Inference of Selection Based on Temporal Genetic Differentiation in the Study of Highly Polymorphic Multigene Families

The co-evolutionary arms race between host immune genes and parasite virulence genes is known as Red Queen dynamics. Temporal fluctuations in allele frequencies, or the ‘turnover’ of alleles at immune genes, are concordant with predictions of the Red Queen hypothesis. Such observations are often taken as evidence of host-parasite co-evolution. Here, we use computer simulations of the Major Histocompatibility Complex (MHC) of guppies (Poecilia reticulata) to study the turnover rate of alleles (temporal genetic differentiation, G’ST). Temporal fluctuations in MHC allele frequencies can be $#order of magnitude larger than changes observed at neutral loci. Although such large fluctuations in the MHC are consistent with Red Queen dynamics, simulations show that other demographic and population genetic processes can account for this observation, these include: (1) overdominant selection, (2) fluctuating population size within a metapopulation, and (3) the number of novel MHC alleles introduced by immigrants when there are multiple duplicated genes. Synergy between these forces combined with migration rate and the effective population size can drive the rapid turnover in MHC alleles. We posit that rapid allelic turnover is an inherent property of highly polymorphic multigene families and that it cannot be taken as evidence of Red Queen dynamics. Furthermore, combining temporal samples in spatial FST outlier analysis may obscure the signal of selection

G-proteins: fighting infection on two fronts.

Animals have evolved multiple strategies for coping with the presence of pathogenic microbes. The best characterized is the immune response where animals activate their physical and cellular defenses to respond to invading microorganisms. However, behavioral changes can also be triggered by exposure to microbes and play an important role in defending many species, including humans, from pathogen attack. In our recent study we demonstrate that, following infection, C. elegans uses the same G-protein signaling pathway in neurons and epithelial cells to coordinate avoidance behaviors and immune responses. Coordination of these responses allows animals to mount an immune response to the immediate threat while simultaneously taking action to remove the pathogen, however, the complicated nature of the mammalian brain and immune system has made it difficult to identify the molecular mechanisms mediating these interactions. With its simple, well described, nervous system and a rapidly growing understanding of its immune system, C. elegans has emerged as an excellent model to study the mechanisms by which animals recognize pathogens and coordinate behavioral and immune responses to infection

G-proteins Fighting infection on two fronts

A nimals have evolved multiple strategies for coping with the presence of pathogenic microbes. The best characterized is the immune response where animals activate their physical and cellular defenses to respond to invading microorganisms. However, behavioral changes can also be triggered by exposure to microbes and play an important role in defending many species, including humans, from pathogen attack. In our recent study we demonstrate that, following infection, C. elegans uses the same G-protein signaling pathway in neurons and epithelial cells to coordinate avoidance behaviors and immune responses. Coordination of these responses allows animals to mount an immune response to the immediate threat while simultaneously taking action to remove the pathogen, however, the complicated nature of the mammalian brain and immune system has made it difficult to identify the molecular mechanisms mediating these interactions. With its simple, well described, nervous system and a rapidly growing understanding of its immune system, C. elegans has emerged as an excellent model to study the mechanisms by which animals recognize pathogens and coordinate behavioral and immune responses to infection. G Protein Signaling is Required for Pathogen Avoidance In its natural environment the C. elegans nervous system is constantly sensing and responding to attractive and aversive signals by altering its locomotion. Work from several labs has defined a networ

Rho deep in thought.

Neuronal communication underlies all aspects of brain function, including learning, memory, and consciousness. How neurons communicate is controlled by both the formation of neuronal connections during neural development and the regulation of neuronal activity in the adult brain. Rho GTPases have a well-known role in neuronal development, and recent studies published in Genes & Development (Steven et al. 2005; McMullan et al. 2006) have demonstrated that they also regulate neuronal activity in the adult brain—at least in Caenorhabditis elegans. Rho in C. elegans acts as part of a network of Gαq pathways that increase neuronal activity by regulating both production and destruction of the second messenger diacylglycerol (DAG), which is a regulator of synaptic vesicle release. In this issue of Genes & Development, Williams et al. (2007) demonstrate that Gαq acts via the UNC-73RhoGEF to increase Rho activity in neurons, and thus increase levels of DAG. The targets of DAG are known and, in one case, a pathway stretching from binding of ligand on the cell surface to changes in synaptic vesicle priming has been mapped out

Neuronal and non-neuronal signals regulate <i>Caernorhabditis elegans</i> avoidance of contaminated food

One way in which animals minimise the risk of infection is to reduce their contact with contaminated food. Here we establish a model of pathogen-contaminated food avoidance using the nematode worm Caernorhabditis elegans. We find that avoidance of pathogen-contaminated food protects C. elegans from the deleterious effects of infection and, using genetic approaches, demonstrate that multiple sensory neurons are required for this avoidance behaviour. In addition, our results reveal that avoidance of contaminated food requires bacterial adherence to non-neuronal cells in the tail of C. elegans that are also required for the cellular immune response. Previous studies in C. elegans have contributed significantly to our understanding of molecular and cellular basis of host-pathogen interactions and our model provides a unique opportunity to gain basic insights into how animals avoid contaminated food

The Pseudomonas aeruginosa Reference Strain PA14 Displays Increased Virulence Due to a Mutation in ladS

Pseudomonas aeruginosa is a pathogen that causes acute and chronic infections in a variety of hosts. The pathogenic potential of P. aeruginosa is strain-dependent. PA14 is a highly virulent strain that causes disease in a wide range of organisms, whereas PAO1 is moderately virulent. Although PA14 carries pathogenicity islands that are absent in PAO1, the presence or absence of specific gene clusters is not predictive of virulence. Here, we show that the virulent strain PA14 has an acquired mutation in the ladS gene. This mutation has a deleterious impact on biofilm, while it results in elevated type III secretion system (T3SS) activity and increased cytotoxicity towards mammalian cells. These phenotypes can be reverted by repairing the ladS mutation on the PA14 genome. The RetS/LadS/GacS signaling cascade is associated with virulence and the switch between acute and chronic infections. RetS is a sensor that down-regulates biofilm formation and up-regulates the T3SS. Mutations in retS are acquired in strains isolated from chronically infected cystic fibrosis patients and lead to hyperbiofilm formation and reduced cytotoxicity. Conversely, the LadS sensor promotes biofilm formation and represses the T3SS. We conclude that the ladS mutation is partly responsible for the high cytotoxicity of PA14, and our findings corroborate the central role of RetS and LadS in the switch between acute and chronic infections. Given the extensive use of the reference strain PA14 in infection and virulence models, the bias caused by the ladS mutation on the observed phenotypes will be crucial to consider in future research

Adverse Response to Exercise: Mouse Model Development

Obesity is extremely prevalent in the U.S., associated with numerous chronic diseases and an economic burden on the health care system. Exercise results in beneficial health outcomes, protects against a variety of chronic diseases and can reduce body mass and fat. U.S. exercise guidelines recommend identical exercise programs for everyone regardless of age, sex or genetic background. Furthermore, individual variation in responses to recommend exercise programs occurs across a variety of responses with some individuals experiencing adverse responses, including fat gain. In order to establish effective exercise guidelines, dissection of underlying physiological mechanisms and driving factors as well as the evaluation of potential interventions needs to occur. Experimental mouse models of exercise-induced adverse outcomes will be valuable in identification of mechanisms and evaluation of interventions while overcoming limitations in human studies. Several studies have identified individual mice exhibiting adverse fat gain following exercise, but no systematic effort has been conducted to identify and characterize models of adverse response. Strains from the Collaborative Cross (CC) genetic reference population were used due to its high levels of genetic variation, its reproducible nature, and the observation that the CC is a rich source of novel disease models, to assess the impact genetic background has on exercise responses. This thesis work aimed to identify and develop mouse models of exercise-induced adverse body composition response and to determine the effect of different factors, including age, sex, exercise program and genetic background, on body composition response. In an initial study, we assessed body composition responses to voluntary exercise in aged females from 42 CC strains. We observed significant variation in body composition responses due to genetic background. Some strains, in particular CC027/GeniUnc, had an adverse body composition response. An additional study identified CC002/Unc as a model of voluntary exercise-induced adverse body composition response in old females. Unlike the initial screen, this study took advantage of age matched females with a case – control experimental design to account for body composition changes due to aging. Additionally, we measured body composition and metabolic responses to different forced exercise programs (HIIT and MICT) in a subset of four CC strains. We found body composition responses to different exercise programs varied by sex and further by genetic background. Overall, females had more beneficial body composition responses to HIIT than MICT programs. Across these studies we have demonstrated that genetic background has a significant effect on responses to exercise and further genetic background interacts with other factors to influence these responses. Additionally, we evaluated body composition and metabolism responses to long-term exercise during aging in C57BL/6J mice. We observed body mass and composition response trajectories to long-term exercise vary dependent on sex. Overall, exercise was protective against age related changes in body mass and composition. This work provides novel models for studies to determine the mechanisms behind adverse metabolic responses to exercise and enables development of more rational personalized exercise recommendations based on factors such as age, sex, and genetic background.Doctor of Philosoph

The effect of the COVID-19 pandemic on disgust sensitivity in a sample of UK adults

The COVID-19 pandemic led to the introduction of a range of infection prevention and control (IPC) measures that resulted in dramatic changes in people’s lives however these IPC measures are not practiced consistently across the population. One predictor of an individual’s responses to the pandemic is disgust sensitivity. Understanding how disgust sensitivity varies within the population could help to inform design of public health messages to promote more uniform behavioral change during future pandemics. To understand the effect of the current COVID-19 pandemic on an individual’s pathogen disgust sensitivity we have compared pathogen disgust sensitivity during the current COVID-19 pandemic to baseline pathogen disgust sensitivity, determined prior to the COVID-19 pandemic, in the same sample of UK adults. We find that the COVID-19 pandemic did not alter overall pathogen disgust sensitivity suggesting that disgust sensitivity is stable despite IPC measures, public health messaging, media coverage and other factors associated with the COVID-19 pandemic

Tackling Antimicrobial Resistance through Professional Learning: The Development and Evaluation of the Global AMR Curriculum

Antimicrobial resistance (AMR) is recognised as one of the most serious global threats to human health in the twenty-first century. AMR is defined as the ability of a microorganism (bacteria, viruses, parasites) to stop an antimicrobial (an antibiotic, antiviral or antimalarial) from working against it (WHO 2020a). Without effective antibiotics, routine medical procedures will be less safe in the future and even minor infections will no longer be treatable. The effects of AMR are predicted to be more acute in resource-limited settings such as in low-to-middle income countries (LMICs) (Seale et al., 2017). However, no country can view itself in isolation and addressing this serious threat to public health is a global priority that requires collective action across all countries (WHO, 2015). In response to this global threat, the UK Government has established the Fleming Fund that plays a critical role in achieving the resolution of the 68th World Health Assembly, 2015 (WHA A68/20), and in realising the ‘Political Declaration of the High-Level Meeting of the United Nations General Assembly (UNGA) on Antimicrobial Resistance, 2016’. The work detailed in this report contributes to the Fleming Fund programme led by the Department of Health and Social Care (DHSC), specifically the objective overseen by Mott MacDonald to improve capacity in AMR surveillance in LMICs. This work is aligned with the World Health Organization’s Global AMR Surveillance System (GLASS), which acts as the blueprint for a multi-stakeholder global response to averting a global health crisis caused by AMR (http://www.who.int/antimicrobial-resistance/global-action-plan/en/). The Open University is the Global Learning Partner of the Fleming Fund Management Agent, Mott MacDonald. The OU has been commissioned to develop and implement a Global AMR Curriculum that will help a range of stakeholders in all twenty-four Fleming Fund participating countries increase their knowledge, skills and understanding of AMR. As defined by the grant agreement between the Open University (OU) and Mott MacDonald, the Grant 2 (February 2020 – September 2021) supported the OU to design, deliver and evaluate a Global AMR curriculum as well as support the development of contextualised learning in two Fleming Fund countries: Nepal and Ghana. It draws on the OU expertise in the use of online and digital technology and the utilisation of different pedagogic approaches. Grant 2 builds on evidence generated in an earlier grant the OU had (Grant 1, April 2018 – September 2019) that involved the design and delivery of two pilot learning events in three LMICs (Bhutan, Tanzania and Ghana). In this report, we draw on the evidence from Grant 2 to inform how human and animal health professionals and policy makers in different countries and work settings made use of information related to AMR and were supported in changing their work practices