Spatial Re-Establishment Dynamics of Local Populations of Vectors of Chagas Disease

Chagas disease is transmitted by blood-sucking bugs (vectors) and presents a severe public health threat in the Americas. Worldwide there are approximately 10 million people infected with Chagas disease, a disease for which there is currently no effective cure. Vector suppression is the main strategy to control the spread of this disease. Unfortunately, the vectors have been resurgent in some areas. It is important to understand the dynamics of reinfestation where it occurs. Here we show how different models fitted to patch-level bug infestation data can elucidate different aspects of re-establishment dynamics. Our results demonstrated a 6-month time lag between detection of a new infestation and dispersal events, seasonality in dispersal rates and effects of previous vector infestation on subsequent vector establishment rates. In addition we provide estimates of dispersal distances and the effect of insecticide spraying on rates of vector re-establishment. While some of our results confirm previous findings, the effects of season and previous infestation on bug establishment challenge our current understanding of T. infestans ecology and highlight important gaps in our knowledge of T. infestans dispersal

Small-molecule dual PLK1 and BRD4 inhibitors are active against preclinical models of pediatric solid tumors

Simultaneous inhibition of multiple molecular targets is an established strategy to improve the continuance of clinical response to therapy. Here, we screened 49 molecules with dual nanomolar inhibitory activity against BRD4 and PLK1, best classified as dual kinase-bromodomain inhibitors, in pediatric tumor cell lines for their antitumor activity. We identified two candidate dual kinase-bromodomain inhibitors with strong and tumor-specific activity against neuroblastoma, medulloblastoma, and rhabdomyosarcoma tumor cells. Dual PLK1 and BRD4 inhibitor treatment suppressed proliferation and induced apoptosis in pediatric tumor cell lines at low nanomolar concentrations. This was associated with reduced MYCN-driven gene expression as assessed by RNA sequencing. Treatment of patient-derived xenografts with dual inhibitor UMB103 led to significant tumor regression. We demonstrate that concurrent inhibition of two central regulators of MYC protein family of protooncogenes, BRD4, and PLK1, with single small molecules has strong and specific antitumor effects in preclinical pediatric cancer models

Evaluation of Spatially Targeted Strategies to Control Non-Domiciliated Triatoma dimidiata Vector of Chagas Disease

Chagas disease is one of the most important parasitic diseases in Latin America. Since the 1980's, many national and international initiatives have contributed to eliminate vectors developing inside human domiciles. Today's challenge is to control vectors that are non-adapted to the human domicile, but still able to transmit the parasite through regular short stay in the houses. Here, we assess the potential of different control strategies applied in specific spatial patterns using a mathematical model that reproduces the dynamic of dispersion of such ‘non-domiciliated’ vectors within a village of the Yucatan Peninsula, Mexico. We show that no single strategy applied in the periphery of the village, where the insects are more abundant, provides satisfying protection to the whole village. However, combining the use of insect screens in houses at the periphery of the village (to simultaneously fight insects dispersing from the garden and the forest), and the cleaning of the peri-domicile areas of the centre of the village (where sylvatic insects are absent), would provide a cost-effective control. This type of spatially mixed strategy offers a promising way to reduce the cost associated with the repeated interventions required to control non-domiciliated vectors that permanently attempt to infest houses

Characterization of the Dispersal of Non-Domiciliated Triatoma dimidiata through the Selection of Spatially Explicit Models

Chagas disease is one of the most important neglected diseases in Latin America. Although insecticides have been successfully sprayed to control domiciliated vector populations, this strategy has proven to be ineffective in areas where non-domiciliated vectors immigrating from peridomestic or sylvatic ecotopes can (re-)infest houses. The development of strategies for the control of non-domiciliated vectors has thus been identified by the World Health Organization as a major challenge. Such development primarily requires a description of the spatio-temporal dynamics of infestation by these vectors, and a good understanding of their dispersal. We combined for the first time extensive spatio-temporal data sets describing house infestation dynamics by Triatoma dimidiata inside one village, and spatially explicit population dynamics models. The models fitted and predicted remarkably the observed infestation dynamics. They thus provided both key insights into the dispersal of T. dimidiata in this area, and a suitable mathematical background to evaluate the efficacy of various control strategies. Interestingly, the observed and modelled patterns of infestation suggest that interventions could focus on the periphery of the village, where there is the highest risk of transmission. Such spatial optimization may allow for reducing the cost of control, compensating for repeated interventions necessary for non-domiciliated vectors

Emergence and Genetic Variation of Neuraminidase Stalk Deletions in Avian Influenza Viruses

When avian influenza viruses (AIVs) are transmitted from their reservoir hosts (wild waterfowl and shorebirds) to domestic bird species, they undergo genetic changes that have been linked to higher virulence and broader host range. Common genetic AIV modifications in viral proteins of poultry isolates are deletions in the stalk region of the neuraminidase (NA) and additions of glycosylation sites on the hemagglutinin (HA). Even though these NA deletion mutations occur in several AIV subtypes, they have not been analyzed comprehensively. In this study, 4,920 NA nucleotide sequences, 5,596 HA nucleotide and 4,702 HA amino acid sequences were analyzed to elucidate the widespread emergence of NA stalk deletions in gallinaceous hosts, the genetic polymorphism of the deletion patterns and association between the stalk deletions in NA and amino acid variants in HA. Forty-seven different NA stalk deletion patterns were identified in six NA subtypes, N1–N3 and N5–N7. An analysis that controlled for phylogenetic dependence due to shared ancestry showed that NA stalk deletions are statistically correlated with gallinaceous hosts and certain amino acid features on the HA protein. Those HA features included five glycosylation sites, one insertion and one deletion. The correlations between NA stalk deletions and HA features are HA-NA-subtype-specific. Our results demonstrate that stalk deletions in the NA proteins of AIV are relatively common. Understanding the NA stalk deletion and related HA features may be important for vaccine and drug development and could be useful in establishing effective early detection and warning systems for the poultry industry

Chagas Disease Risk in Texas

Chagas disease is endemic in Texas and spread through triatomine insect vectors known as kissing bugs, assassin bugs, or cone–nosed bugs, which transmit the protozoan parasite, Trypanosoma cruzi. We examined the threat of Chagas disease due to the three most prevalent vector species and from human case occurrences and human population data at the county level. We modeled the distribution of each vector species using occurrence data from México and the United States and environmental variables. We then computed the ecological risk from the distribution models and combined it with disease incidence data to produce a composite risk map which was subsequently used to calculate the populations expected to be at risk for the disease. South Texas had the highest relative risk. We recommend mandatory reporting of Chagas disease in Texas, testing of blood donations in high risk counties, human and canine testing for Chagas disease antibodies in high risk counties, and that a joint initiative be developed between the United States and México to combat Chagas disease

Modeling Disease Vector Occurrence when Detection Is Imperfect: Infestation of Amazonian Palm Trees by Triatomine Bugs at Three Spatial Scales

Blood-sucking bugs of the genus Rhodnius are major vectors of Chagas disease. Control and surveillance of Chagas disease transmission critically depend on ascertaining whether households and nearby ecotopes (such as palm trees) are infested by these vectors. However, no bug detection technique works perfectly. Because more sensitive methods are more costly, vector searches face a trade-off between technical prowess and sample size. We compromise by using relatively inexpensive sampling techniques that can be applied multiple times to a large number of palms. With these replicated results, we estimate the probability of failing to detect bugs in a palm that is actually infested. We incorporate this information into our analyses to derive an unbiased estimate of palm infestation, and find it to be about 50% – twice the observed proportion of infested palms. We are then able to model the effects of regional, landscape, and local environmental variables on palm infestation. Individual palm attributes contribute overwhelmingly more than landscape or regional covariates to explaining infestation, suggesting that palm tree management can help mitigate risk locally. Our results illustrate how explicitly accounting for vector, pathogen, or host detection failures can substantially improve epidemiological parameter estimation when perfect detection techniques are unavailable

Interactions between four species in a complex wildlife: livestock disease community : implications for Mycobacterium bovis maintenance and transmission

Livestock diseases such as bovine tuberculosis can have considerable negative effects on human health and economic activity. Wildlife reservoirs often hinder disease eradication in sympatric livestock populations. Therefore, quantifying interactions between wildlife and livestock is an important aspect of understanding disease persistence. This study was conducted on an extensive cattle farm in southwest Spain, where cattle, domestic pigs, wild boar and red deer are considered to be part of a tuberculosis host community. We tested the hypothesis that the frequency of both types of interactions would be greater at food and water sites, due to the aggregation of individuals from multiple species at these locations. We measured direct and indirect interactions between individuals using GPS and proximity loggers. Over 57,000 direct interactions were recorded over a 2-year period, of which 875 (1.5 %) occurred between different species and 216 (0.38 %) occurred between wildlife and livestock. Most direct and indirect interactions occurred at water sites. Over 90 % of indirect interactions between wildlife and livestock took place within the estimated 3-day environmental survival time of Mycobacterium bovis in this habitat. Red deer home ranges and daily activity patterns revealed significant spatial and temporal overlaps with cattle, particularly in autumn. Suids and red deer also cross the farm boundary regularly, introducing a between-farm interaction risk. The infrequent occurrence of direct interactions between individuals from different species suggests that they are unlikely to be the sole mode of disease transmission and that indirect interactions may play an important role