Mice, myeloid cells, and dengue: a new model for unraveling vascular leakage mysteries.

INTRODUCTION

Severe dengue is thought to be caused by an excessive host immune response.

METHODS

To study the pathogenesis of severe dengue, we developed a novel model using LysM Cre mice carrying depleted expression only in subsets of murine myeloid cells.

RESULTS

Although dengue virus (DENV) clinical isolates were not virulent in LysM Cre mice, mouse-adapted DV1-5P7Sp and DV3P12/08P4Bm, which were obtained by passaging the spleen or bone marrow of mice, demonstrated 100% lethality with severe vascular leakage in the liver and small intestine. DV1-5P7Sp and DV3P12/08P4Bm harbored five and seven amino acid substitutions, respectively. Infection also induced neutrophil infiltration in the small intestine, and increased expression of IL-6 and MMP-8 and blockade of TNF-α signaling protected the mice, as demonstrated in a previous severe dengue mouse model using C57/BL6 mice lacking both IFN-α/β and IFN-γ receptors. Notably, the new models with DV1-5P7Sp and DV3P12/08P4Bm showed an increased proliferative capacity of the adapted viruses in the thymus and bone marrow.

DISCUSSION

These observations suggest that myeloid cell infection is sufficient to trigger cytokine storm-induced vascular leakage. This model can refine the factors involved in the pathology of severe dengue leading to vascular leakage.