Because an enriched environment (EE) enhances T-cell activity and T-lymphocytes contribute to immunopathogenesis during heterologous dengue virus (DENV) infections, we hypothesised that an EE increases dengue severity. To compare single serotype (SS) and antibody-enhanced disease (AED) infections regimens, serial intraperitoneal were performed with DENV3 (genotype III) infected brain homogenate or anti-DENV2 hyperimmune serum followed 24 h later by DENV3 (genotype III) infected brain homogenate. Compared AED for which significant differences were detected between the EE and impoverished environmental (IE) groups (Kaplan-Meyer log-rank test, p = 0.0025), no significant differences were detected between the SS experimental groups (Kaplan-Meyer log-rank test, p = 0.089). Survival curves from EE and IE animals infected with the AED regimen were extended after corticoid injection and this effect was greater in the EE than in the IE group (Kaplan-Meyer log-rank test, p = 0.0162). Under the AED regimen the EE group showed more intense clinical signs than the IE group. Dyspnoea, tremor, hunched posture, ruffled fur, immobility, pre-terminal paralysis, shock and death were associated with dominant T-lymphocytic hyperplasia and presence of viral antigens in the liver and lungs. We propose that the increased expansion of these memory T-cells and serotype cross-reactive antibodies facilitates the infection of these cells by DENV and that these events correlate with disease severity in an EE

We previously demonstrated in young mice that in comparison with animals raised in an impoverished environment (IE), animals from an enriched environment (EE) show more severe dengue disease, associated with an increased expansion of memory T target cells. Because active older adults show less functional decline in T-cell adaptive immunity, we hypothesized that aged mice from EE would show higher mortality and T-lymphocyte expansion than mice from IE. To test this hypothesis, we administered serial i.p. injections of anti-DENV2 hyperimmune serum, followed 24 h later by DENV3 (genotype III)-infected brain homogenate. Control mice received equal volumes of serum but received uninfected brain homogenate. The presence of virus or viral antigens was indirectly detected by real-time quantitative RT-PCR and immunohistochemistry. Compared to infected IE animals, EE mice, independent of age, showed higher mortality and more intense clinical signs. Compared to young mice, the higher mortality of aged mice was associated with a higher degree of T lymphocytic hyperplasia in the spleen and infiltration in kidneys, liver, and lungs, but less viral antigen immunolabeling. We propose that a higher expansion of T cells and serotype cross-reactive antibodies are associated with disease severity in aged mice.

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