Tropism of Dengue Virus in Mice and Humans Defined by Viral Nonstructural Protein 3-Specific Immunostaining

Scott J. Balsitis Division of Infectious Diseases, School of Public Health, and Department of Molecular and Cell Biology, University of California, Berkeley, California; Hospital de Infectología, Ministerio de Salud, Guayaquil, Ecuador; Instituto Nacional de Higiene, Ministerio de Salud, Guayaquil, Ecuador; Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, California

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Josefina Coloma Division of Infectious Diseases, School of Public Health, and Department of Molecular and Cell Biology, University of California, Berkeley, California; Hospital de Infectología, Ministerio de Salud, Guayaquil, Ecuador; Instituto Nacional de Higiene, Ministerio de Salud, Guayaquil, Ecuador; Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, California

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Glenda Castro Division of Infectious Diseases, School of Public Health, and Department of Molecular and Cell Biology, University of California, Berkeley, California; Hospital de Infectología, Ministerio de Salud, Guayaquil, Ecuador; Instituto Nacional de Higiene, Ministerio de Salud, Guayaquil, Ecuador; Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, California

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Aracely Alava Division of Infectious Diseases, School of Public Health, and Department of Molecular and Cell Biology, University of California, Berkeley, California; Hospital de Infectología, Ministerio de Salud, Guayaquil, Ecuador; Instituto Nacional de Higiene, Ministerio de Salud, Guayaquil, Ecuador; Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, California

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Diana Flores Division of Infectious Diseases, School of Public Health, and Department of Molecular and Cell Biology, University of California, Berkeley, California; Hospital de Infectología, Ministerio de Salud, Guayaquil, Ecuador; Instituto Nacional de Higiene, Ministerio de Salud, Guayaquil, Ecuador; Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, California

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James H. McKerrow Division of Infectious Diseases, School of Public Health, and Department of Molecular and Cell Biology, University of California, Berkeley, California; Hospital de Infectología, Ministerio de Salud, Guayaquil, Ecuador; Instituto Nacional de Higiene, Ministerio de Salud, Guayaquil, Ecuador; Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, California

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P. Robert Beatty Division of Infectious Diseases, School of Public Health, and Department of Molecular and Cell Biology, University of California, Berkeley, California; Hospital de Infectología, Ministerio de Salud, Guayaquil, Ecuador; Instituto Nacional de Higiene, Ministerio de Salud, Guayaquil, Ecuador; Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, California

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Eva Harris Division of Infectious Diseases, School of Public Health, and Department of Molecular and Cell Biology, University of California, Berkeley, California; Hospital de Infectología, Ministerio de Salud, Guayaquil, Ecuador; Instituto Nacional de Higiene, Ministerio de Salud, Guayaquil, Ecuador; Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, California

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Previous attempts to define dengue virus (DENV) tropism in human autopsy tissues have detected DENV antigens that are abundant in circulation during severe dengue, and thus may be present in uninfected cells. To better define DENV tropism, we performed immunostaining for the DENV2 nonstructural protein 3 (NS3) in humans and in a mouse model of DENV infection. In mice, NS3 was detected in phagocytes of the spleen and lymph node, hepatocytes in liver, and myeloid cells in bone marrow. In human autopsy tissues, NS3 was present in phagocytes in lymph node and spleen, alveolar macrophages in lung, and perivascular cells in brain. This protein was also found in hepatocytes in liver and endothelial cells in spleen, although NS3 was not present in endothelium in any other tissue. Thus, NS3-specific immunostaining supports roles for infected phagocytes, hepatocytes, and, to a limited degree, endothelial cells in the pathogenesis of severe dengue.

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  • 1

    Gubler DJ, 1998. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 11 :480–496.

  • 2

    Mackenzie JS, Gubler DJ, Petersen LR, 2004. Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med 10 :S98–S109.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Bhoopat L, Bhamarapravati N, Attasiri C, Yoksarn S, Chaiwun B, Khunamornpong S, Sirisanthana V, 1996. Immunohistochemical characterization of a new monoclonal antibody reactive with dengue virus-infected cells in frozen tissue using immunoperoxidase technique. Asian Pac J Allergy Immunol 14 :107–113.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Boonpucknavig S, Boonpucknavig V, Bhamarapravati N, Nimmannitya S, 1979. Immunofluorescence study of skin rash in patients with dengue hemorrhagic fever. Arch Pathol Lab Med 103 :463–466.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Couvelard A, Marianneau P, Bedel C, Drouet MT, Vachon F, Henin D, Deubel V, 1999. Report of a fatal case of dengue infection with hepatitis: demonstration of dengue antigens in hepatocytes and liver apoptosis. Hum Pathol 30 :1106–1110.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Hall WC, Crowell TP, Watts DM, Barros VL, Kruger H, Pinheiro F, Peters CJ, 1991. Demonstration of yellow fever and dengue antigens in formalin-fixed paraffin-embedded human liver by immunohistochemical analysis. Am J Trop Med Hyg 45 :408–417.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Huerre MR, Lan NT, Marianneau P, Hue NB, Khun H, Hung NT, Khen NT, Drouet MT, Huong VT, Ha DQ, Buisson Y, Deubel V, 2001. Liver histopathology and biological correlates in five cases of fatal dengue fever in Vietnamese children. Virchows Arch 438 :107–115.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Jessie K, Fong MY, Devi S, Lam SK, Wong KT, 2004. Localization of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ hybridization. J Infect Dis 189 :1411–1418.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Miagostovich MP, Ramos RG, Nicol AF, Nogueira RM, Cuzzi-Maya T, Oliveira AV, Marchevsky RS, Mesquita RP, Schatzmayr HG, 1997. Retrospective study on dengue fatal cases. Clin Neuropathol 16 :204–208.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Ramos C, Sanchez G, Pando RH, Baquera J, Hernandez D, Mota J, Ramos J, Flores A, Llausas E, 1998. Dengue virus in the brain of a fatal case of hemorrhagic dengue fever. J Neurovirol 4 :465–468.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Libraty DH, Young PR, Pickering D, Endy TP, Kalayanarooj S, Green S, Vaughn DW, Nisalak A, Ennis FA, Rothman AL, 2002. High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis 186 :1165–1168.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Murgue B, Roche C, Chungue E, Deparis X, 2000. Prospective study of the duration and magnitude of viraemia in children hospitalised during the 1996–1997 dengue-2 outbreak in French Polynesia. J Med Virol 60 :432–438.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Vaughn DW, Green S, Kalayanarooj S, Innis BL, Nimmannitya S, Suntayakorn S, Endy TP, Raengsakulrach B, Rothman AL, Ennis FA, Nisalak A, 2000. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis 181 :2–9.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Durbin AP, Vargas MJ, Wanionek K, Hammond SN, Gordon A, Rocha C, Balmaseda A, Harris E, 2008. Phenotyping of peripheral blood mononuclear cells during acute dengue illness demonstrates infection and increased activation of monocytes in severe cases compared to classic dengue fever. Virology 376 :429–435.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Kyle JL, Beatty PR, Harris E, 2007. Dengue virus infects macrophages and dendritic cells in a mouse model of infection. J Infect Dis 195 :1808–1817.

  • 16

    Lindenbach B, Rice CM, 2001. Flaviviridae: the viruses and their replication. Knipe DM, Howley PM, eds. Fields Virology. Fourth edition. Philadelphia: Lippincott Williams & Wilkins, 991–1042.

    • PubMed
    • Export Citation
  • 17

    Shresta S, Kyle JL, Snider HM, Basavapatna M, Beatty PR, Harris E, 2004. Interferon-dependent immunity is essential for resistance to primary dengue virus infection in mice, whereas T- and B-cell-dependent immunity are less critical. J Virol 78 :2701–2710.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Lanciotti RS, Calisher CH, Gubler DJ, Chang GJ, Vorndam AV, 1992. Rapid detection and typing of dengue viruses from clinical samples by using reverse transcriptase-polymerase chain reaction. J Clin Microbiol 30 :545–551.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Shresta S, Sharar KL, Prigozhin DM, Beatty PR, Harris E, 2006. A murine model for dengue virus-induced lethal disease with increased vascular permeability. J Virol 80 :10208–10217.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Calvert AE, Huang CY, Kinney RM, Roehrig JT, 2006. Non-structural proteins of dengue 2 virus offer limited protection to interferon-deficient mice after dengue 2 virus challenge. J Gen Virol 87 :339–346.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Johnson AJ, Roehrig JT, 1999. New mouse model for dengue virus vaccine testing. J Virol 73 :783–786.

  • 22

    Schul W, Liu W, Xu HY, Flamand M, Vasudevan SG, 2007. A dengue fever viremia model in mice shows reduction in viral replication and suppression of the inflammatory response after treatment with antiviral drugs. J Infect Dis 195 :665–674.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Rothwell SW, Putnak R, La Russa VF, 1996. Dengue-2 virus infection of human bone marrow: characterization of dengue-2 antigen-positive stromal cells. Am J Trop Med Hyg 54 :503–510.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Nakao S, Lai CJ, Young NS, 1989. Dengue virus, a flavivirus, propagates in human bone marrow progenitors and hematopoietic cell lines. Blood 74 :1235–1240.

  • 25

    King AD, Nisalak A, Kalayanrooj S, Myint KS, Pattanapanyasat K, Nimmannitya S, Innis BL, 1999. B cells are the principal circulating mononuclear cells infected by dengue virus. Southeast Asian J Trop Med Public Health 30 :718–728.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Blackley S, Kou Z, Chen H, Quinn M, Rose RC, Schlesinger JJ, Coppage M, Jin X, 2007. Primary human splenic macrophages, but not T or B cells, are the principal target cells for dengue virus infection in vitro. J Virol 81 :13325–13334.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Kou Z, Quinn M, Chen H, Rodrigo WW, Rose RC, Schlesinger JJ, Jin X, 2008. 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 :134–146.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Gubler DJ, Zaki SR, 1998. Dengue and other viral hemorrhagic fevers. Nelson AM, Horsburgh CR, eds. Pathology of Emerging Infections 2. Washington, DC: American Society for Microbiology Press, 43–71.

    • PubMed
    • Export Citation
  • 29

    Marianneau P, Steffan AM, Royer C, Drouet MT, Jaeck D, Kirn A, Deubel V, 1999. Infection of primary cultures of human Kupffer cells by dengue virus: no viral progeny synthesis, but cytokine production is evident. J Virol 73 :5201–5206.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Kuo CH, Tai DI, Chang-Chien CS, Lan CK, Chiou SS, Liaw YF, 1992. Liver biochemical tests and dengue fever. Am J Trop Med Hyg 47 :265–270.

  • 31

    Mohan B, Patwari AK, Anand VK, 2000. Hepatic dysfunction in childhood dengue infection. J Trop Pediatr 46 :40–43.

  • 32

    de Souza LJ, Nogueira RM, Soares LC, Soares CE, Ribas BF, Alves FP, Vieira FR, Pessanha FE, 2007. The impact of dengue on liver function as evaluated by aminotransferase levels. Braz J Infect Dis 11 :407–410.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Rosen L, Khin MM, U T, 1989. Recovery of virus from the liver of children with fatal dengue: reflections on the pathogenesis of the disease and its possible analogy with that of yellow fever. Res Virol 140 :351–360.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Ling LM, Wilder-Smith A, Leo YS, 2007. Fulminant hepatitis in dengue haemorrhagic fever. J Clin Virol 38 :265–268.

  • 35

    Suksanpaisan L, Cabrera-Hernandez A, Smith DR, 2007. Infection of human primary hepatocytes with dengue virus serotype 2. J Med Virol 79 :300–307.

  • 36

    Nogueira RM, Schatzmayr HG, Miagostovich MP, Farias MF, Farias Filho JD, 1988. Virological study of a dengue type 1 epidemic at Rio de Janeiro. Mem Inst Oswaldo Cruz 83 :219–225.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Monath TP, Brinker KR, Chandler FW, Kemp GE, Cropp CB, 1981. Pathophysiologic correlations in a rhesus monkey model of yellow fever with special observations on the acute necrosis of B cell areas of lymphoid tissues. Am J Trop Med Hyg 30 :431–443.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Tigertt WD, Berge TO, Gochenour WS, Gleiser CA, 1960. Experimental yellow fever. Trans N Y Acad Sci 22 :323–333.

  • 39

    Kumar R, Tripathi S, Tambe JJ, Arora V, Srivastava A, Nag VL, 2008. Dengue encephalopathy in children in northern India: clinical features and comparison with non dengue. J Neurol Sci 269 :41–48.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Lum LC, Lam SK, Choy YS, George R, Harun F, 1996. Dengue encephalitis: a true entity? Am J Trop Med Hyg 54 :256–259.

  • 41

    Andrews BS, Theofilopoulos AN, Peters CJ, Loskutoff DJ, Brandt WE, Dixon FJ, 1978. Replication of dengue and junin viruses in cultured rabbit and human endothelial cells. Infect Immun 20 :776–781.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Avirutnan P, Malasit P, Seliger B, Bhakdi S, Husmann M, 1998. Dengue virus infection of human endothelial cells leads to chemokine production, complement activation, and apoptosis. J Immunol 161 :6338–6346.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Miller JL, deWet BJ, Martinez-Pomares L, Radcliffe CM, Dwek RA, Rudd PM, Gordon S, 2008. The mannose receptor mediates dengue virus infection of macrophages. PLoS Pathog 4 :e17.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Martinez-Pomares L, Hanitsch LG, Stillion R, Keshav S, Gordon S, 2005. Expression of mannose receptor and ligands for its cysteine-rich domain in venous sinuses of human spleen. Lab Invest 85 :1238–1249.

    • PubMed
    • Search Google Scholar
    • Export Citation
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