Increasing transmission of dengue virus across ecologically diverse regions of Ecuador and associated risk factors.

The distribution and intensity of viral diseases transmitted by Aedes aegypti mosquitoes, including dengue, have rapidly increased over the last century. Here, we study dengue virus (DENV) transmission across the ecologically and demographically distinct regions or Ecuador. We analyzed province-level age-stratified dengue incidence data from 2000-2019 using catalytic models to estimate the force of infection of DENV over eight decades. We found that provinces established endemic DENV transmission at different time periods. Coastal provinces with the largest and most connected cities had the earliest and highest increase in DENV transmission, starting around 1980 and continuing to the present. In contrast, remote and rural areas with reduced access, like the northern coast and the Amazon regions, experienced a rise in DENV transmission and endemicity only in the last 10 to 20 years. The newly introduced chikungunya and Zika viruses have age-specific distributions of hospital-seeking cases consistent with recent emergence across all provinces. To evaluate factors associated with geographic differences in DENV transmission potential, we modeled DENV vector risk using 11,693 Aedes aegypti presence points to the resolution of 1 hectare. In total, 56% of the population of Ecuador, including in provinces identified as having increasing DENV transmission in our models, live in areas with high risk of Aedes aegypti, with population size, trash collection, elevation, and access to water as important determinants. Our investigation serves as a case study of the changes driving the expansion of DENV and other arboviruses globally and suggest that control efforts should be expanded to semi-urban and rural areas and to historically isolated regions to counteract increasing dengue outbreaks.

Increasing transmission of dengue virus across ecologically diverse regions of Ecuador and associated risk factors.

The distribution and intensity of viral diseases transmitted by Aedes aegypti mosquitoes, including dengue, have rapidly increased over the last century. Ecuador is an interesting country to study drivers of dengue virus (DENV) transmission given it has multiple ecologically and demographically distinct regions. Here, we analyze province-level age-stratified dengue prevalence data from 2000-2019 using catalytic models to estimate the force of infection of DENV over eight decades and across provinces in Ecuador. We found that provinces established endemic DENV transmission at different time periods. Coastal provinces with the largest and most connected cities had the earliest and highest increase in DENV transmission, starting around 1980 and continuing to the present. In contrast, remote and rural areas with reduced access, like the northern coast and the Amazon regions, experienced a rise in DENV transmission and endemicity only in the last 10 to 20 years. The newly introduced chikungunya and Zika viruses have distinct age-specific prevalence distributions consistent with recent emergence across all provinces. We evaluated factors to the resolution of 1 hectare associated with geographic differences in vector suitability and arbovirus disease in the last 10 years by modeling 11,693 A aegypti presence points and 73,550 arbovirus cases. In total, 56% of the population of Ecuador lives in areas with high risk of Aedes aegypti. Most suitable provinces had hotspots for arbovirus disease risk, with population size, elevation, sewage connection, trash collection, and access to water as important determinants. Our investigation serves as a case study of the changes driving the expansion of DENV and other arboviruses globally and suggest that control efforts should be expanded to semi-urban and rural areas and to historically isolated regions to counteract increasing dengue outbreaks.

Validity of Self-Reported Mosquito Bites to Assess Household Mosquito Abundance in Six Communities of Esmeraldas Province, Ecuador.

Mosquito-borne diseases are a global burden; however, current methods of evaluating human-mosquito contact rates are expensive and time consuming. Validated surveys of self-reported mosquito bites may be an inexpensive way to determine mosquito presence and bite exposure level in an area, but this remains untested. In this study, a survey of self-reported mosquito bites was validated against household mosquito abundance from six communities in Esmeraldas, Ecuador. From February 2021 to July 2022, households were interviewed monthly, and five questions were used to ask participants how often they were bitten by mosquitoes at different times during the day. At the same time, adult mosquitoes were collected using a Prokopack aspirator. Species were identified and counted. Survey responses were compared with the total number of mosquitoes found in the home using negative binomial regression. More frequent self-reported mosquito bites were significantly associated with higher numbers of collected adult mosquitoes. These associations were driven by the prevalence of the dominant genera, Culex. These results suggest that surveys of perceived mosquito bites relate to actual mosquito presence, making them a potentially useful tool for determining the impact of vector-control interventions on community perceptions of risk but less useful for assessing the risk of nondominant species such as Aedes aegypti. Further work is needed to examine the robustness of these results in other contexts.

Household-level risk factors for Aedes aegypti pupal density in Guayaquil, Ecuador.

BACKGROUND: Vector-borne diseases are a major cause of disease burden in Guayaquil, Ecuador, especially arboviruses spread by Aedes aegypti mosquitoes. Understanding which household characteristics and risk factors lead to higher Ae. aegypti densities and consequent disease risk can help inform and optimize vector control programs. METHODS: Cross-sectional entomological surveys were conducted in Guayaquil between 2013 and 2016, covering household demographics, municipal services, potential breeding containers, presence of Ae. aegypti larvae and pupae, and history of using mosquito control methods. A zero-truncated negative binomial regression model was fitted to data for estimating the household pupal index. An additional model assessed the factors of the most productive breeding sites across all of the households. RESULTS: Of surveyed households, 610 satisfied inclusion criteria. The final household-level model found that collection of large solid items (e.g., furniture and tires) and rainfall the week of and 2 weeks before collection were negatively correlated with average pupae per container, while bed canopy use, unemployment, container water volume, and the interaction between large solid collection and rainfall 2 weeks before the sampling event were positively correlated. Selection of these variables across other top candidate models with ∆AICc < 1 was robust, with the strongest effects from large solid collection and bed canopy use. The final container-level model explaining the characteristics of breeding sites found that contaminated water is positively correlated with Ae. aegypti pupae counts while breeding sites composed of car parts, furniture, sewerage parts, vases, were all negatively correlated. CONCLUSIONS: Having access to municipal services like bulky item pickup was effective at reducing mosquito proliferation in households. Association of bed canopy use with higher mosquito densities is unexpected, and may be a consequence of large local mosquito populations or due to limited use or effectiveness of other vector control methods. The impact of rainfall on mosquito density is multifaceted, as it may both create new habitat and "wash out" existing habitat. Providing services and social/technical interventions focused on monitoring and eliminating productive breeding sites is important for reducing aquatic-stage mosquito densities in households at risk for Ae. aegypti-transmitted diseases.

Activation of 3-phosphoinositide-dependent kinase 1 (PDK1) and serum- and glucocorticoid-induced protein kinase 1 (SGK1) by short-chain sphingolipid C4-ceramide rescues the trafficking defect of ΔF508-cystic fibrosis transmembrane conductance regulator (ΔF508-CFTR).

Cystic fibrosis (CF) is due to a folding defect in the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, ΔF508, prevents CFTR from trafficking to the apical plasma membrane. Here we show that activation of the PDK1/SGK1 signaling pathway with C4-ceramide (C4-CER), a non-toxic small molecule, functionally corrects the trafficking defect in both cultured CF cells and primary epithelial cell explants from CF patients. The mechanism of C4-CER action involves a series of mutual autophosphorylation and phosphorylation events between PDK1 and SGK1. Detailed mechanistic studies indicate that C4-CER initially induces autophosphorylation of SGK1 at Ser(422). SGK1[Ser(P)(422)] and C4-CER coincidently bind PDK1 and permit PDK1 to autophosphorylate at Ser(241). Then PDK1[Ser(P)(241)] phosphorylates SGK1[Ser(P)(422)] at Thr(256) to generate fully activated SGK1[Ser(422), Thr(P)(256)]. SGK1[Ser(P)(422),Thr(P)(256)] phosphorylates and inactivates the E3 ubiquitin ligase Nedd4-2. ΔF508-CFTR is thus free to traffic to the plasma membrane. Importantly, C4-CER-mediated activation of both PDK1 and SGK1 is independent of the PI3K/Akt/mammalian target of rapamycin signaling pathway. Physiologically, C4-CER significantly increases maturation and stability of ΔF508-CFTR (t½ ∼10 h), enhances cAMP-activated chloride secretion, and suppresses hypersecretion of interleukin-8 (IL-8). We suggest that candidate drugs for CF directed against the PDK1/SGK1 signaling pathway, such as C4-CER, provide a novel therapeutic strategy for a life-limiting disorder that affects one child, on average, each day.