Environmental influences on antibody-enhanced dengue disease outcomes

Abstract

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

Aging and Environmental Enrichment Exacerbate Inflammatory Response on Antibody-Enhanced Dengue Disease in Immunocompetent Murine Model

“…Because it has been suggested that antibody-enhanced dengue disease is associated with an enhanced inflammatory host response in outbred mice (32), and exercised aged EE mice in the current work showed more intense clinical outcomes and T-lymphocyte infiltration than age-matched IE animals, we suggest that a higher degree of inflammatory response occurs in EE. Although our descriptive immunopathology data in outbred mice in a previous study (11) and in the present report are coherent with this hypothesis, the molecular mechanisms to explain differential pathological inflammatory response in different tissues in mice after antibody-enhanced DENV3 disease remain to be investigated.…”

Hierarchical Cluster Analysis of Three-Dimensional Reconstructions of Unbiased Sampled Microglia Shows not Continuous Morphological Changes from Stage 1 to 2 after Multiple Dengue Infections in Callithrix penicillata

“…Dengue virus infection of myeloid cells is facilitated by serotype cross-reactive antibodies through Fc receptors (Halstead, 2003 ; Ng et al, 2014 ). Anti-DENV antibodies injection enhance dengue virus infection and disease in mice (Balsitis et al, 2010 ; Diniz et al, 2012 ) and all anti-DENV antibodies enhanced infection at subneutralizing concentrations (Beltramello et al, 2010 ). Thus, cross-reactivity during acute primary and secondary infections (Friberg et al, 2011 ) may increase cytokine levels and viremia observed in severe disease (Boonnak et al, 2011 ; Ng et al, 2014 ).…”

“…In a previous report, we tested the ADE model in mice (Diniz et al, 2012 , 2013 ) and translated ADE to Callithrix penicillata (the black-tufted marmoset) (Vasconcelos et al, 2016 ). The inflammatory response was characterized, both in the periphery and in the CNS, and marked changes in CNS pathology characterized by extensive microglial activation and TNFα immunolabeling was confirmed.…”

Antibody‐enhanced dengue disease generates a marked CNS inflammatory response in the black‐tufted marmoset Callithrix penicillata

“…In ADE severe dengue disease seems to be associated with serotype cross‐reactive antibodies that facilitate DENV infection of myeloid cells by promoting viral entry via Fc receptors; this process is known as antibody‐dependent enhancement . Passive administration of anti‐DENV antibodies is sufficient to enhance DENV infection and disease in mice and all anti‐DENV antibodies enhanced infection at subneutralizing concentrations . Thus, cross‐reactivity during acute primary and secondary infections may contribute to the higher viremia and excess cytokine levels observed in severe disease …”

“…These signs were accompanied by dominant T lymphocytic infiltration and the presence of viral antigens in the liver and lungs. We proposed that the increased expansion of memory T cells and serotype cross‐reactive antibodies facilitates the infection of these cells by dengue virus and that these events correlate with disease severity …”