Serotype-Specific Host Responses in Rhesus Macaques after Primary Dengue Challenge

Andrew C. Hickey Department of Microbiology, National Emerging Infectious Diseases Laboratories Institute, Laboratory Animal Science Center, Boston University, Boston, Massachusetts; Venture Technologies, Penang, Malaysia; Sentinext Therapeutics, Penang, Malaysia

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Jacob A. Koster Department of Microbiology, National Emerging Infectious Diseases Laboratories Institute, Laboratory Animal Science Center, Boston University, Boston, Massachusetts; Venture Technologies, Penang, Malaysia; Sentinext Therapeutics, Penang, Malaysia

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Claudia M. Thalmann Department of Microbiology, National Emerging Infectious Diseases Laboratories Institute, Laboratory Animal Science Center, Boston University, Boston, Massachusetts; Venture Technologies, Penang, Malaysia; Sentinext Therapeutics, Penang, Malaysia

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Kathy Hardcastle Department of Microbiology, National Emerging Infectious Diseases Laboratories Institute, Laboratory Animal Science Center, Boston University, Boston, Massachusetts; Venture Technologies, Penang, Malaysia; Sentinext Therapeutics, Penang, Malaysia

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Phaik-Hooi Tio Department of Microbiology, National Emerging Infectious Diseases Laboratories Institute, Laboratory Animal Science Center, Boston University, Boston, Massachusetts; Venture Technologies, Penang, Malaysia; Sentinext Therapeutics, Penang, Malaysia

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Mary J. Cardosa Department of Microbiology, National Emerging Infectious Diseases Laboratories Institute, Laboratory Animal Science Center, Boston University, Boston, Massachusetts; Venture Technologies, Penang, Malaysia; Sentinext Therapeutics, Penang, Malaysia

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Katharine N. Bossart Department of Microbiology, National Emerging Infectious Diseases Laboratories Institute, Laboratory Animal Science Center, Boston University, Boston, Massachusetts; Venture Technologies, Penang, Malaysia; Sentinext Therapeutics, Penang, Malaysia

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Dengue virus (DENV) is considered to be the most important arthropod-borne viral disease and causes more than 100 million human infections annually. To further characterize primary DENV infection in vivo, rhesus macaques were infected with DENV-1, DENV-2, DENV-3, or DENV-4 and clinical parameters, as well as specificity and longevity of serologic responses, were assessed. Overt clinical symptoms were not present after infection. However, abnormalities in blood biochemical parameters consistent with heart, kidney, and liver damage were observed, and changes in plasma fibrinogen, D-dimers, and protein C indicated systemic activation of the blood coagulation pathway. Significant homotypic and heterotypic serum immunoglobulins were present in all animals, and IgG persisted for at least 390 days. Serum neutralizing antibody responses were highly serotype specific by day 120. However, some heterotypic neutralizing activity was noted in infected animals. Identification of serotype-specific host responses may help elucidate mechanisms that mediate severe DENV disease after reinfection.

Author Notes

* Address correspondence to Katharine N. Bossart, Department of Microbiology, National Emerging Infectious Diseases Laboratories Institute, Boston University, 620 Albany Street, Boston, MA 02118. E-mail: kbossart@bu.edu

Financial support: This study was supported in part by National Institutes of Health contract HSN272201000007I-HHSN27200001 to Katharine N. Bossart.

Authors' addresses: Andrew C. Hickey, Jacob A. Koster, Claudia M. Thalmann, and Katharine N. Bossart, Department of Microbiology, National Emerging Infectious Diseases Laboratories Institute, Boston University, Boston, MA, Emails: drewh44@bu.edu, jkoster@bu.edu, thalmann@bu.edu, and kbossart@bu.edu. Kathy Hardcastle, Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, E-mail: Kath.hardcastle@nih.gov. Phaik-Hooi Tio, Venture Technologies Sdn Bhd, INFORMM Building, Universiti Sains Malaysia, Minden, Penang, Malaysia, E-mail: phtio@yahoo.com. Mary J. Cardosa, Sentinext Therapeutics Sdn Bhd, 55 Jalan Sultan Ahmad Shah, Georgetown, Penang, Malaysia, E-mail: jc@sentinext.com.

  • 1.

    Gubler DJ, 2007. Flaviviruses. Knipe DM, Howley PM, eds. Fields Virology. Fifth edition. Philadelphia, PA: Lippincott Williams and Wilkins, 1153–1252.

  • 2.

    Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, Hunsperger E, Kroeger A, Margolis HS, Martinez E, Nathan MB, Pelegrino JL, Simmons C, Yoksan S, Peeling RW, 2010. Dengue: a continuing global threat. Nat Rev Microbiol 8: S7–S16.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Kyle JL, Harris E, 2008. Global spread and persistence of dengue. Annu Rev Microbiol 62: 71–92.

  • 4.

    Whitehead SS, Blaney JE, Durbin AP, Murphy BR, 2007. Prospects for a dengue virus vaccine. Nat Rev Microbiol 5: 518–528.

  • 5.

    Shepard DS, Undurraga EA, Lees RS, Halasa Y, Lum LC, Ng CW, 2012. Use of multiple data sources to estimate the economic cost of dengue illness in Malaysia. Am J Trop Med Hyg 87: 796–805.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Halstead SB, Palumbo NE, 1973. Studies on the immunization of monkeys against dengue. II. Protection following inoculation of combinations of viruses. Am J Trop Med Hyg 22: 375–381.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Peiris JS, Dittus WP, Ratnayake CB, 1993. Seroepidemiology of dengue and other arboviruses in a natural population of toque macaques (Macaca sinica) at Polonnaruwa, Sri Lanka. J Med Primatol 22: 240–245.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Rodhain F, 1991. The role of monkeys in the biology of dengue and yellow fever. Comp Immunol Microbiol Infect Dis 14: 9–19.

  • 9.

    Halstead SB, Shotwell H, Casals J, 1973. Studies on the pathogenesis of dengue infection in monkeys. I. Clinical laboratory responses to primary infection. J Infect Dis 128: 7–14.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Halstead SB, Shotwell H, Casals J, 1973. Studies on the pathogenesis of dengue infection in monkeys. II. Clinical laboratory responses to heterologous infection. J Infect Dis 128: 15–22.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Onlamoon N, Noisakran S, Hsiao HM, Duncan A, Villinger F, Ansari AA, Perng GC, 2010. Dengue virus-induced hemorrhage in a nonhuman primate model. Blood 115: 1823–1834.

  • 12.

    Cassetti MC, Durbin A, Harris E, Rico-Hesse R, Roehrig J, Rothman A, Whitehead S, Natarajan R, Laughlin C, 2009. Report of an NIAID workshop on dengue animal models. Vaccine 28: 4229–4234.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Raviprakash K, Wang D, Ewing D, Holman DH, Block K, Woraratanadharm J, Chen L, Hayes C, Dong JY, Porter K, 2008. A tetravalent dengue vaccine based on a complex adenovirus vector provides significant protection in rhesus monkeys against all four serotypes of dengue virus. J Virol 82: 6927–6934.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Durbin AP, Karron RA, Sun W, Vaughn DW, Reynolds MJ, Perreault JR, Thumar B, Men R, Lai CJ, Elkins WR, Chanock RM, Murphy BR, Whitehead SS, 2001. Attenuation and immunogenicity in humans of a live dengue virus type-4 vaccine candidate with a 30 nucleotide deletion in its 3′-untranslated region. Am J Trop Med Hyg 65: 405–413.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Blaney JE Jr, Matro JM, Murphy BR, Whitehead SS, 2005. Recombinant, live-attenuated tetravalent dengue virus vaccine formulations induce a balanced, broad, and protective neutralizing antibody response against each of the four serotypes in rhesus monkeys. J Virol 79: 5516–5528.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Bernardo L, Izquierdo A, Prado I, Rosario D, Alvarez M, Santana E, Castro J, Martínez R, Rodríguez R, Morier L, Guillén G, Guzmán MG, 2008. Primary and secondary infections of Macaca fascicularis monkeys with Asian and American genotypes of dengue virus 2. Clin Vaccine Immunol 15: 439–446.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Freire MS, Marchevsky RS, Almeida LF, Yamamura AM, Caride EC, Brindeiro PA, Motta MC, Nogueira RM, Kubelka CF, Bonaldo MC, Galler R, 2007. Wild dengue virus types 1, 2 and 3 viremia in rhesus monkeys. Mem Inst Oswaldo Cruz 102: 203–208.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Kochel TJ, Watts DM, Gozalo AS, Ewing DF, Porter KR, Russell KL, 2005. Cross-Serotype neutralization of dengue virus in Aotus nancymae monkeys. J Infect Dis 191: 1000–1004.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Martín J, Hermida L, Castro J, Lazo L, Martínez R, Gil L, Romero Y, Puente P, Zaragoza S, Cosme K, Guzmán MG, Cardosa J, Guillén G, 2009. Viremia and antibody response in green monkeys (Chlorocebus aethiops sabaeus) infected with dengue virus type 2: a potential model for vaccine testing. Microbiol Immunol 53: 216–223.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Martın J, Hermida L, Castro J, Romero Y, Cardosa J, Guillen G, 2009. Viremia and the magnitude of the immune response upon infection of green monkeys with dengue virus type 2 are strain-dependent. Curr Microbiol 59: 579–583.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Koraka P, Benton S, van Amerongen G, Stittelaar KJ, Osterhaus AD, 2007. Efficacy of a live attenuated tetravalent candidate dengue vaccine in naïve and previously infected macaques. Vaccine 25: 5409–5416.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Koraka P, Benton S, van Amerongen G, Stittelaar KJ, Osterhaus AD, 2007. Characterization of humoral and cellular immune responses in cynomolgus macaques upon primary and subsequent heterologous infections with dengue viruses. Microbes Infect 9: 940–946.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Ferguson M, Johnes S, Li L, Heath A, Barrett A, 2008. Effect of genomic variation in the challenge virus on the neutralization titres of recipients of inactivated JE vaccines–report of a collaborative study on PRNT50 assays for Japanese encephalitis virus (JE) antibodies. Biologicals 36: 111–116.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Committee for the Update of the Guide for the Care and Use of Laboratory Animals, 2011. Guide for the Care and Use of Laboratory Animals. Eighth edition. Washington, DC: National Academies of Science Press.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Bossart KN, Rockx B, Feldmann F, Brining D, Scott D, LaCasse R, Geisbert JB, Feng YR, Chan YP, Hickey AC, Broder CC, Feldmann H, Geisbert TW, 2012. A Hendra virus G glycoprotein subunit vaccine protects African green monkeys from Nipah virus challenge. Sci Transl Med 4: 146ra107.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Lee JI, Shin JS, Lee JE, Jung WY, Lee G, Kim MS, Park CG, Kim SJ, 2012. Reference values of hematology, chemistry, electrolytes, blood gas, coagulation time, and urinalysis in the Chinese rhesus macaques (Macaca mulatta). Xenotransplantation 19: 244–248.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Messer WB, Yount B, Hacker KE, Donaldson EF, Huynh JP, de Silva AM, Baric RS, 2012. Development and characterization of a reverse genetic system for studying dengue virus serotype 3 strain variation and neutralization. PLoS Negl Trop Dis 6: e1486.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Henchal EA, Gentry MK, McCown JM, Brandt WE, 1982. Dengue virus-specific and flavivirus group determinants identified with monoclonal antibodies by indirect immunofluorescence. Am J Trop Med Hyg 31: 830–836.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Geisbert TW, Daddario-DiCaprio KM, Hickey AC, Smith MA, Chan YP, Wang LF, Mattapallil JJ, Geisbert JB, Bossart KN, Broder CC, 2010. Development of an acute and highly pathogenic nonhuman primate model of Nipah virus infection. PLoS ONE 5: e10690.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Pang T, Cardosa MJ, Guzman MG, 2007. Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS). Immunol Cell Biol 85: 43–45.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Halstead SB, Marchette NJ, Sung Chow JS, Lolekha S, 1976. Dengue virus replication enhancement in peripheral blood leukocytes from immune human beings. Proc Soc Exp Biol Med 151: 136–139.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Potts JA, Rothman AL, 2008. Clinical and laboratory features that distinguish dengue from other febrile illnesses in endemic populations. Trop Med Int Health 13: 1328–1340.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Deparis X, Murgue B, Roche C, Cassar O, Chungue E, 1998. Changing clinical and biological manifestations of dengue during the dengue-2 epidemic in French Polynesia in 1996/97: description and analysis in a prospective study. Trop Med Int Health 3: 859–865.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Wilder-Smith A, Earnest A, Paton NI, 2004. Use of simple laboratory features to distinguish the early stage of severe acute respiratory syndrome from dengue fever. Clin Infect Dis 39: 1818–1823.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    McBride WJ, Mullner H, LaBrooy JT, Wronski I, 1998. The 1993 dengue 2 epidemic in Charters Towers, North Queensland: clinical features and public health impact. Epidemiol Infect 121: 151–156.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Lee IK, Lee WH, Liu JW, Yang KD, 2010. Acute myocarditis in dengue hemorrhagic fever: a case report and review of cardiac complications in dengue-affected patients. Int J Infect Dis 14: e919–e922.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Marques N, Gan VC, Leo YS, 2013. Dengue myocarditis in Singapore: two case reports. Infection 41: 709–714.

  • 38.

    Lima EQ, Gorayeb FS, Zanon JR, Nogueira ML, Ramalho HJ, Burdmann EA, 2007. Dengue haemorrhagic fever-induced acute kidney injury without hypotension, haemolysis or rhabdomyolysis. Nephrol Dial Transplant 22: 3322–3326.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Lima EQ, Nogueira ML, 2008. Viral hemorrhagic fever-induced acute kidney injury. Semin Nephrol 28: 409–415.

  • 40.

    Mehra N, Patel A, Abraham G, Reddy YN, 2012. Acute kidney injury in dengue fever using Acute Kidney Injury Network criteria: incidence and risk factors. Trop Doct 42: 160–162.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    de Macedo FC, Nicol AF, Cooper LD, Yearsley M, Pires AR, Nuovo GJ, 2006. Histologic, viral, and molecular correlates of dengue fever infection of the liver using highly sensitive immunohistochemistry. Diagn Mol Pathol 15: 223–228.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    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
  • 43.

    Tristao-Sa R, Kubelka CF, Zandonade E, Zagne SM, Rocha N de S, Zagne LO, Araujo NF, Amin B, Fazoli F, Souza LJ, Cruz OG, Cunha RV, Nascimento D, Froes IB, Nogueira RM, 2012. Clinical and hepatic evaluation in adult dengue patients: a prospective two-month cohort study. Rev Soc Bras Med Trop 45: 675–681.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Mammen EF, 1992. Coagulation abnormalities in liver disease. Hematol Oncol Clin North Am 6: 1247–1257.

  • 45.

    Amitrano L, Guardascione MA, Brancaccio V, Balzano A, 2002. Coagulation disorders in liver disease. Semin Liver Dis 22: 83–96.

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