Utility of humanized BLT mice for analysis of dengue virus infection and antiviral drug testing

Natalia Frias-Staheli, Marcus Dorner, Svetlana Marukian, Eva K. Billerbeck, Rachael N. Labitt, Charles M. Rice, Alexander Ploss

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Dengue virus (DENV) is the cause of a potentially life-threatening disease that affects millions of people worldwide. The lack of a small animal model that mimics the symptoms of DENV infection in humans has slowed the understanding of viral pathogenesis and the development of therapies and vaccines. Here, we investigated the use of humanized "bone marrow liver thymus" (BLT) mice as a model for immunological studies and assayed their applicability for preclinical testing of antiviral compounds. Human immune system (HIS) BLT-NOD/SCID mice were inoculated intravenously with a lowpassage, clinical isolate of DENV-2, and this resulted in sustained viremia and infection of leukocytes in lymphoid and nonlymphoid organs. In addition, DENV infection increased serum cytokine levels and elicited DENV-2-neutralizing human IgM antibodies. Following restimulation with DENV-infected dendritic cells, in vivo-primed T cells became activated and acquired effector function. An adenosine nucleoside inhibitor of DENV decreased the circulating viral RNA when administered simultaneously or 2 days postinfection, simulating a potential treatment protocol for DENV infection in humans. In summary, we demonstrate that BLT mice are susceptible to infection with clinical DENV isolates, mount virusspecific adaptive immune responses, and respond to antiviral drug treatment. Although additional refinements to the model are required, BLT mice are a suitable platform to study aspects of DENV infection and pathogenesis and for preclinical testing of drug and vaccine candidates.

Original languageEnglish (US)
Pages (from-to)2205-2218
Number of pages14
JournalJournal of Virology
Volume88
Issue number4
DOIs
StatePublished - Feb 1 2014
Externally publishedYes

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antiviral agents
Dengue virus
Dengue Virus
Virus Diseases
bone marrow
Thymus Gland
Antiviral Agents
Bone Marrow
liver
Liver
mice
infection
testing
Immunological Models
pathogenesis
vaccines
Active Immunotherapy
Inbred NOD Mouse
SCID Mice
nucleosides

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Frias-Staheli, N., Dorner, M., Marukian, S., Billerbeck, E. K., Labitt, R. N., Rice, C. M., & Ploss, A. (2014). Utility of humanized BLT mice for analysis of dengue virus infection and antiviral drug testing. Journal of Virology, 88(4), 2205-2218. https://doi.org/10.1128/JVI.03085-13

Utility of humanized BLT mice for analysis of dengue virus infection and antiviral drug testing. / Frias-Staheli, Natalia; Dorner, Marcus; Marukian, Svetlana; Billerbeck, Eva K.; Labitt, Rachael N.; Rice, Charles M.; Ploss, Alexander.

In: Journal of Virology, Vol. 88, No. 4, 01.02.2014, p. 2205-2218.

Research output: Contribution to journalArticle

Frias-Staheli, N, Dorner, M, Marukian, S, Billerbeck, EK, Labitt, RN, Rice, CM & Ploss, A 2014, 'Utility of humanized BLT mice for analysis of dengue virus infection and antiviral drug testing', Journal of Virology, vol. 88, no. 4, pp. 2205-2218. https://doi.org/10.1128/JVI.03085-13
Frias-Staheli, Natalia ; Dorner, Marcus ; Marukian, Svetlana ; Billerbeck, Eva K. ; Labitt, Rachael N. ; Rice, Charles M. ; Ploss, Alexander. / Utility of humanized BLT mice for analysis of dengue virus infection and antiviral drug testing. In: Journal of Virology. 2014 ; Vol. 88, No. 4. pp. 2205-2218.
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