Historical setbacks due to lack of human-like mouse models of dengue were partially remedied with characterization of lethal DENV-2 infection in immunocompromised AG129 mice (deficient in IFN-α/β/γ receptors).
Patients with antigenemia had the highest levels of IFN-α in plasma but the lowest frequency of IFN-α-producing pDCs, suggesting that DENV infection stimulates a systemic type I IFN response but affects the pDCs function.
Herein, we highlight key studies using the IFN receptor-deficient mouse models toward understanding the contribution of antibodies and T cells in impacting the outcome of DENV infection.
The IFN-α levels were found significantly higher in DF than DHF patients irrespective of the infecting serotype (DENV1 or 2), and were found to decline rapidly at day 3 after fever onset.
Importantly, we demonstrate that conditional IFN receptor knockout mice generate a better immune response to live virus and a candidate dengue vaccine compared to IFNAR mice and are resistant to subsequent challenge.
We utilized mice transgenic for human leukocyte antigens (HLA) lacking the alpha/beta interferon (IFN-α/β) receptor to study responses to heterologous DENV infection.
THP-1, expressing CD123, which is a plasmacytoid dendritic cell marker, but not CD14, CD11b or CD11c revealed IFNα mRNA expression while stimulated by dengue-2.
In summary, (i) IFN-alpha/beta is critical for early immune responses to DEN infection, (ii) IFN-gamma-mediated immune responses are crucial for both early and late clearance of DEN infection in mice, and (iii) the IFN system plays a more important role than T- and B-cell-dependent immunity in resistance to primary DEN infection in mice.