5 using purified capped RNA oligonucleotides (7Me) GpppAC(n) and GpppAC(n).
J Gen Virol, 91 (2010), pp. 112-121
[38.]
M. Nomaguchi, M. Ackermann, C. Yon, S. You, R. Padmanabhan.
De novo synthesis of negative-strand RNA by dengue virus RNA-dependent RNA polymerase in vitro: Nucleotide, primer and template parameters.
J Virol, 77 (2003), pp. 8831-8842
[39.]
P. Tio, W. Jong, M. Cardosa.
Two dimensional VOPBA reveals laminin receptor (LAMR1) interaction with dengue virus serotypes 1, 2 and 3.
Virol J, 2 (2005), pp. 25-36
[40.]
J. Nelson, N. McFerran, G. Pivato, E. Chambers, C. Doherty, D. Steele, et al.
The 67kDa laminin receptor: Structure, function and role in disease.
Biosci Rep, 28 (2008), pp. 33-48
[41.]
B. Tassaneetrithep, T. Burgess, A. Granelli-Piperno, C. Trumpfheller, J. Finke, W. Sun, et al.
DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells.
J Exp Med, 197 (2003), pp. 823-829
[42.]
R. Germi, J.M. Crance, D. Garin, J. Guimet, H. Lortat-Jacob, R.W. Ruigrok, et al.
Heparan sulfate-mediated binding of infectious dengue virus type 2 and yellow fever virus.
Virology, 292 (2002), pp. 162-168
[43.]
D. Mosier.
How HIV changes its tropism: Evolution and adaptation?.
Curr Opin HIV AIDS, 4 (2009), pp. 125-130
[44.]
M.S. Diamond, D. Edgil, T.G. Roberts, B. Lu, E. Harris.
Infection of human cells by dengue virus is modulated by different cell types and viral strains.
J Virol, 74 (2000), pp. 7814-7823
[45.]
C. Mosso, I. Galván-Mendoza, J. Ludert, R. Ángel.
Endocytic pathway followed by dengue virus to infect the mosquito cell line C6/36 HT.
Virology, 378 (2009), pp. 193-199
[46.]
A. Rothman, F. Ennis.
Toga/Flaviviruses: Immunophathology.
Effects of microbes on the immune system, pp. 473-490
[47.]
H. van der Schaar, M. Rust, B. Waarts, H. van der Ende-Metselaar, R. Kuhn, J. Wilschut, et al.
Characterization of the early events in dengue virus cell entry by biochemical assay and single-virus tracking.
J Virol, 81 (2007), pp. 12019-12028
[48.]
H. van der Schaar, M. Rust, C. Chen, H. van der Ende-Merselaar, J. Wilschur, X. Zhuang, et al.
Dissecting the cell entry pathway of dengue virus by single-particle tracking in living cells.
PLoS Pathog, 4 (2008), pp. e1000244
[49.]
H. van der Schaar, J. Wilschut, J. Smit.
Role of antibodies in controlling dengue virus infection.
Inmunobiology, 214 (2009), pp. 613-629
[50.]
R. Qi, L. Zhang, C. Chi.
Biological characteristics of dengue virus and potential targets for drug design.
Acta Biochim Biophys Sin, 40 (2008), pp. 91-101
[51.]
T. Limjindaporn, W. Wongwiwat, S. Noisakran, C. Srisawat, J. Netsawang, C. Puttikhunt, et al.
Interaction of dengue virus envelope protein with endoplasmic reticulum-resident chaperones facilitates dengue virus production.
Biochem Biophys Res Commun, 379 (2009), pp. 196-200
[52.]
S. Elsuhuber, S.L. Allison, F. Heinz, C. Mandl.
Cleavage of protein prM is necessary for infection of BHK-21 cells by tick-borne encephalitis virus.
J Gen Virol, 84 (2003), pp. 183-191
[53.]
C. Jones, L. Ma, J. Burgener, T. Groesch, C. Post, R. Kuhn.
Flavivirus capside protein is a dimeric alpha-helical protein.
J Virol, 77 (2003), pp. 7143-7149
[54.]
S. Kiermayr, R. Kofler, C. Mandl, P. Messner, F. Heinz.
Isolation of capsid protein dimers from the tick-borne encephalitis flavivirus and in vitro assembly of capsid-like particles.
J Virol, 78 (2004), pp. 8078-8084
[55.]
S. Wang, W. Syu, S. Hu.
Identification of the homotypic interaction domain of the core protein of dengue virus type 2.
J Gen Virol, 85 (2004), pp. 2307-2314
[56.]
R. Perera, M. Khaliq, R. Kuhn.
Closing the door on flaviviruses: Entry as a target for antiviral drug design.
Antiviral Res, 80 (2008), pp. 11-22
[57.]
R. Perera, R. Kuhn.
Structural proteomics of dengue virus.
Curr Opin Microbiol, 11 (2008), pp. 369-377
[58.]
D. Gubler.
Dengue and dengue hemorrhagic fever.
Clin Microbiol Rev, 11 (1998), pp. 480-496
[59.]
A. Rothman.
Dengue: Defining protective versus pathologic immunity.
J Clin Invest, 113 (2004), pp. 946-951
[60.]
T. Pang, M. Cardosa, M. Guzmán.
Of cascades and perfect storms: The immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS).
Immunol Cell Biol, 85 (2007), pp. 42-45
[61.]
N. King, B. Shrestha, A. Kesson.
Immune modulation by flaviviruses.
Adv Virus Res, 60 (2003), pp. 121-155
[62.]
S. Thomas, D. Strickman, D. Vaughn.
Dengue epidemiology: Virus epidemiology, ecology and emergence.
Adv Virus Res, 61 (2003), pp. 235-289
[63.]
K. Oishi, M. Saito, C. Mapua, F. Natividad.
Dengue illness: Clinical features and pathogenesis.
J Infect Chemother, 13 (2007), pp. 125-133
[64.]
C. Lin, S. Wan, H. Cheng, H. Lei, Y. Lin.
Autoimmune pathogenesis in dengue virus infection.
Viral Immunol, 19 (2006), pp. 127-132
[65.]
M. Martínez-Gutiérrez, J.E. Castellanos.
Dengue hemorrágico, ¿una aberración inmunológica?.
Revista Escuela Colombiana de Medicina, 11 (2006), pp. 10-19
[66.]
Z. Kou, M. Quinn, H. Chen, W. Rodrigo, R. Rose, J. Schlesinger, et al.
Monocytes but not T or B cells, are the principal target cells for dengue virus (DV) infection among human peripheral blood mononuclear cells.
J Med Virol, 80 (2008), pp. 46
[67.]
S. Halstead.
Dengue.
Tropical medicine science and practice, pp. 285-326
[68.]
A. Srikiatkhachorn.
Plasma leakage in dengue hemorrhagic fever.
Thromb Haemost, 102 (2009), pp. 1042-1049
[69.]
M. Guzmán.
Deciphering dengue: The cuban experience.
Science, 309 (2005), pp. 1495-1497
[70.]
B. Murge.
Severe dengue: Questioning the paradigm.
Microb Infect, 12 (2010), pp. 113-118
[71.]
B. Martina, P. Koraka, A. Osterhaus.
Dengue virus pathogenesis: An integrated view.
Clin Microbiol Rev, 22 (2009), pp. 564-581
[72.]
S. Kabra, Y. Jain, R. Pandey, M. Singhal, P. Tripathi, B. Seth, et al.
Dengue haemorrhagic fever in children in the 1996 Delhi epidemic.
Trans R Soc Trop Med Hyg, 93 (1999), pp. 294-298
[73.]
S. Hongsiriwon.
Dengue hemorrhagic fever in infants.
Southeast Asian J Trop Med Public Health, 33 (2002), pp. 49-55
[74.]
M.T. Fernández-Mestre, K. Gendzekhadze, P. Rivas-Vetencourt, Z. Layrisse.
TNFalpha 308-A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients.
Tissue Antigens, 64 (2004), pp. 469-472
[75.]
U. Chaturvedi, R. Nagar, R. Shrivastava.
Dengue and dengue hemorrhagic fever: Implications of host genetics.
FEMS Immunol Med Microbiol, 47 (2006), pp. 155-166
[76.]
Y. Chao, C. Huang, C. Lee, S. Chang, C. King, C. Kao.
Higher infection of dengue virus serotype 2 in human monocytes of patients with G6PD deficiency.
Plos ONE, 3 (2008), pp. e1557
[77.]
R. Warke, K. Xhaja, K. Martin, M. Fournier, S. Shaw, N. Brizuela, et al.
Dengue virus induces novel changes in gene expression of human umbilical vein endothelial cells.
J Virol, 77 (2003), pp. 11822-11832
[78.]
S. Green, A. Rothman.
Immunopathological mechanisms in dengue and dengue hemorrhagic fever.
Curr Opin Infect Dis, 19 (2006), pp. 429-436
[79.]
U. Chaturvedi, R. Agarwal, E. Elbishbish, A. Mustafa.
Cytokine cascade in dengue hemorrhagic fever: Implications for pathogenesis.
FEMS Immunol Med Microbiol, 28 (2000), pp. 183-188
[80.]
N. Houghton-Triviño, D. Salgado, J. Rodríguez, I. Bosch, J.E. Castellanos.
Levels of soluble ST2 in serum associated with severity of dengue due to tumor necrosis factor alpha stimulation.
J Gen Virol, 91 (2010), pp. 697-706
Copyright © 2011. Asociación Colombiana de Infectología (ACIN)
