piperidines and Dengue

Arboviruses represent a group of pathogens that can spread efficiently throughout human populations by hematophagous arthropod vectors. The mosquito-borne (re)emerging Chikungunya and Dengue viruses belong to the alphavirus and flavivirus genus, respectively, with no approved therapeutics or safe vaccines for humans. Transmitted by the same vector Aedes spp., these viruses cause significant morbidity and mortality in endemic areas. Due to the increasing likelihood of co-circulation and co-infection with viruses, we aimed to identify a pharmacologically targetable host factor that can inhibit multiple viruses and show that a potent antagonist of prolyl tRNA synthetase (halofuginone) suppresses both Chikungunya and Dengue viruses. Host tRNA synthetase inhibition may signify an additional approach to combat present and future epidemic pathogens.

Topics: Aedes; Amino Acyl-tRNA Synthetases; Animals; Antiviral Agents; Cells, Cultured; Chikungunya Fever; Chikungunya virus; Dengue; Dengue Virus; Fibroblasts; Foreskin; Host Microbial Interactions; Humans; Insect Proteins; Male; Mosquito Vectors; Piperidines; Quinazolinones; Receptor, Interferon alpha-beta

Dengue is the most frequent hemorrhagic viral disease and re-emergent infection in the world. Although thrombocytopenia is characteristically observed in mild and severe forms of dengue, the role of platelet activation in dengue pathogenesis has not been fully elucidated. We hypothesize that platelets have major roles in inflammatory amplification and increased vascular permeability during severe forms of dengue. Here we investigate interleukin (IL)-1β synthesis, processing, and secretion in platelets during dengue virus (DV) infection and potential contribution of these events to endothelial permeability during infection. We observed increased expression of IL-1β in platelets and platelet-derived microparticles from patients with dengue or after platelet exposure to DV in vitro. We demonstrated that DV infection leads to assembly of nucleotide-binding domain leucine rich repeat containing protein (NLRP3) inflammasomes, activation of caspase-1, and caspase-1-dependent IL-1β secretion. Our findings also indicate that platelet-derived IL-1β is chiefly released in microparticles through mechanisms dependent on mitochondrial reactive oxygen species-triggered NLRP3 inflammasomes. Inflammasome activation and platelet shedding of IL-1β-rich microparticles correlated with signs of increased vascular permeability. Moreover, microparticles from DV-stimulated platelets induced enhanced permeability in vitro in an IL-1-dependent manner. Our findings provide new evidence that platelets contribute to increased vascular permeability in DV infection by inflammasome-dependent release of IL-1β.

Topics: Adult; Blood Platelets; Capillary Permeability; Carrier Proteins; Caspase 1; Cell-Derived Microparticles; Dengue; Endothelium, Vascular; Female; Flow Cytometry; Gene Expression Regulation; Humans; Imidazoles; Indoles; Inflammasomes; Interleukin-1beta; Male; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Organophosphorus Compounds; Piperidines; Platelet Activation; Reactive Oxygen Species; Tosylphenylalanyl Chloromethyl Ketone; Up-Regulation

The effects of cyclophosphamide and 1,3-(piperidinomethyl)-5-phenyl-5-ethylbarbituric acid on certain flavi- and enterovirus infections in mice were studied. Differential enhancement of mortality rates after extraneural and, less markedly, intracerebral virus inoculation was noted. While depression of humoral and/or cell-mediated immunity is considered to be responsible for the effects observed in flavivirus infections, impaired function of the reticuloendothelial system seems to contribute mainly to the potentiation of Mengo virus infection by the immunodepressants used.

Topics: Animals; Arbovirus Infections; Barbiturates; Cyclophosphamide; Dengue; Disease Models, Animal; Encephalitis Viruses, Tick-Borne; Enterovirus Infections; Immunosuppressive Agents; Mengovirus; Mice; Piperidines; West Nile Fever