Dengue is a mosquito-borne disease caused by one of four serotypes of Dengue virus (DENV-1–4). Severe dengue infection in humans is characterized by thrombocytopenia, increased vascular permeability, hemorrhage and shock. However, there is little information about host response to DENV infection. Here, mechanisms accounting for IFN-γ production and effector function during dengue disease were investigated in a murine model of DENV-2 infection. IFN-γ expression was greatly increased after infection of mice and its production was preceded by increase in IL-12 and IL-18 levels. In IFN-γ？/？ mice, DENV-2-associated lethality, viral loads, thrombocytopenia, hemoconcentration, and liver injury were enhanced, when compared with wild type-infected mice. IL-12p40？/？ and IL-18？/？ infected-mice showed decreased IFN-γ production, which was accompanied by increased disease severity, higher viral loads and enhanced lethality. Blockade of IL-18 in infected IL-12p40？/？ mice resulted in complete inhibition of IFN-γ production, greater DENV-2 replication, and enhanced disease manifestation, resembling the response seen in DENV-2-infected IFN-γ？/？ mice. Reduced IFN-γ production was associated with diminished Nitric Oxide-synthase 2 (NOS2) expression and NOS2？/？ mice had elevated lethality, more severe disease evolution and increased viral load after DENV-2 infection. Therefore, IL-12/IL-18-induced IFN-γ production and consequent NOS2 induction are of major importance to host resistance against DENV infection.
References
[1]
Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, et al. (2010) Dengue: a continuing global threat. Nat Rev Microbiol 8: S7–S16. doi: 10.1038/nrmicro2460
[2]
Fagundes CT, Costa VV, Cisalpino D, Souza DG, Teixeira MM (2011) Therapeutic opportunities in dengue infection. Drug Development Res. In press. doi: 10.1002/ddr.20455
[3]
Rothman AL (2011) Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat Rev Immunol 11: 532–543. doi: 10.1038/nri3014
[4]
Guzman MG, Kouri G, Bravo J, Valdes L, Vazquez S, et al. (2002) Effect of age on outcome of secondary dengue 2 infections. Int J Infect Dis 6: 118–124. doi: 10.1016/S1201-9712(02)90072-X
[5]
Balmaseda A, Hammond SN, Perez L, Tellez Y, Saborio SI, et al. (2006) Serotype-specific differences in clinical manifestations of dengue. Am J Trop Med Hyg 74: 449–456.
[6]
Messer WB, Gubler DJ, Harris E, Sivananthan K, de Silva AM (2003) Emergence and global spread of a dengue serotype 3, subtype III virus. Emerg Infect Dis 9: 800–809. doi: 10.3201/eid0907.030038
[7]
Rico-Hesse R, Harrison LM, Salas RA, Tovar D, Nisalak A, et al. (1997) Origins of dengue type 2 viruses associated with increased pathogenicity in the Americas. Virology 230: 244–251. doi: 10.1006/viro.1997.8504
[8]
Halstead SB, Streit TG, Lafontant JG, Putvatana R, Russell K, et al. (2001) Haiti: absence of dengue hemorrhagic fever despite hyperendemic dengue virus transmission. Am J Trop Med Hyg 65: 180–183.
[9]
Halstead SB, Nimmannitya S, Cohen SN (1970) Observations related to pathogenesis of dengue hemorrhagic fever. IV. Relation of disease severity to antibody response and virus recovered. Yale J Biol Med 42: 311–328.
[10]
Sangkawibha N, Rojanasuphot S, Ahandrik S, Viriyapongse S, Jatanasen S, et al. (1984) Risk factors in dengue shock syndrome: a prospective epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am J Epidemiol 120: 653–669.
[11]
Thein S, Aung MM, Shwe TN, Aye M, Zaw A, et al. (1997) Risk factors in dengue shock syndrome. Am J Trop Med Hyg 56: 566–572.
[12]
Vaughn DW, Green S, Kalayanarooj S, Innis BL, Nimmannitya S, et al. (2000) Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis 181: 2–9. doi: 10.1086/315215
[13]
Clyde K, Kyle JL, Harris E (2006) Recent advances in deciphering viral and host determinants of dengue virus replication and pathogenesis. J Virol 80: 11418–11431. doi: 10.1128/JVI.01257-06
[14]
Chen RF, Liu JW, Yeh WT, Wang L, Chang JC, et al. (2005) Altered T helper 1 reaction but not increase of virus load in patients with dengue hemorrhagic fever. FEMS Immunol Med Microbiol 44: 43–50. doi: 10.1016/j.femsim.2004.11.012
[15]
Chen LC, Lei HY, Liu CC, Shiesh SC, Chen SH, et al. (2006) Correlation of serum levels of macrophage migration inhibitory factor with disease severity and clinical outcome in dengue patients. Am J Trop Med Hyg 74: 142–147.
[16]
Bozza FA, Cruz OG, Zagne SM, Azeredo EL, Nogueira RM, et al. (2008) Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity. BMC Infect Dis 8: 86. doi: 10.1186/1471-2334-8-86
[17]
Shresta S, Kyle JL, Snider HM, Basavapatna M, Beatty PR, et al. (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. doi: 10.1128/JVI.78.6.2701-2710.2004
[18]
Shresta S, Sharar KL, Prigozhin DM, Snider HM, Beatty PR, et al. (2005) Critical roles for both STAT1-dependent and STAT1-independent pathways in the control of primary dengue virus infection in mice. J Immunol 175: 3946–3954.
[19]
Shresta S, Sharar KL, Prigozhin DM, Beatty PR, Harris E (2006) Murine model for dengue virus-induced lethal disease with increased vascular permeability. J Virol 80: 10208–10217. doi: 10.1128/JVI.00062-06
[20]
Magram J, Connaughton SE, Warrier RR, Carvajal DM, Wu CY, et al. (1996) IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity 4: 471–481. doi: 10.1016/S1074-7613(00)80413-6
[21]
Pien GC, Satoskar AR, Takeda K, Akira S, Biron CA (2000) Cutting edge: selective IL-18 requirements for induction of compartmental IFN-gamma responses during viral infection. J Immunol 165: 4787–4791.
[22]
Akaike T, Maeda H (2000) Nitric oxide and virus infection. Immunology 101: 300–308. doi: 10.1046/j.1365-2567.2000.00142.x
[23]
Atrasheuskaya A, Petzelbauer P, Fredeking TM, Ignatyev G (2003) Anti-TNF antibody treatment reduces mortality in experimental dengue virus infection. FEMS Immunol Med Microbiol 35: 33–42. doi: 10.1111/j.1574-695X.2003.tb00646.x
[24]
Souza DG, Fagundes CT, Sousa LP, Amaral FA, Souza RS, et al. (2009) Essential role of platelet-activating factor receptor in the pathogenesis of Dengue virus infection. Proc Natl Acad Sci U S A 106: 14138–14143. doi: 10.1073/pnas.0906467106
[25]
Assuncao-Miranda I, Amaral FA, Bozza FA, Fagundes CT, Sousa LP, et al. (2010) Contribution of macrophage migration inhibitory factor to the pathogenesis of dengue virus infection. FASEB J 24: 218–228. doi: 10.1096/fj.09-139469
[26]
Wei XQ, Leung BP, Arthur HM, McInnes IB, Liew FY (2001) Reduced incidence and severity of collagen-induced arthritis in mice lacking IL-18. J Immunol 166: 517–521.
[27]
Ghilardi N, Kljavin N, Chen Q, Lucas S, Gurney AL, et al. (2004) Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice. J Immunol 172: 2827–2833.
[28]
Plitz T, Saint-Mezard P, Satho M, Herren S, Waltzinger C, et al. (2003) IL-18 binding protein protects against contact hypersensitivity. J Immunol 171: 1164–1171.
[29]
Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, et al. (1999) An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 223: 77–92. doi: 10.1016/S0022-1759(98)00204-X
[30]
Green LC, Ruiz de Luzuriaga K, Wagner DA, Rand W, Istfan N, et al. (1981) Nitrate biosynthesis in man. Proc Natl Acad Sci U S A 78: 7764–7768. doi: 10.1073/pnas.78.12.7764
[31]
Gunther VJ, Putnak R, Eckels KH, Mammen MP, Scherer JM, et al. (2011) A human challenge model for dengue infection reveals a possible protective role for sustained interferon gamma levels during the acute phase of illness. Vaccine 29: 3895–3904. doi: 10.1016/j.vaccine.2011.03.038
[32]
Nishiura H, Halstead SB (2007) Natural history of dengue virus (DENV)-1 and DENV-4 infections: reanalysis of classic studies. J Infect Dis 195: 1007–1013. doi: 10.1086/511825
[33]
Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, et al. (2010) Cross-reacting antibodies enhance dengue virus infection in humans. Science 328: 745–748. doi: 10.1126/science.1185181
[34]
Balsitis SJ, Williams KL, Lachica R, Flores D, Kyle JL, et al. (2010) Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLoS Pathog 6: e1000790. doi: 10.1371/journal.ppat.1000790
[35]
Zellweger RM, Prestwood TR, Shresta S (2010) Enhanced infection of liver sinusoidal endothelial cells in a mouse model of antibody-induced severe dengue disease. Cell Host Microbe 7: 128–139. doi: 10.1016/j.chom.2010.01.004
[36]
Chaturvedi UC, Elbishbishi EA, Agarwal R, Raghupathy R, Nagar R, et al. (1999) Sequential production of cytokines by dengue virus-infected human peripheral blood leukocyte cultures. J Med Virol 59: 335–340. doi: 10.1002/(SICI)1096-9071(199911)59:3<335::AID-JMV13>3.0.CO;2-E
[37]
Chaturvedi UC, Agarwal R, Elbishbishi EA, Mustafa AS (2000) Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis. FEMS Immunol Med Microbiol 28: 183–188. doi: 10.1111/j.1574-695X.2000.tb01474.x
[38]
Rachman A, Rinaldi I (2006) Coagulopathy in dengue infection and the role of interleukin-6. Acta Med Indones 38: 105–108. doi: 10.1267/science.040579197
[39]
Mangada MM, Endy TP, Nisalak A, Chunsuttiwat S, Vaughn DW, et al. (2002) Dengue-specific T cell responses in peripheral blood mononuclear cells obtained prior to secondary dengue virus infections in Thai schoolchildren. J Infect Dis 185: 1697–1703. doi: 10.1086/340822
[40]
Beaumier CM, Mathew A, Bashyam HS, Rothman AL (2008) Cross-reactive memory CD8(+) T cells alter the immune response to heterologous secondary dengue virus infections in mice in a sequence-specific manner. J Infect Dis 197: 608–617. doi: 10.1086/526790
[41]
Suthar MS, Ma DY, Thomas S, Lund JM, Zhang N, et al. (2010) IPS-1 is essential for the control of West Nile virus infection and immunity. PLoS Pathog 6: e1000757. doi: 10.1371/journal.ppat.1000757
[42]
Jacques A, Bleau C, Turbide C, Beauchemin N, Lamontagne L (2009) A synergistic interferon-gamma production is induced by mouse hepatitis virus in interleukin-12 (IL-12)/IL-18-activated natural killer cells and modulated by carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1a receptor. Immunology 128: e551–561. doi: 10.1111/j.1365-2567.2008.03030.x
Wang Y, Chaudhri G, Jackson RJ, Karupiah G (2009) IL-12p40 and IL-18 play pivotal roles in orchestrating the cell-mediated immune response to a poxvirus infection. J Immunol 183: 3324–3331. doi: 10.4049/jimmunol.0803985
[45]
Shresta S, Kyle JL, Robert Beatty P, Harris E (2004) Early activation of natural killer and B cells in response to primary dengue virus infection in A/J mice. Virology 319: 262–273. doi: 10.1016/j.virol.2003.09.048
[46]
Gil L, Lopez C, Blanco A, Lazo L, Martin J, et al. (2009) The cellular immune response plays an important role in protecting against dengue virus in the mouse encephalitis model. Viral Immunol 22: 23–30. doi: 10.1089/vim.2008.0063
[47]
Yauch LE, Zellweger RM, Kotturi MF, Qutubuddin A, Sidney J, et al. (2009) A protective role for dengue virus-specific CD8+ T cells. J Immunol 182: 4865–4873. doi: 10.4049/jimmunol.0801974
[48]
Green S, Pichyangkul S, Vaughn DW, Kalayanarooj S, Nimmannitya S, et al. (1999) Early CD69 expression on peripheral blood lymphocytes from children with dengue hemorrhagic fever. J Infect Dis 180: 1429–1435. doi: 10.1086/315072
[49]
Azeredo EL, De Oliveira-Pinto LM, Zagne SM, Cerqueira DI, Nogueira RM, et al. (2006) NK cells, displaying early activation, cytotoxicity and adhesion molecules, are associated with mild dengue disease. Clin Exp Immunol 143: 345–356. doi: 10.1111/j.1365-2249.2006.02996.x
[50]
Hatch S, Endy TP, Thomas S, Mathew A, Potts J, et al. (2011) Intracellular cytokine production by dengue virus-specific T cells correlates with subclinical secondary infection. J Infect Dis 203: 1282–1291. doi: 10.1093/infdis/jir012
[51]
Duangchinda T, Dejnirattisai W, Vasanawathana S, Limpitikul W, Tangthawornchaikul N, et al. (2010) Immunodominant T-cell responses to dengue virus NS3 are associated with DHF. Proc Natl Acad Sci U S A 107: 16922–16927. doi: 10.1073/pnas.1010867107
[52]
Neves-Souza PC, Azeredo EL, Zagne SM, Valls-de-Souza R, Reis SR, et al. (2005) Inducible nitric oxide synthase (iNOS) expression in monocytes during acute Dengue Fever in patients and during in vitro infection. BMC Infect Dis 5: 64. doi: 10.1186/1471-2334-5-64
[53]
Valero N, Espina LM, Anez G, Torres E, Mosquera JA (2002) Short report: increased level of serum nitric oxide in patients with dengue. Am J Trop Med Hyg 66: 762–764.
[54]
Charnsilpa W, Takhampunya R, Endy TP, Mammen MP Jr, Libraty DH, et al. (2005) Nitric oxide radical suppresses replication of wild-type dengue 2 viruses in vitro. J Med Virol 77: 89–95. doi: 10.1002/jmv.20418
[55]
Takhampunya R, Padmanabhan R, Ubol S (2006) Antiviral action of nitric oxide on dengue virus type 2 replication. J Gen Virol 87: 3003–3011. doi: 10.1099/vir.0.81880-0
[56]
Ubol S, Chareonsirisuthigul T, Kasisith J, Klungthong C (2008) Clinical isolates of dengue virus with distinctive susceptibility to nitric oxide radical induce differential gene responses in THP-1 cells. Virology 376: 290–296. doi: 10.1016/j.virol.2008.03.030
[57]
Renneson J, Guabiraba R, Maillet I, Marques RE, Ivanov S, et al. (2011) A detrimental role for invariant natural killer T cells in the pathogenesis of experimental dengue virus infection. Am J Pathol. In press. doi: 10.1016/j.ajpath.2011.06.023
[58]
Lin CF, Lei HY, Shiau AL, Liu HS, Yeh TM, et al. (2002) Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide. J Immunol 169: 657–664.
[59]
Yen YT, Chen HC, Lin YD, Shieh CC, Wu-Hsieh BA (2008) Enhancement by tumor necrosis factor alpha of dengue virus-induced endothelial cell production of reactive nitrogen and oxygen species is key to hemorrhage development. J Virol 82: 12312–12324. doi: 10.1128/JVI.00968-08
