title: Maternal Antibody-Mediated Disease Enhancement in Type I Interferon-Deficient Mice Leads to Lethal Disease Associated with Liver Damage.
abstract: Epidemiological studies have reported that most of the severe dengue cases occur upon a secondary heterologous infection. Furthermore, babies born to dengue immune mothers are at greater risk of developing severe disease upon primary infection with a heterologous or homologous dengue virus (DENV) serotype when maternal antibodies reach sub-neutralizing concentrations. These observations have been explained by the antibody mediated disease enhancement (ADE) phenomenon whereby heterologous antibodies or sub-neutralizing homologous antibodies bind to but fail to neutralize DENV particles, allowing Fc-receptor mediated entry of the virus-antibody complexes into host cells. This eventually results in enhanced viral replication and heightened inflammatory responses. In an attempt to replicate this ADE phenomenon in a mouse model, we previously reported that upon DENV2 infection 5-week old type I and II interferon (IFN) receptors-deficient mice (AG129) born to DENV1-immune mothers displayed enhancement of disease severity characterized by increased virus titers and extensive vascular leakage which eventually led to the animals' death. However, as dengue occurs in immune competent individuals, we sought to reproduce this mouse model in a less immunocompromised background. Here, we report an ADE model that is mediated by maternal antibodies in type I IFN receptor-deficient A129 mice. We show that 5-week old A129 mice born to DENV1-immune mothers succumbed to a DENV2 infection within 4 days that was sub-lethal in mice born to naïve mothers. Clinical manifestations included extensive hepatocyte vacuolation, moderate vascular leakage, lymphopenia, and thrombocytopenia. Anti-TNFα therapy totally protected the mice and correlated with healthy hepatocytes. In contrast, blocking IL-6 did not impact the virus titers or disease outcome. This A129 mouse model of ADE may help dissecting the mechanisms involved in dengue pathogenesis and evaluate the efficacy of vaccine and therapeutic candidates.
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Immunology programme, Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Julia María
authors.initials: JM
authors.lastname: Martínez Gómez
authors.affiliation: Infectious Disease programme, Singapore-MIT alliance for Research and Technology (SMART), National University of Singapore, Singapore.
authors.forename: Li Ching
authors.initials: LC
authors.lastname: Ong
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Immunology programme, Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Jian Hang
authors.initials: JH
authors.lastname: Lam
authors.affiliation: Emerging Infectious Diseases programme, Duke-NUS, Singapore.
authors.forename: Siti Amanlina
authors.initials: SA
authors.lastname: Binte Aman
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Immunology programme, Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Eshele Anak
authors.initials: EA
authors.lastname: Libau
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Immunology programme, Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Pei Xuan
authors.initials: PX
authors.lastname: Lee
authors.affiliation: Emerging Infectious Diseases programme, Duke-NUS, Singapore.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: St John
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Immunology programme, Life Sciences Institute, National University of Singapore, Singapore.|Infectious Disease programme, Singapore-MIT alliance for Research and Technology (SMART), National University of Singapore, Singapore.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Alonso
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D016207:Cytokines / Q000378:metabolism; D003715:Dengue / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D003716:Dengue Virus / Q000145:classification; D005260:Female; D017353:Gene Deletion; D007074:Immunoglobulin G / Q000097:blood; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D008107:Liver Diseases / Q000209:etiology*; D051379:Mice; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D007074:Immunoglobulin G; D007370:Interferon Type I; D017471:Receptors, Interferon