Bridging the Knowledge Gap in Transmission-Blocking Immunity to Malaria: Deciphering Molecular Mechanisms in Mosquitoes

The worldwide decline over the last decade in the number of clinical cases of malaria does not mean an end to the universal problem of malaria pathogenesis in those afflicted by infection. Resistance to drugs, higher risk of disease relapse and failure to maintain effective memory of the pathogen in the absence of persistent exposure result in the repeated failure of anti-malarialtreatments. The artificial blocking of transmission of the Plasmodium parasite between hosts from human to Anopheles mosquito, and vice versa, is crucial to restricting the spread of disease. However, a limited knowledge of the molecular mechanisms in operation for transmission of malaria has impeded progress towards a transmission-blocking vaccine. This review highlights the role of anti-malarial immune responses to antigen-specific targets for designing effective vaccines against the sexual stages of Plasmodium that occur within the invertebrate vector. In particular, artificial induction of gametocyte and ookinete apoptosis as a novel means to prevent gamete fertilization and oocyte development, respectively, is highlighted. This and other recent insights into our understanding of the molecular regulation of transmission-blocking immunity are discussed and future prospects considered.

Slow-release praziquantel for dogs:presentation of a new formulation for echinococcosis control

Background:Echinococcosis is a serious,zoonotic,parasitic disease with worldwide distribution.According to a epidemiological survey in 2012 in China,there are 20,000 infected patients and more than 50 million people at the risk.As the dog is the main,definitive host,the Government of China encourages monthly praziquantel treatment of every dog.However,this is difficult to achieve in geographically challenging areas,such as the Tibetan plateau,where there are also many dogs without owners.To overcome these problems,we investigated the transmission blocking capacity of a slow-release formulation of praziquantel administered by subcutaneous injection.Methods:The impact of a slow-release preparation of two pharmacokinetically stereoselective praziquantel enantiomers,i.e.,R-(−)-praziquantel(R-PZQ)and S-(+)-praziquantel(S-PZQ)absorbed into a biodegradable polymer was studied in beagle dogs(N=6).The preparation was given by subcutaneous injection using a single dose of 100 mg/kg.Chiral-selective,high-performance liquid chromatography(HPLC)and high-resolution mass spectrometry(HRMS)were applied to measure the praziquantel enantiomers in the plasma of the dogs.The lower limit for estimating plasma concentrations accurately for R-PZQ was 4 ng/ml and for S-PZQ 20 ng/ml.The pharmacokinetic parameters were calculated by a noncompartmental analysis model using Drug Analyze System(DAS)software 2.0.The SPSS 19.0 software was used for statistical analysis,and the statistical comparison between enantiomers was assessed using the two-tailed t-test.Results:Two hours after administration,peak concentrations of R-PZQ and S-PZQ:321±26 and 719±263 ng/ml,respectively,were achieved.After 180 days,the average plasma concentration of R-PZQ in the six dogs had decreased to 13 ng/ml.The average concentration value of S-PZQ was higher than that of R-PZQ in the first 90-day period but fell afterwards and could not be accurately estimated when dropping below 20 ng/ml(the lower methodological limit for this enantiomer).Taking all the dogs into account,the average maximum concentration(Cmax)of S-PZQ in plasma over the first 3 months was higher than that of R-PZQ by 114.0%(P<0.05),while the average mean retention time(MRT)of R-PZQ in plasma was higher than that of S-PZQ by 96.3%(P<0.05).Conclusions:Praziquantel given as an in situ slow-release formulation by subcutaneous injection resulted in concentrations of the active principle in beagle dogs,which should be capable of resisting new Echinococcus infections for at least 6 months.The new formulation of praziquantel represents a potential,alternative way of presenting medication against tapeworm infections in dogs.