title: Dengue virus infection induces broadly cross-reactive human IgM antibodies that recognize intact virions in humanized BLT-NSG mice.
abstract: The development of small animal models that elicit human immune responses to dengue virus (DENV) is important since prior immunity is a major risk factor for developing severe dengue disease. This study evaluated anti-DENV human antibody (hAb) responses generated from immortalized B cells after DENV-2 infection in NOD-scid IL2rγ(null) mice that were co-transplanted with human fetal thymus and liver tissues (BLT-NSG mice). DENV-specific human antibodies predominantly of the IgM isotype were isolated during acute infection and in convalescence. We found that while a few hAbs recognized the envelope protein produced as a soluble recombinant, a number of hAbs only recognized epitopes on intact virions. The majority of the hAbs isolated during acute infection and in immune mice were serotype-cross-reactive and poorly neutralizing. Viral titers in immune BLT-NSG mice were significantly decreased after challenge with a clinical strain of dengue. DENV-specific hAbs generated in BLT-NSG mice share some of the characteristics of Abs isolated in humans with natural infection. Humanized BLT-NSG mice provide an attractive preclinical platform to assess the immunogenicity of candidate dengue vaccines.
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Jaiswal
authors.affiliation: Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Smith
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ramirez
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Woda
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Pazoles
authors.affiliation: The Jackson Laboratory, Bar Harbor Maine, Maine 04609, USA.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brehm
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01655, USA anuja.mathew@umassmed.edu.
authors.forename: Anuja
authors.initials: A
authors.lastname: Mathew
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood*; D001402:B-Lymphocytes / Q000276:immunology*; D003715:Dengue / Q000276:immunology / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood*; D008099:Liver / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D013950:Thymus Gland / Q000276:immunology; D019562:Viral Load
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007075:Immunoglobulin M
keywords: B cells; dengue; human; transgenic mice; viral