Zika virus (ZIKV) constitutes an increasing public health problem. Previous studies have shown that CD8+ T cells play an important role in ZIKV-specific protective immunity. We have previously defined antigenic targets of the ZIKV-specific CD8+ T cell response in humans. In this study, we characterized the quality and phenotypes of these responses by a combined use of flow cytometry and transcriptomic methods, using PBMCs from donors deriving from different geographical locations collected in the convalescent phase of infection. We show that ZIKV-specific CD8+ T cells are characterized by a polyfunctional IFN-γ signature with upregulation of TNF-α, TNF receptors, and related activation markers, such as CD69, as well as a cytotoxic signature characterized by strong upregulation of GZMB and CRTAM. The signature is stable and not influenced by previous dengue virus exposure, geographical location, or time of sample collection postinfection. To our knowledge, this work elucidates the first in-depth characterization of human CD8+ T cells responding to ZIKV infection.
Natural killer (NK) cells control viral infection through the interaction between inhibitory receptors and human leukocyte antigen (HLA) ligands and bound peptide. NK cells expressing the inhibitory receptor NKG2A/CD94 recognize and respond to autologous B cells latently infected with Epstein–Barr virus (EBV). The mechanism is not yet understood, thus we investigated peptides derived from seven latent proteins of EBV in the interaction of NKG2A and its ligand HLA-E. Functional analysis demonstrated that EBV peptides can bind to HLA-E and block inhibition of NK cell effector function. Moreover, analysis of DNA from 79 subjects showed sequence variations in the latent protein, LMP1, which alters NK responses to EBV. We provide evidence that peptides derived from EBV latent cycle proteins can impair the recognition of NKG2A despite being presented by HLA-E, resulting in NK cell activation.
Introduction. Since the methodologies used to calculate Stegomyia indices have been shown to be inadequate for assessing the risk of dengue virus transmission and targeting Aedes aegypti control strategies, new surveillance methods are needed. Objective. To evaluate the water-surface sweeping method in combination with calibration factors to estimate the total number of Ae. aegypti late larval stages (L3/L4) in large water-storage containers at different temperatures at which transmission of dengue virus occurs. Materials and methods. Calibration factors were derived based on the proportion of L3/L4 recovered from a predetermined number of larvae using a net of specific dimensions and water-storage containers of different capacities and water levels in semi-field conditions and at four different altitudes (14, 358, 998 and 1,630 meters above sea level). The calibration factors obtained at 14 masl were then fully validated in a field study site at this altitude. Results. Four calibration factors were derived at 14 masl (28-30°C) that were used to estimate the total L3/L4 numbers in large water storage containers greater than 20 L (n=478) at 1/3, 2/3 and full waterlevels. This methodology was accurate and robust within and between the 10 pairs of field workers who applied it. Different calibration factors were, however, derived to accurately estimate the total L3/L4 numbers at each of the study sites located at 358, 998 and 1,630 masl, where average temperatures were 19°C, 24°C, and 26°C respectively. Conclusions. The accurate estimates of L3/L4 numbers calculated using the water surface sweeping method can be useful for evaluating intervention strategies directed against the larval stages.
Human schistosomiasis is a neglected tropical disease caused by parasitic worms. It affects over 250 million people globally. Most human infections are caused by S. mansoni, S. haematobium, and S. japonicum. Currently there is only one method of treatment for human schistosomiasis, the drug praziquantel. Constant selection pressure has caused a serious concern for a rise in resistance to praziquantel leading to the necessity for additional pharmaceuticals, with a distinctly different mechanism of action, to be used in combination therapy with praziquantel.
Previous treatment of Schistosoma mansoni included the use of oxamniquine (OXA), a prodrug that is enzymatically activated by a Sulfotransferase, an enzyme produced by S. mansoni (SmSULT). Although sulfotransferases are produced by S. haematobium and S. japonicum, OXA is not effective against these two species. By using information from the crystal structure of SmSULT bound to OXA, 250 OXA derivatives were designed and tested in vitro against the adult parasites. We were able to identify effective derivatives that kill Schistosoma mansoni (85%), S. haematobium (40%) and S. japonicum (83%). Recently, we identified CIDD‐149830 as an effective derivative that can kill all three schistosome species (100%) within 7 days in vitro. In vivo studies results show a significant reduction in the number of harvested worms from infected animals after treating them with CIDD‐149830.
In this study, we re‐engineered and tested 42 derivatives based on the structure of CIDD‐149830 and we were able to identify CIDD‐0150610 as a very powerful derivative that kills 100 % of Schistosoma mansoni overnight in vitro.
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R01 AI115691
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