PATHOGEN EMERGENCE IN THE AGE OF PANDEMICS

The emergence of novel or previously rare pathogens is not new. Throughout recorded history, catastrophic mortality has followed the arrival of new infectious diseases to areas that had no previous experience with the offending agent. The second plague pandemic, more commonly known as the Black Death, was caused by a bacterium that originated in China but then spread throughout Asia, Europe, and Africa via the Silk Road and other routes of commerce. The emergence of rinderpest in Africa, associated with Asian cattle imported by European colonists, killed millions of domestic livestock and wild animal species in the 1890s. The result was widespread starvation—reports from Tanzania alone suggest that more than 60 percent of Maasai people died—the collapse of existing economic institutions, and long-term ecological changes associated with the loss of grazing animals. Transmission of chikungunya virus and Zika virus, two pathogens that are transmitted to people by mosquitoes, have recently been documented for the first time in the Western Hemisphere. Although pathogen emergence is not new, it remains a fascinating and terrifying topic. Recent emergence events have led to a wealth of books on the subject

Spillover of SARS-CoV-2 into novel wild hosts in North America: A conceptual model for perpetuation of the pathogen

There is evidence that the current outbreak of the novel coronavirus SARS-CoV-2, which causes COVID-19, is of animal origin. As with a number of zoonotic pathogens, there is a risk of spillover into novel hosts. Here, we propose a hypothesized conceptual model that illustrates the mechanism whereby the SARS-CoV-2 could spillover from infected humans to naive wildlife hosts in North America. This proposed model is premised on transmission of SARS-CoV-2 from human feces through municipal wastewater treatment plants into the natural aquatic environment where potential wildlife hosts become infected. We use the existing literature on human coronaviruses, including SARS CoV, to support the potential pathways and mechanisms in the conceptual model. Although we focus on North America, our conceptual model could apply to other parts of the globe as well

Potential role of wildlife in the USA in the event of a foot-and-mouth disease virus incursion

Foot-and-mouth disease (FMD) is caused by foot-and-mouth disease virus (FMDV) which affects domestic and wild cloven-hoofed species. The FMD-free status of the USA and the tremendous economic impact of a virus incursion motivated the development of this evaluation of the potential role of wildlife in the event of a virus introduction. Additionally, this manuscript contains a summary of US vulnerabilities for viral incursion and persistence which focuses specifically on the possible role of wildlife. The legal movement of susceptible live animals, animal products, by-products and animal feed containing animal products pose a risk of virus introduction and spread. Additionally, the illegal movement of FMD-susceptible animals and their products and an act of bioterrorism present additional routes where FMDV could be introduced to the USA. Therefore, robust surveillance and rapid diagnostics in the face of a possible introduction are essential for detecting and controlling FMD as quickly as possible. Wildlife species and feral pigs present an added complexity in the case of FMDV introduction as they are typically not closely monitored or managed and there are significant logistical concerns pertaining to disease surveillance and control in these populations. Recommendations highlight the need to address existing knowledge gaps relative to the potential role of wildlife in FMDV introduction events

Plague risk in the western United States over seven decades of environmental change

After several pandemics over the last two millennia, the wildlife reservoirs of plague (Yersinia pestis) now persist around the world, including in the western United States. Routine surveillance in this region has generated comprehensive records of human cases and animal seroprevalence, creating a unique opportunity to test how plague reservoirs are responding to environmental change. Here, we test whether animal and human data suggest that plague reservoirs and spillover risk have shifted since 1950. To do so, we develop a new method for detecting the impact of climate change on infectious disease distributions, capable of disentangling long-term trends (signal) and interannual variation in both weather and sampling (noise). We find that plague foci are associated with high-elevation rodent communities, and soil biochemistry may play a key role in the geography of long-term persistence. In addition, we find that human cases are concentrated only in a small subset of endemic areas, and that spillover events are driven by higher rodent species richness (the amplification hypothesis) and climatic anomalies (the trophic cascade hypothesis). Using our detection model, we find that due to the changing climate, rodent communities at high elevations have become more conducive to the establishment of plague reservoirs—with suitability increasing up to 40% in some places—and that spillover risk to humans at mid-elevations has increased as well, although more gradually. These results highlight opportunities for deeper investigation of plague ecology, the value of integrative surveillance for infectious disease geography, and the need for further research into ongoing climate change impacts

An agent-based movement model to assess the impact of landscape fragmentation on disease transmission

Landscape changes can result in habitat fragmentation and reduced landscape connectivity, limiting the ability of animals to move across space and altering infectious disease dynamics in wildlife. In this study, we develop and implement an agent-based model to assess the impacts of animal movement behavior and landscape structure on disease dynamics. We model a susceptible/infective disease state system applicable to the transmission of feline immunodeficiency virus in bobcats in the urbanized landscape of coastal southern California. Our agent-based model incorporates animal movement behavior, pathogen prevalence, transmission probability, and habitat fragmentation to evaluate how these variables influence disease spread in urbanizing landscapes. We performed a sensitivity analysis by simulating the system under 4200 different combinations of model parameters and evaluating disease transmission outcomes. Our model reveals that host movement behavior and response to landscape features play a pivotal role in determining how habitat fragmentation influences disease dynamics. Importantly, interactions among habitat fragmentation and movement had non-linear and counter-intuitive effects on disease transmission. For example, the model predicts that an intermediate level of non-habitat permeability and directionality will result in the highest rates of between-patch disease transmission. Agent-based models serve as computational laboratories that provide a powerful approach for quantitatively and visually exploring the role of animal behavior and anthropogenic landscape change on contacts among agents and the spread of disease. Such questions are challenging to study empirically given that it is difficult or impossible to experimentally manipulate actual landscapes and the animals and pathogens that move through them. Modeling the relationship between habitat fragmentation, animal movement behavior, and disease spread will improve understanding of the spread of potentially destructive pathogens through wildlife populations, as well as domestic animals and humans

Bone health assessment via digital wrist tomosynthesis in the mammography setting

Bone fractures attributable to osteoporosis are a significant problem. Though preventative treatment options are available for individuals who are at risk of a fracture, a substantial number of these individuals are not identified due to lack of adherence to bone screening recommendations. The issue is further complicated as standard diagnosis of osteoporosis is based on bone mineral density (BMD) derived from dual energy x-ray absorptiometry (DXA), which, while helpful in identifying many at risk, is limited in fully predicting risk of fracture. It is reasonable to expect that bone screening would become more prevalent and efficacious if offered in coordination with digital breast tomosynthesis (DBT) exams, provided that osteoporosis can be assessed using a DBT modality. Therefore, the objective of the current study was to explore the feasibility of using digital tomosynthesis imaging in a mammography setting. To this end, we measured density, cortical thickness and microstructural properties of the wrist bone, correlated these to reference measurements from microcomputed tomography and DXA, demonstrated the application in vivo in a small group of participants, and determined the repeatability of the measurements. We found that measurements from digital wrist tomosynthesis (DWT) imaging with a DBT scanner were highly repeatable ex vivo (error = 0.05%-9.62%) and in vivo (error = 0.06%-10.2%). In ex vivo trials, DWT derived BMDs were strongly correlated with reference measurements (R = 0.841-0.980), as were cortical thickness measured at lateral and medial cortices (R = 0.991 and R = 0.959, respectively) and the majority of microstructural measures (R = 0.736-0.991). The measurements were quick and tolerated by human patients with no discomfort, and appeared to be different between young and old participants in a preliminary comparison. In conclusion, DWT is feasible in a mammography setting, and informative on bone mass, cortical thickness, and microstructural qualities that are known to deteriorate in osteoporosis. To our knowledge, this study represents the first application of DBT for imaging bone. Future clinical studies are needed to further establish the efficacy for diagnosing osteoporosis and predicting risk of fragility fracture using DWT

The views of five participating undergraduate students of the Student Associates Scheme in England

This paper reports findings from a study which explored undergraduate perceptions of the Student Associates Scheme in England (SAS). The scheme was established by the Training and Development Agency for Schools in an attempt to increase the number of graduates entering the teaching profession, particularly in shortage subjects such as the physical sciences and mathematics. The scheme places undergraduate students on short-term placements in secondary schools throughout England to provide them with experiences that may encourage them to consider teaching as a career option. Findings show that the SAS school placements were a positive experience for the students participating in this study. However, a question emerged as to whether or not the scheme is targeting students who have yet to decide upon teaching as a career or just reinforcing the existing aspirations of students who have already decided to teach. As the scheme is attempting to increase the number of teachers entering the profession this question has important implications for this study and further work which will focus on undergraduates who think that their career ambitions would not be fulfilled by teaching

Adaptive risk-based targeted surveillance for foreign animal diseases at the wildlife-livestock interface

Animal disease surveillance is an important component of the national veterinary infrastructure to protect animal agriculture and facilitates identification of foreign animal disease (FAD) introduction. Once introduced, pathogens shared among domestic and wild animals are especially challenging to manage due to the complex ecology of spillover and spillback. Thus, early identification of FAD in wildlife is critical to minimize outbreak severity and potential impacts on animal agriculture as well as potential impacts on wildlife and biodiversity. As a result, national surveillance and monitoring programs that include wildlife are becoming increasingly common. Designing surveillance systems in wildlife or, more importantly, at the interface of wildlife and domestic animals, is especially challenging because of the frequent lack of ecological and epidemiological data for wildlife species and technical challenges associated with a lack of non-invasive methodologies. To meet the increasing need for targeted FAD surveillance and to address gaps in existing wildlife surveillance systems, we developed an adaptive risk-based targeted surveillance approach that accounts for risks in source and recipient host populations. The approach is flexible, accounts for changing disease risks through time, can be scaled from local to national extents and permits the inclusion of quantitative data or when information is limited to expert opinion. We apply this adaptive risk-based surveillance framework to prioritize areas for surveillance in wild pigs in the United States with the objective of early detection of three diseases: classical swine fever, African swine fever and foot-and-mouth disease. We discuss our surveillance framework, its application to wild pigs and discuss the utility of this framework for surveillance of other host species and diseases

T-cell derived acetylcholine aids host defenses during enteric bacterial infection with Citrobacter rodentium.

The regulation of mucosal immune function is critical to host protection from enteric pathogens but is incompletely understood. The nervous system and the neurotransmitter acetylcholine play an integral part in host defense against enteric bacterial pathogens. Here we report that acetylcholine producing-T-cells, as a non-neuronal source of ACh, were recruited to the colon during infection with the mouse pathogen Citrobacter rodentium. These ChAT+ T-cells did not exclusively belong to one Th subset and were able to produce IFNγ, IL-17A and IL-22. To interrogate the possible protective effect of acetylcholine released from these cells during enteric infection, T-cells were rendered deficient in their ability to produce acetylcholine through a conditional gene knockout approach. Significantly increased C. rodentium burden was observed in the colon from conditional KO (cKO) compared to WT mice at 10 days post-infection. This increased bacterial burden in cKO mice was associated with increased expression of the cytokines IL-1β, IL-6, and TNFα, but without significant changes in T-cell and ILC associated IL-17A, IL-22, and IFNγ, or epithelial expression of antimicrobial peptides, compared to WT mice. Despite the increased expression of pro-inflammatory cytokines during C. rodentium infection, inducible nitric oxide synthase (Nos2) expression was significantly reduced in intestinal epithelial cells of ChAT T-cell cKO mice 10 days post-infection. Additionally, a cholinergic agonist enhanced IFNγ-induced Nos2 expression in intestinal epithelial cell in vitro. These findings demonstrated that acetylcholine, produced by specialized T-cells that are recruited during C. rodentium infection, are a key mediator in host-microbe interactions and mucosal defenses

Genetic dissection of EphA receptor signaling dynamics during retinotopic mapping.

Retinal ganglion cells (RGCs) project axons from their cell bodies in the eye to targets in the superior colliculus of the midbrain. The wiring of these axons to their synaptic targets creates an ordered representation, or "map," of retinal space within the brain. Many lines of experiments have demonstrated that the development of this map requires complementary gradients of EphA receptor tyrosine kinases and their ephrin-A ligands, yet basic features of EphA signaling during mapping remain to be resolved. These include the individual roles played by the multiple EphA receptors that make up the retinal EphA gradient. We have developed a set of ratiometric "relative signaling" (RS) rules that quantitatively predict how the composite low-nasal-to-high-temporal EphA gradient is translated into topographic order among RGCs. A key feature of these rules is that the component receptors of the gradient--in the mouse, EphA4, EphA5, and EphA6--must be functionally equivalent and interchangeable. To test this aspect of the model, we generated compound mutant mice in which the periodicity, slope, and receptor composition of the gradient are systematically altered with respect to the levels of EphA4, EphA5, and a closely related receptor, EphA3, that we ectopically express. Analysis of the retinotopic maps of these new mouse mutants establishes the general utility of the RS rules for predicting retinocollicular topography, and demonstrates that individual EphA gene products are approximately equivalent with respect to axon guidance and target selection.journal articleresearch support, n.i.h., extramuralresearch support, non-u.s. gov't2011 Jul 13importe