A Novel System for Identification of Inhibitors of Rift Valley Fever Virus Replication

Rift Valley fever virus (RVFV) is a human and livestock pathogen endemic to sub-Saharan Africa. We have developed a T7-dependent system for the efficient production of RVFV-like particles (RVF-VLPs) based on the virulent ZH-501 strain of RVFV. The RVF-VLPs are capable of performing a single round of infection, allowing for the study of viral replication, assembly, and infectivity. We demonstrate that these RVF-VLPs are antigenically indistinguishable from authentic RVFV and respond similarly to a wide array of known and previously unknown chemical inhibitors. This system should be useful for screening for small molecule inhibitors of RVFV replication

Feminist Perspectives on Disaster, Pandemics, and Intimate Partner Violence

The COVID-19 pandemic brought international awareness to the likelihood of increased abuse of those in abusive intimate partner relationships because of the forced confinement with their abusers (Bettinger-Lopez and Bro, A double pandemic: domestic violence in the age of COVID 19, Council on Foreign Relations. https://www.cfr.org/in-brief/double-pandemic-domestic-violence-age-covid-19, 2020). While this awareness was much discussed, assistance to survivors of abuse was limited because survivors often could not reach out for help, nor could advocates wishing to offer assistance safely reach in to advise them (Taub, A new Covid-19 crisis: domestic abuse rises worldwide. https://www.nytimes.com/2020/04/06/world/coronavirus-domestic-violence.html, 2020). The ever-present influence of the abuser prevented or limited the delivery of effective aid in many cases (Taub, A new Covid-19 crisis: domestic abuse rises worldwide. https://www.nytimes.com/2020/04/06/world/coronavirus-domestic-violence.html, 2020). But this was not the first disaster to place those experiencing intimate partner abuse at greater risk. Other disasters have in various ways increased women’s safety risks both during and after crisis. Other crises routinely resulted in increased abuse of survivors in intimate partner relationships including sexual and other assault by intimate partners (Rao 2020; Sohrabizadeh Prehosp Disaster Med, 31(4):407–412. https://www.ncbi.nlm.nih.gov/pubmed/27212204, 2016). This chapter briefly identifies some forms of abuse experienced by women outside of the home during times of crisis and their connection to intimate partner abuse. Then, the impact of COVID-19 on intimate partner survivors will be explored and some of their experiences described. Gaps and flaws in nations’ approaches to gender violence are often highlighted during and after disasters. Lack of planning to protect survivors of intimate partner violence and other highly vulnerable populations during crises was exacerbated by the additional dangers brought by COVID-19. Primarily, the heightened dangers resulted from stay-at-home orders, which made services for abused partners more difficult to obtain and highlighted the possibility of unintended consequences resulting from policies designed to protect the public as a whole (Godin 2020). This chapter concludes by considering what has been lacking in strategic disaster planning, including what lessons have been learned thus far through the COVID-19 experience. Recommendations for effective disaster planning to protect survivors of intimate partner abuse, while also protecting other vulnerable populations, are suggested. This information is presented with the caution that as of this writing the global pandemic continues to limit access to hard data. Long-term analysis of the implications of the pandemic on Intimate Partner Violence (IPV) survivors awaits the passage of time

Risk factors associated with Rift Valley fever epidemics in South Africa in 2008–11

Rift Valley fever (RVF) is a zoonotic and vector-borne disease, mainly present in Africa, which represents a threat to human health, animal health and production. South Africa has experienced three major RVF epidemics (1950–51, 1973–75 and 2008–11). Due to data scarcity, no previous study has quantified risk factors associated with RVF epidemics in animals in South Africa. Using the 2008–11 epidemic datasets, a retrospective longitudinal study was conducted to identify and quantify spatial and temporal environmental factors associated with RVF incidence. Cox regressions with a Besag model to account for the spatial effects were fitted to the data. Coefficients were estimated by Bayesian inference using integrated nested Laplace approximation. An increase in vegetation density was the most important risk factor until 2010. In 2010, increased temperature was the major risk factor. In 2011, after the large 2010 epidemic wave, these associations were reversed, potentially confounded by immunity in animals, probably resulting from earlier infection and vaccination. Both vegetation density and temperature should be considered together in the development of risk management strategies. However, the crucial need for improved access to data on population at risk, animal movements and vaccine use is highlighted to improve model predictions

Infection and Transmission of Rift Valley Fever Viruses Lacking the NSs and/or NSm Genes in Mosquitoes: Potential Role for NSm in Mosquito Infection

Rift Valley fever virus is transmitted mainly by mosquitoes and causes disease in humans and animals throughout Africa and the Arabian Peninsula. The impact of disease is large in terms of human illness and mortality, and economic impact on the livestock industry. For these reasons, and because there is a risk of this virus spreading to Europe and North America, it is important to develop a vaccine that is stable, safe and effective in preventing infection. Potential vaccine viruses have been developed through deletion of two genes (NSs and NSm) affecting virus virulence. Because this virus is normally transmitted by mosquitoes we must determine the effects of the deletions in these vaccine viruses on their ability to infect and be transmitted by mosquitoes. An optimal vaccine virus would not infect or be transmitted. The viruses were tested in two mosquito species: Aedes aegypti and Culex quinquefasciatus. Deletion of the NSm gene reduced infection of Ae. aegypti mosquitoes indicating a role for the NSm protein in mosquito infection. The virus with deletion of both NSs and NSm genes was the best vaccine candidate since it did not infect Ae. aegypti and showed reduced infection and transmission rates in Cx. quinquefasciatus

West Nile Virus Risk Assessment and the Bridge Vector Paradigm

In the northeast United States, control of West Nile virus (WNV) vectors has been unfocused because of a lack of accurate knowledge about the roles different mosquitoes play in WNV transmission. We analyzed the risk posed by 10 species of mosquitoes for transmitting WNV to humans by using a novel risk-assessment measure that combines information on the abundance, infection prevalence, vector competence, and biting behavior of vectors. This analysis suggests that 2 species (Culex pipiens L. and Cx. restuans Theobald [Diptera: Cilicidae]) not previously considered important in transmitting WNV to humans may be responsible for up to 80% of human WNV infections in this region. This finding suggests that control efforts should be focused on these species which may reduce effects on nontarget wetland organisms. Our risk measure has broad applicability to other regions and diseases and can be adapted for use as a predictive tool of future human WNV infections

A hierarchical network approach for modeling Rift Valley fever epidemics with applications in North America

Rift Valley fever is a vector-borne zoonotic disease which causes high morbidity and mortality in livestock. In the event Rift Valley fever virus is introduced to the United States or other non-endemic areas, understanding the potential patterns of spread and the areas at risk based on disease vectors and hosts will be vital for developing mitigation strategies. Presented here is a general network-based mathematical model of Rift Valley fever. Given a lack of empirical data on disease vector species and their vector competence, this discrete time epidemic model uses stochastic parameters following several PERT distributions to model the dynamic interactions between hosts and likely North American mosquito vectors in dispersed geographic areas. Spatial effects and climate factors are also addressed in the model. The model is applied to a large directed asymmetric network of 3,621 nodes based on actual farms to examine a hypothetical introduction to some counties of Texas, an important ranching area in the United States of America (U.S.A.). The nodes of the networks represent livestock farms, livestock markets, and feedlots, and the links represent cattle movements and mosquito diffusion between different nodes. Cattle and mosquito (Aedes and Culex) populations are treated with different contact networks to assess virus propagation. Rift Valley fever virus spread is assessed under various initial infection conditions (infected mosquito eggs, adults or cattle). A surprising trend is fewer initial infectious organisms result in a longer delay before a larger and more prolonged outbreak. The delay is likely caused by a lack of herd immunity while the infections expands geographically before becoming an epidemic involving many dispersed farms and animals almost simultaneously

High Seroprevalence of Rift Valley Fever and Evidence for Endemic Circulation in Mbeya Region, Tanzania, in a Cross-Sectional Study

We describe a high seropositivity rate for Rift Valley fever virus, in up to 29.3% of tested individuals from the shore of Lake Malawi in southwestern Tanzania, and much lower rates from areas distant to the lake. Rift Valley fever disease or outbreaks have not been observed there in the past, which suggests that the virus is circulating under locally favorable conditions and is either a non-pathogenic strain, or that occasional occurrence of disease is missed. We were able to identify a low socio-economic status and cattle ownership as possible socio-economic risk factors for an individual to be seropositive. Environmental risk factors associated with seropositivity include dense vegetation, and ambient land surface temperatures which may be important for breeding success of the mosquitoes which transmit Rift Valley fever, and for efficient multiplication of the virus in the mosquito. Low elevation of the home, and proximity to Lake Malawi probably lead to abundant surface water collections, which serve as breeding places for mosquitoes. These findings will inform patient care in the areas close to Lake Malawi, and may help to design models which predict low-level virus circulation

The chemical basis of thiol addition to nitro-conjugated linoleic acid, a protective cell-signaling lipid

Nitroalkene fatty acids are formed in vivo and exert protective and anti-inflammatory effects via reversible Michael addition to thiol-containing proteins in key signaling pathways. Nitro-conjugated linoleic acid (NO2-CLA) is preferentially formed, constitutes the most abundant nitrated fatty acid in humans, and contains two carbons that could potentially react with thiols, modulating signaling actions and levels. In this work, we examined the reactions of NO2-CLA with low molecular weight thiols (glutathione, cysteine, homocysteine, cysteinylglycine, and β-mercaptoethanol) and human serum albumin. Reactions followed reversible biphasic kinetics, consistent with the presence of two electrophilic centers in NO2-CLA located on the β- and δ-carbons with respect to the nitro group. The differential reactivity was confirmed by computational modeling of the electronic structure. The rates (kon and koff) and equilibrium constants for both reactions were determined for different thiols. LC-UV-Visible and LC-MS analyses showed that the fast reaction corresponds to β-adduct formation (the kinetic product), while the slow reaction corresponds to the formation of the δ-adduct (the thermodynamic product). The pH dependence of the rate constants, the correlation between intrinsic reactivity and thiol pKa, and the absence of deuterium solvent kinetic isotope effects suggested stepwise mechanisms with thiolate attack on NO2-CLA as rate-controlling step. Computational modeling supported the mechanism and revealed additional features of the transition states, anionic intermediates, and final neutral products. Importantly, the detection of cysteine-δ-adducts in human urine provided evidence for the biological relevance of this reaction. Finally, human serum albumin was found to bind NO2-CLA both non-covalently and to form covalent adducts at Cys-34, suggesting potential modes for systemic distribution. These results provide new insights into the chemical basis of NO2-CLA signaling actions

Predicting Distribution of Aedes Aegypti and Culex Pipiens Complex, Potential Vectors of Rift Valley Fever Virus in Relation to Disease Epidemics in East Africa.

The East African region has experienced several Rift Valley fever (RVF) outbreaks since the 1930s. The objective of this study was to identify distributions of potential disease vectors in relation to disease epidemics. Understanding disease vector potential distributions is a major concern for disease transmission dynamics. DIVERSE ECOLOGICAL NICHE MODELLING TECHNIQUES HAVE BEEN DEVELOPED FOR THIS PURPOSE: we present a maximum entropy (Maxent) approach for estimating distributions of potential RVF vectors in un-sampled areas in East Africa. We modelled the distribution of two species of mosquitoes (Aedes aegypti and Culex pipiens complex) responsible for potential maintenance and amplification of the virus, respectively. Predicted distributions of environmentally suitable areas in East Africa were based on the presence-only occurrence data derived from our entomological study in Ngorongoro District in northern Tanzania. Our model predicted potential suitable areas with high success rates of 90.9% for A. aegypti and 91.6% for C. pipiens complex. Model performance was statistically significantly better than random for both species. Most suitable sites for the two vectors were predicted in central and northwestern Tanzania with previous disease epidemics. Other important risk areas include western Lake Victoria, northern parts of Lake Malawi, and the Rift Valley region of Kenya. Findings from this study show distributions of vectors had biological and epidemiological significance in relation to disease outbreak hotspots, and hence provide guidance for the selection of sampling areas for RVF vectors during inter-epidemic periods