Strain-specific pathogenicity and antibody-dependent enhancement of dengue virus infection in Ifnar1–Ifngr1 double-knockout mice

This study investigated the pathogenicity of various dengue virus (DENV) strains using a newly established double-knockout (DKO) mouse model lacking both type I and type II IFN receptors ( Ifnar1–Ifngr1 DKO), rendering the mice highly susceptible to DENV infection. Survival, body weight changes and histopathological outcomes were assessed to characterize strain-specific pathogenicity and the potential for antibody-dependent enhancement (ADE). We observed significant strain-dependent variation in virulence. Notably, certain strains, such as DENV-1 02-20, exhibited pronounced ADE, evidenced by increased mortality and weight loss following pre-administration of the anti-DENV monoclonal antibody 4G2. These effects were more severe than those observed in single-knockout mice ( Ifnar1 KO or Ifngr1 KO) and in control groups. Histopathological examination revealed necrotic lesions in the brain and spinal cord, particularly in the olfactory bulb and cerebral cortex, along with extensive apoptosis of splenic lymphocytes, indicating severe immune activation and tissue damage. Our findings demonstrate that this lethal dengue infection model using Ifnar1–Ifngr1 DKO mice is an effective and valuable platform for studying the complex dynamics of DENV pathogenesis, immune responses and antibody interactions, as well as for evaluating vaccines and therapeutic strategies aimed at improving future prevention and treatment strategies for DENV infection.