Activation of Akt Signaling Reduces the Prevalence and Intensity of Malaria Parasite Infection and Lifespan in Anopheles stephensi Mosquitoes

Malaria (Plasmodium spp.) kills nearly one million people annually and this number will likely increase as drug and insecticide resistance reduces the effectiveness of current control strategies. The most important human malaria parasite, Plasmodium falciparum, undergoes a complex developmental cycle in the mosquito that takes approximately two weeks and begins with the invasion of the mosquito midgut. Here, we demonstrate that increased Akt signaling in the mosquito midgut disrupts parasite development and concurrently reduces the duration that mosquitoes are infective to humans. Specifically, we found that increased Akt signaling in the midgut of heterozygous Anopheles stephensi reduced the number of infected mosquitoes by 60–99%. Of those mosquitoes that were infected, we observed a 75–99% reduction in parasite load. In homozygous mosquitoes with increased Akt signaling parasite infection was completely blocked. The increase in midgut-specific Akt signaling also led to an 18–20% reduction in the average mosquito lifespan. Thus, activation of Akt signaling reduced the number of infected mosquitoes, the number of malaria parasites per infected mosquito, and the duration of mosquito infectivity

DOGS: Reaction-Driven de novo Design of Bioactive Compounds

We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties

Reproductive Phase Locking of Mosquito Populations in Response to Rainfall Frequency

The frequency of moderate to heavy rainfall events is projected to change in response to global warming. Here we show that these hydrologic changes may have a profound effect on mosquito population dynamics and rates of mosquito-borne disease transmission. We develop a simple model, which treats the mosquito reproductive cycle as a phase oscillator that responds to rainfall frequency forcing. This model reproduces observed mosquito population dynamics and indicates that mosquito-borne disease transmission can be sensitive to rainfall frequency. These findings indicate that changes to the hydrologic cycle, in particular the frequency of moderate to heavy rainfall events, could have a profound effect on the transmission rates of some mosquito-borne diseases

Rainfall and sentinel chicken seroconversions predict human cases of Murray Valley encephalitis in the north of Western Australia

Background Murray Valley encephalitis virus (MVEV) is a flavivirus that occurs in Australia and New Guinea. While clinical cases are uncommon, MVEV can cause severe encephalitis with high mortality. Sentinel chicken surveillance is used at many sites around Australia to provide an early warning system for risk of human infection in areas that have low population density and geographical remoteness. MVEV in Western Australia occurs in areas of low population density and geographical remoteness, resulting in logistical challenges with surveillance systems and few human cases. While epidemiological data has suggested an association between rainfall and MVEV activity in outbreak years, it has not been quantified, and the association between rainfall and sporadic cases is less clear. In this study we analysed 22 years of sentinel chicken and human case data from Western Australia in order to evaluate the effectiveness of sentinel chicken surveillance for MVEV and assess the association between rainfall and MVEV activity. Methods Sentinel chicken seroconversion, human case and rainfall data from the Kimberley and Pilbara regions of Western Australia from 1990 to 2011 were analysed using negative binomial regression. Sentinel chicken seroconversion and human cases were used as dependent variables in the model. The model was then tested against sentinel chicken and rainfall data from 2012 and 2013.Results Sentinel chicken seroconversion preceded all human cases except two in March 1993. Rainfall in the prior three months was significantly associated with both sentinel chicken seroconversion and human cases across the regions of interest. Sentinel chicken seroconversion was also predictive of human cases in the models. The model predicted sentinel chicken seroconversion in the Kimberley but not in the Pilbara, where seroconversions early in 2012 were not predicted. The latter may be due to localised MVEV activity in isolated foci at dams, which do not reflect broader virus activity in the region. Conclusions We showed that rainfall and sentinel chickens provide a useful early warning of MVEV risk to humans across endemic and epidemic areas, and that a combination of the two indicators improves the ability to assess MVEV risk and inform risk management measures

Field site selection: getting it right first time around

The selection of suitable field sites for integrated control of Anopheles mosquitoes using the sterile insect technique (SIT) requires consideration of the full gamut of factors facing most proposed control strategies, but four criteria identify an ideal site: 1) a single malaria vector, 2) an unstructured, relatively low density target population, 3) isolation of the target population and 4) actual or potential malaria incidence. Such a site can exist in a diverse range of situations or can be created. Two contrasting SIT field sites are examined here: the desert-flanked Dongola Reach of the Nile River in Northern State, Sudan, where malaria is endemic, and the island of La Reunion, where autochthonous malaria is rare but risk is persistent. The single malaria-transmitting vector at both sites is Anopheles arabiensis. In Sudan, the target area is a narrow 500 km corridor stretching from the rocky terrain at the Fourth Cataract - just above the new Merowe Dam, to the northernmost edge of the species range, close to Egypt. Vector distribution and temporal changes in density depend on the Nile level, ambient temperature and human activities. On La Reunion, the An. arabiensis population is coastal, limited and divided into three areas by altitude and exposure to the trade winds on the east coast. Mosquito vectors for other diseases are an issue at both sites, but of primary importance on La Reunion due to the recent chikungunya epidemic. The similarities and differences between these two sites in terms of suitability are discussed in the context of area-wide integrated vector management incorporating the SIT

The abundance and host-seeking behavior of culicine species (Diptera: Culicidae) and Anopheles sinensis in Yongcheng city, people's Republic of China

<p>Abstract</p> <p>Background</p> <p>The knowledge of mosquito species diversity and the level of anthropophily exhibited by each species in a region are of great importance to the integrated vector control. Culicine species are the primary vectors of Japanese encephalitis (JE) virus and filariasis in China. <it>Anopheles sinensis </it>plays a major role in the maintenance of <it>Plasmodium vivax </it>malaria transmission in China. The goal of this study was to compare the abundance and host-seeking behavior of culicine species and <it>An. sinensis </it>in Yongcheng city, a representative region of <it>P. vivax </it>malaria. Specifically, we wished to determine the relative attractiveness of different animal baits versus human bait to culicine species and <it>An. sinensis</it>.</p> <p>Results</p> <p><it>Culex tritaeniorhynchus </it>was the most prevalent mosquito species and <it>An. sinensis </it>was the sole potential vector of <it>P. vivax </it>malaria in Yongcheng city. There were significant differences (P < 0.01) in the abundance of both <it>An. sinensis </it>and <it>Cx. tritaeniorhynchus </it>collected in distinct baited traps. The relative attractiveness of animal versus human bait was similar towards both <it>An. sinensis </it>and <it>Cx. tritaeniorhynchus</it>. The ranking derived from the mean number of mosquitoes per bait indicated that pigs, goats and calves frequently attracted more mosquitoes than the other hosts tested (dogs, humans, and chickens). These trends were similar across all capture nights at three distinct villages. The human blood index (HBI) of female <it>An. sinensis </it>was 2.94% when computed with mixed meals while 3.70% computed with only the single meal. 19:00~21:00 was the primary peak of host-seeking female <it>An. sinensis </it>while 4:00~5:00 was the smaller peak at night. There was significant correlation between the density of female <it>An. sinensis </it>and the average relative humidity (P < 0.05) in Wangshanzhuang village.</p> <p>Conclusions</p> <p>Pigs, goats and calves were more attractive to <it>An. sinensis </it>and <it>Cx. tritaeniorhynchus </it>than dogs, humans, and chickens. Female <it>An. sinensis </it>host-seeking activity mainly occurred from 19:00 to 21:00. Thus, we propose that future vector control against <it>An. sinensis </it>and <it>Cx. tritaeniorhynchus </it>in the areas along the Huang-Huai River of central China should target the interface of human activity with domestic animals and adopt before human hosts go to bed at night.</p

Susceptibility and Antibody Response of the Laboratory Model Zebra Finch (Taeniopygia guttata) to West Nile Virus

Since the introduction of West Nile virus (WNV) into North America in 1999 a number of passerine bird species have been found to play a role in the amplification of the virus. Arbovirus surveillance, observational studies and experimental studies have implicated passerine birds (songbirds, e.g., crows, American robins, house sparrows, and house finches) as significant reservoirs of WNV in North America, yet we lack a tractable passerine animal model for controlled studies of the virus. The zebra finch (Taeniopygia guttata) serves as a model system across a diversity of fields, and here we develop the zebra finch a songbird model for WNV. Like many natural hosts of WNV, we found that zebra finches developed sufficient viremia to serve as a competent host, yet in general resisted mortality from infection. In the Australian zebra finch (AZF) T. g. castanotis, we detected WNV in the majority of sampled tissues by 4 days post injection (dpi). However, WNV was not detected in tissues of sacrificed birds at 14 dpi, shortly after the development of detectable anti-WNV antibodies in the majority of birds indicating successful viral clearance. We compared susceptibility between the two zebra finch subspecies AZF and Timor zebra finch (TZF) T. g. guttata. Compared to AZF, WNV RNA was detected in a larger proportion of challenged TZF and molecular detection of virus in the serum of TZF was significantly higher than in AZF. Given the observed moderate host competence and disease susceptibility, we suggest that zebra finches are appropriate as models for the study of WNV and although underutilized in this respect, may be ideal models for the study of the many diseases carried and transmitted by songbirds