“Resistance in the Wild: Understanding Where, When and Why Organisms Persist in the Wild” Seed Grant (2017): PIs are Siddhartha Thakur, Rob Dunn, and Matthew Koci, North Carolina State University. Despite major improvements in hygiene, quality of food and water, and advanced methods to detect antimicrobial resistant pathogens, these agents continue to pose a tremendous burden by them on public health agencies. By 2050, death due to infection by such resistant bacteria is predicted to be more common than due to cancer. In the standard telling, the problem of antibiotic resistance has simple causes. Doctors have overprescribed antibiotics for problems for which they are not suitable and farmers have overused antibiotics in animal feed in such a way as to both favor the origin of resistance and permit its maintenance. In this telling, the way forward to a world in which our antibiotics remain useful requires us “simply” to more sensibly manage the use of antibiotics. Of course, there is nothing simple about achieving such a goal, but at least in theory it seems conceptually possible and, in fact, some countries have both reduced use of antibiotics and, in doing so, reduced the prevalence of resistant bacteria in some settings, such as hospitals. A key component of this narrative is the idea that the plasmids that encode resistance are costly for bacteria to maintain. In the absence of antibiotics, those plasmids should become more rare (and the bacteria that have them, disadvantaged). Yet, one set of observations seems at odds with this narrative. Namely, resistant bacteria have, increasingly, been found in natural environments far from anthropogenic selective pressures that might favor their persistence. These anecdotes are now numerous and present a serious challenge to our understanding of antibiotic resistance. We seek to explore the possibility that some conditions in nature also favor the persistence of antibiotic resistance. Such conditions might both be important to understanding how to mitigate antibiotic resistance and useful for prediction the location of novel antibiotics.
“Genetic, demographic, and disease vector interactions with apocrine microbiota” Seed Grant (2017): PIs are Julie Horvath and Reade Roberts, North Carolina Central University/NC Museum of Natural Sciences, North Carolina State University. Diverse communities of microscopic organisms (microbiota) live in and on the human body. The skin microbiota aid in skin barrier function and help our immune system mature, as well as produce odor by metabolizing sweat and other secretions produced by our bodies. Some compounds produced by skin microbiota may influence variation in attractiveness to mosquitoes and other disease vectors. Modern high throughput sequencing technology allows thorough sampling of the diversity of the skin microbiota by using their DNA sequence to identify specific microbes. The proposed work will reveal differences in microbiota by body site, comparing samples from areas with (ear, underarm, eye) and without (face, ankle) apocrine sweat glands. This work will also identify differences in microbiota associated with differences in host genes, specifically variants of the ABCC11 gene known to impact apocrine sweat gland biology, with impacts on consistency of earwax and degree of body odor. Sampling of populations in both the United States and rural Madagascar will allow correlation of microbiota composition and cultural differences. Finally, underarm swabs will be used in mosquito attractiveness tests to determine if microbiota differences associated with host genetics or culture impact attractiveness to common insect disease vectors.
“Population genomics and geospatial analytics to track the origins, evolution, and emergence of Phytophthora infestans” Seed Grant (2016): PIs are Jean Ristaino, Hanelle Lindqvist-Krueze, Michael Martin, and Laura Tateosian, North Carolina State University, North Carolina Museum of Natural Sciences, and North Carolina Wildlife Resources Commission. Late blight of potato and tomato caused by Phytophthora infestans is a devastating disease worldwide and led to the Irish potato famine in 1845. Under favorable weather conditions, tomato and potato crops can be destroyed within days. Yield losses caused by late blight and the cost of control measures have been estimated to exceed 6.7 billion dollars annually and the disease is a major threat to food security worldwide. In this project we plan to examine the genetic diversity of the pathogen at the center of origin of the potato host in the Andean region of Peru and determine whether host biodiversity has impacted the evolution of the pathogen.
“Stability of colitis-associated adaptations in resident intestinal bacteria” Seed Grant (2016): PIs are Jonathan Hansen and Todd Vision, UNC-Chapel Hill. Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, are chronic and often progressive disorders that afflict about 5 in 1000 people and for which there is no medical cure. Normal intestinal bacteria are thought to play a role in the development and progression of IBDs, but how this occurs is poorly understood. We believe that the environment of the inflamed intestine causes the bacteria to change/evolve to a more “aggressive” state that contributes to worsening disease and treatment failure. To test this, we will compare genetic mutations and IBD-causing-capacity of intestinal bacteria from mouse models of IBD with those of bacteria from healthy mice. We will also determine how long the IBD-associated changes in bacteria persist when the bacteria are transferred to a healthy intestine. These studies will help us understand how normal intestinal bacteria contribute to the chronic, progressive nature of IBDs and may identify new pathways that could be targeted for therapeutic purposes.
“The Role of Pleiotropy in De Novo Evolution of Silver Resistance” Seed Grant (2016): PIs are Joseph Graves, Dennis LaJuenesse, Ram Mohan, Scott Harrison, and Mehrdad Tajkarimi, North Carolina A&T State University. Silver nanoparticles have been proposed as the new “miracle drug” against multidrug resistant bacteria. Unfortunately, we have recently found that bacteria handle silver just as well as they handle traditional antibiotics. This research project will attempt to help us better understand why and how bacteria can do this. Gaining this knowledge will aid us in developing more sustainable treatments for multidrug resistant bacteria.
“Prevalence and Zoonotic Potential of Emerging Tick-borne Pathogens in Madagascar” Seed Grant (2016): PIs are Barbara Qurollo, Peter Larsen, Kathy Williams, and Ed Breitschwerdt, North Carolina State University. Tick-borne diseases that negatively impact human health, such as Lyme disease and tick-borne encephalitis,are becoming more common. The pathogens that cause these diseases circulate in a number of host species that include wildlife, domesticated animals, and humans. In order to minimize tick-borne disease spread in communities where animals and people live in close proximity, it is critical to characterize newly identified tick-borne diseases. This includes identifying the variety of animals infected by tick-borne parasite sand ecological changes that could affect infection rates. Members of our team have discovered new tick-borne parasites in Madagascar that may cause disease in wildlife, domesticated animals, and/or humans. We propose to build upon this discovery by 1) determining the prevalence of newly discovered tick-borne parasites and tick species feeding on wild primates (lemurs) in both areas of forest that have been undisturbed and disturbed by local nickel mining in eastern Madagascar and 2) identifying the zoonotic potential of these parasites in domestic animals and the genetic similarities between strains previously identified in lemurs. The outcome of this study will illustrate how human-disturbed forests influence prevalence of tick-borne parasites and tick species, and inform medical professionals and veterinarians in Madagascar of new tick-borne diseases in their community, addressing the potential for zoonotic transmission and disease in humans.
“Finding the next antibiotics: Putting evolutionary theory into practice” Seed Grant (2016): PIs are Adrian Smith, Clint Penick, Stephanie Mathews, and Margarita Lopez-Uribe, North Carolina Museum of Natural Sciences and North Carolina State University. The first antibiotic was discovered by famous accident when Alexander Fleming observed a zone of bacterial inhibition around a culture of Penicillium notatum, the source of penicillin. Since that time, the search for new antibiotics has relied on similar, though industrialized methods to screen for species that produce antibiotic compounds. This approach requires screening large numbers of species, most of which are unlikely to yield effective antibiotics. Instead, we propose a more targeted approach focused on social insects. By living in densely populated groups, social insects have been dealt with pathogen challenges similar to humans during their 150 million year evolution and offer insights into pathogen control and new antimicrobials. This proposal is for developing an antimicrobial assay to compare antimicrobial strength among social insect species. We will test multiple ant species to determine what ecological and evolutionary traits (i.e. evolutionary history, nesting biology, and life history) are drivers of novel antimicrobial evolution.This approach will target future research in discovery of new antibiotics as well as mechanisms for selection of antimicrobial production in social insects.
Biodiversity, Conservation, and Human Health Catalysis Meeting (May 4-6, 2015): Organizers are Charles Nunn, Hillary Young, Gavin Smith and Jeffrey Vincent. The goal of the meeting is to understand how changes in biodiversity impact infectious disease risk in humans and wildlife. Remarkably little effort has synthesized either theory or data on the efficacy of biodiversity and conservation practices as a disease management strategy, the effects of different anthropogenic changes on infectious disease risk in the tropics, or the impacts of different conservation strategies on human health. We will take a broad view on this important issue by examining the many potential links between changes in biodiversity and infectious disease risk, and by considering the diversity of ways to investigate these questions using empirical and theoretical approaches. We will also engage with the conflicting views that natural systems appear to buffer some disease risks, yet they can also serve as the source of new infectious diseases.
- Ecological Immunology Applied to Vector Biology and Vector-Borne Disease Catalysis Meeting (August 2015): Organizers are Lyric Bartholomay and Brian Lazzaro. Diseases vectored by insects and other arthropods impose tremendous public health burden on human populations. In the course of transmission, the vector is itself also infected by the pathogen, so factors that alter immunological status of the vector no doubt shape disease transmission. The proposed Catalysis Meeting would bring principles established in the ecological immunology of wildlife systems to bear on vector biological systems. These principles include the premise that immune function and evolution is constrained by competing physiological demands on the host, and that environmental conditions impact immunological and physiological state in ways that modulate pathogen establishment and transmission. The meeting will specifically focus on the role of genetic variability in the vector. Of particular interest is understanding how genetic matches and mismatches between host and parasite predict disease infection outcome, how abiotic environmental conditions including pesticide applications can alter genetically-determined host susceptibility to infection, and the role that secondary infections and associations with commensals play in altering immunological status. Investigators at all career stages will be invited to participate in the Catalysis Meeting, with the ultimate objectives of producing a synthetic and coherent road map for future study and establishing a research network that has the capacity to address the most pressing questions.
- Forgotten Memories: immune memory beyond the adaptive immune system Catalysis Meeting (June 1-3, 2015): Organizers are Seth Michael Barribeau, David Schneider, Ann Tate, and Benjamin Sadd. With consequences for disease severity, resistance or clearance of a pathogen infection by an individual can be enhanced by a previous exposure to that pathogen, occurring either within an individual or even in its parents. This form of immune memory, traditionally thought the province of the vertebrate adaptive immune response, can also arise from innate immune pathways of vertebrates and invertebrates, and through distinct pathways in plants and bacteria. Researchers studying this phenomenon rarely interact across taxonomic boundaries, however, and use a preponderance of disparate terms to describe this innate immune mediated memory, including immune memory, immune priming, trained immunity, and systemic acquired resistance. This catalysis meeting will facilitate a synthesis of disparate researchers to better understand commonalities among these different forms of innate immune memory and key consequences for disease. They will use this opportunity to produce a broad interest synthesis manuscript elaborating upon specific avenues by which an improved understanding of innate immune memory will inspire future research, with direct and indirect benefits for human health. First, better understanding of how vertebrate immune memory works in retaining specific memory stands to improve vaccine design and delivery. Second, the specificity of immune memory could be manipulated to leave harmful pests, vectors, and human parasites susceptible to pathogen mediated biocontrol, while improving the health of beneficial organisms such as agricultural plants, animals, and pollinators that ensure human food security. Their approach aims to identify model systems functionally analogous to human innate immune memory that maximize our flexibility to interrogate the genetics, constraints, and functional manipulations of innate immune memory. Finally, this synthesis will elucidate fundamental concepts underlying host-pathogen evolution and the limits of immunological plasticity.
- Emerging human-mediated pathogens in North Carolina amphibians and reptiles (2016): Organizers are Bryan Stuart, Brenna Forrester, Thomas Lentz, Daniel Dembrowski, Lori Williams, and Julie Horvath. Newly discovered pathogens (three fungal, one viral) that cause disease have been implicated in declines of wild populations of amphibians and reptiles around the world. Humans are spreading these pathogens through commerce of live amphibians and
reptiles for pets, food, medicine and research, as well as through changes to the environment. The presence and negative impacts of these pathogens are unknown or poorly understand in NC, a state that harbors a very high diversity of amphibians and reptiles, especially salamanders. This project will test wild and captive amphibians and reptiles, especially declining native species, across the state for the presence of these four pathogens. The results will be used as a baseline for research on where these pathogens originated, how they spread, and the consequences of their infection in wild amphibians and reptiles in NC.
- A “One Health” approach to antibiotic-resistant Enterobateriaceae in South Asia (2016): Organizers are L. Gayani Tillekeratne and Siddhartha Thakur. Infections due to antibiotic-resistant gram-negative bacteria are becoming increasingly prevalent worldwide. In certain regions such as South Asia, a high proportion of otherwise healthy persons carry antibiotic-resistant gram-negative bacteria in their gastrointestinal tracts. Since asymptomatic carriage is a precursor to infection, understanding the mechanisms by which antibiotic resistance has developed in these organisms may help identify targets for infection prevention. In this proposal, infectious diseases physicians, veterinarians, molecular epidemiologists, and phylogeneticists will team up under the “One Health” umbrella to determine the prevalence and transmission of antibiotic-resistance-encoding β-lactamases in a South Asian population. Identification of genetic relationships between β-lactamases may provide insight into the transmission of resistance between mothers,neonates, and their environments. The overall goal of this work is to identify intervention points that could be leveraged to prevent acquisition of antibiotic-resistant organisms and their resistance-encoding genes.
- The use of pathogen genetic data for informing the spread of infectious diseases within and between individuals (November 2015): Organizers are Steve Meshnick, Katia Koelle, Jeff Thorne, and Corbin Jones. A variety of epidemiological approaches are currently being used to track infectious disease outbreaks and identify pathways by which pathogens spread at the level of the host population. With advances in sequencing technologies, pathogen genetic data have become increasingly available over the years. While epidemiologists, virologists, and other infectious disease researchers are increasingly considering pathogen sequence data to address the fundamental questions of concern to them, it is clear from published studies that the quantitative interpretation of pathogen phylogenies and calculated population genetic metrics by a subset of these researchers can still be considerably improved. Evolutionary biologists, on the other hand, are often naïve in their understanding of epidemiological issues such as selection bias and confounding, while having a firm grasp on the interpretation of genetic data. Thus, the purpose of this meeting is to bring together experts in infectious disease with experts in phylogenetics/population genetics across the Triangle. The primary aim is for both sets of researchers to develop a more in-depth appreciation of the complexities and issues surrounding the use of pathogen genetic data in infectious disease research.
- Ecology and Evolution of the Human Microbiome in Health and Disease (March 2015): A talk by Dr. Rob Knight, Professor in the Department of Pediatrics and the Department of Computer Science at the University of California San Diego.
- “You Are Where You Live” – Influence of Environment Exposures on the Gut Microbiome and Allergic Asthma (April 2015): A talk by Dr. Susan Lynch, Associate Professor of Medicine and Director of the Coltis and Crohn’s Disease Microbiome Research Core at the University of California San Francisco.
- Scary Viruses, Killer Tapeworms, and Nostril Ticks: Unanticipated Adventures in One Health (November 2015): A talk by Dr. Tony Goldberg, John D. MacArthur Chair, Professor of Epidemiology, Department of Pathobiological Sciences, School of Veterinary Medicine and Associate Director for Research, UW-Madison Global Health Institute.