Association of Intracellular TH1-TH2 Balance in CD4+ T-cells and MIP-1α in CD8+ T-cells with Disease Severity in Adults with Dengue

Background: We tested the hypothesis that dengue haemorrhagic fever (DHF) is associated with a TH1-skewed immune response as opposed to dengue fever (DF). Methods: We estimated intracellular (in T-cells) and serum levels of designate TH1/TH2 cytokines [interferon-γ (IFN-γ), interleukin-4 (IL-4), and tumor necrosis factor-α] and macrophage inflammatory protein-1α (MIP-1α) at admission, 48 h, and day 5 in 20 adults with dengue (DF=10, DHF=10) and 10 dengue-naive healthy controls. Results: At admission, intracellular IFN-γ/IL-4 ratio in CD4+ T-cells and proportion of MIP-1a-positive CD8+ T-cells were significantly higher in patients with DHF [7.21 (5.36 ~ 10.81) vs. 3.04 (1.75 ~ 4.02); p=0.011 and 6.2% (3.2 ~ 8.2%) vs. 2.4% (2.0 ~ 3.6%); p=0.023]. The latter showed a significant positive correlation with IFN-γ/IL-4 ratio in CD4+ T-cells (Spearman's rho=0.64; p=0.003), percentage-change in haematocrit (rho=0.47; p=0.048), and serum alanine aminotransferase level (rho=0.61; p=0.009). Conclusion: We conclude that DHF is associated with a TH1-skewed immune response. Further, MIP-1α in CD8+ T-cells is an important immunologic correlate of disease severity in dengue

Susceptibility and Response of Human Blood Monocyte Subsets to Primary Dengue Virus Infection

Human blood monocytes play a central role in dengue infections and form the majority of virus infected cells in the blood. Human blood monocytes are heterogeneous and divided into CD16− and CD16+ subsets. Monocyte subsets play distinct roles during disease, but it is not currently known if monocyte subsets differentially contribute to dengue protection and pathogenesis. Here, we compared the susceptibility and response of the human CD16− and CD16+ blood monocyte subsets to primary dengue virus in vitro. We found that both monocyte subsets were equally susceptible to dengue virus (DENV2 NGC), and capable of supporting the initial production of new infective virus particles. Both monocyte subsets produced anti-viral factors, including IFN-α, CXCL10 and TRAIL. However, CD16+ monocytes were the major producers of inflammatory cytokines and chemokines in response to dengue virus, including IL-1β, TNF-α, IL-6, CCL2, 3 and 4. The susceptibility of both monocyte subsets to infection was increased after IL-4 treatment, but this increase was more profound for the CD16+ monocyte subset, particularly at early time points after virus exposure. These findings reveal the differential role that monocyte subsets might play during dengue disease

Role of the Chemokine Receptors CCR1, CCR2 and CCR4 in the Pathogenesis of Experimental Dengue Infection in Mice

Dengue virus (DENV), a mosquito-borne flavivirus, is a public health problem in many tropical countries. Recent clinical data have shown an association between levels of different chemokines in plasma and severity of dengue. We evaluated the role of CC chemokine receptors CCR1, CCR2 and CCR4 in an experimental model of DENV-2 infection in mice. Infection of mice induced evident clinical disease and tissue damage, including thrombocytopenia, hemoconcentration, lymphopenia, increased levels of transaminases and pro-inflammatory cytokines, and lethality in WT mice. Importantly, infected WT mice presented increased levels of chemokines CCL2/JE, CCL3/MIP-1α and CCL5/RANTES in spleen and liver. CCR1-/- mice had a mild phenotype with disease presentation and lethality similar to those of WT mice. In CCR2-/- mice, lethality, liver damage, levels of IL-6 and IFN-γ, and leukocyte activation were attenuated. However, thrombocytopenia, hemoconcentration and systemic TNF-α levels were similar to infected WT mice. Infection enhanced levels of CCL17/TARC, a CCR4 ligand. In CCR4-/- mice, lethality, tissue injury and systemic inflammation were markedly decreased. Despite differences in disease presentation in CCR-deficient mice, there was no significant difference in viral load. In conclusion, activation of chemokine receptors has discrete roles in the pathogenesis of dengue infection. These studies suggest that the chemokine storm that follows severe primary dengue infection associates mostly to development of disease rather than protection

MIP-1 alpha and MIP-1 beta induction by dengue virus

Dengue virus (DV) infection can result in either a mild febrile illness known as dengue fever (DF) or a life-threatening disease called dengue hemorrhagic fever (DHF). DHF is more prevalent in patients undergoing secondary DV infection. This observation has led to the hypothesis that DHF may be the result of immune reactions to the secondary DV infection; an event termed immunopathology. Two cellular factors, MIP-1 alpha and MIP-1 beta, have been found to be induced by infection with DV. MIP-1 induction by DV infection was observed in a myelomonocytic cell line, as well as in peripheral blood mononuclear cells isolated from a dengue naive donor. MIP-1 induction was not due to factors secreted by infected cells. In fact, replication-competent virus was required to induce MIP-1. Evidence is also provided that MIP-1 genes are expressed in patients with dengue disease. It is hypothesized that these chemokines may have roles in the immunopathology of dengue infections and may contribute to fever and bone marrow suppression observed in patients with DV infections

Understanding the relationship between biomass production and water use of Populus tomentosa trees throughout an entire short-rotation

Understanding the relationship between tree production and water use, as well as the main environmental and plant-related drivers of water use, is crucial for the establishment of production prediction models and reliable water management under current and future climatic conditions. However, the relation between tree water use and biomass production has never been assessed throughout the entire life-cycle of a poplar rotation; nor have detailed investigations been reported on how poplar transpiration and its regulation change inter-annually. Therefore, we studied the relationship between transpiration ( E ) and aboveground biomass (ABM), as well as the main drivers of E , in a plantation established on the North China Plain, with 2- to 5-year-old (2016 to 2019) Populus tomentosa trees under three water treatments. Our results indicated that ABM increase depended on annually accumulated E and that their relationship can be fitted with a logistic curve for the entire life cycle ( R 2 > 0.89). Throughout the whole rotation period, compared with non-irrigated trees, full irrigation trees produced 59% more biomass with only 12% more E , while deficit irrigation trees attained 46% more biomass with 32% more E . The daily E had a strong exponential relationship with vapor pressure deficit ( D ) during years 3-5 of their growth cycle, which the asymptote of this relationship increasing with tree age (1.6 kPa (2017), 2 kPa (2018), 2.5 kPa (2019)). The E was also strongly linearly correlated to solar radiation ( R s ) for each year although with slightly weaker relationships than for D . Similar to other poplar clones, P. tomentosa showed effective stomatal control on E . However, soil water content had almost no effect, for all treatments, no matter which soil layer was considered. Finally, our research quantified the relationship between tree production and water use throughout the rotation. We also confirmed that D and R s are indeed the major drivers of transpiration during the growing season as well as during drought in this semi-humid boreal region. Our findings should enable a better understanding of the water-use strategies of poplars in the North China Plain and will help sustainably manage plantations in water-scarce regions around the world under changing environmental conditions