Rabies management structures and challenges in the North in a One Health framework.

Rabies is often described as the quintessential One Health problem, linking especially animal health to human health. I examined how rabies is managed in the circumpolar North through semi-structured interviews of key informants in three cases: Alaska, Northwest Territories, and Svalbard. While rabies is controlled at the territorial or state level in the Northwest Territories and Alaska, respectively, the perception of where authority lies in rabies management is less evident in Norway concerning Svalbard than in the other two cases. Respondents generally characterised the working relationship between sectors and scales of governments as positive. However, coordination remains one of the main challenges to rabies management, with harsh environmental conditions and small remote communities adding additional challenges in all three cases. Rabies managers in Svalbard also face unique conditions, such as risks associated with hunting and the particular administrative structure of Svalbard. Due to limited veterinary services in dispersed small and remote communities, dogs present challenges to rabies management in Alaska and the Northwest Territories. Personal relationships are important in disease management across agencies, and the unique challenges in the far North will likely pose challenges in adopting approaches to disease management from temperate climates.

SARS-CoV-2 spike ectodomain targets α7 nicotinic acetylcholine receptors.

Virus entry into animal cells is initiated by attachment to target macromolecules located on host cells. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) trimeric spike glycoprotein targets host angiotensin converting enzyme 2 to gain cellular access. The SARS-CoV-2 glycoprotein contains a neurotoxin-like region that has sequence similarities to the rabies virus and the HIV glycoproteins, as well as to snake neurotoxins, which interact with nicotinic acetylcholine receptor (nAChR) subtypes via this region. Using a peptide of the neurotoxin-like region of SARS-CoV-2 (SARS-CoV-2 glycoprotein peptide [SCoV2P]), we identified that this area moderately inhibits α3ß2, α3ß4, and α4ß2 subtypes, while potentiating and inhibiting α7 nAChRs. These nAChR subtypes are found in target tissues including the nose, lung, central nervous system, and immune cells. Importantly, SCoV2P potentiates and inhibits ACh-induced α7 nAChR responses by an allosteric mechanism, with nicotine enhancing these effects. Live-cell confocal microscopy was used to confirm that SCoV2P interacts with α7 nAChRs in transfected neuronal-like N2a and human embryonic kidney 293 cells. The SARS-CoV-2 ectodomain functionally potentiates and inhibits the α7 subtype with nanomolar potency. Our functional findings identify that the α7 nAChR is a target for the SARS-CoV-2 glycoprotein, providing a new aspect to our understanding of SARS-CoV-2 and host cell interactions, in addition to disease pathogenesis.

Enhancing grant-writing expertise in BUILD institutions: Building infrastructure leading to diversity.

BACKGROUND: The lack of race/ethnic and gender diversity in grants funded by the National Institutes of Health (NIH) is a persistent challenge related to career advancement and the quality and relevance of health research. We describe pilot programs at nine institutions supported by the NIH-sponsored Building Infrastructure Leading to Diversity (BUILD) program aimed at increasing diversity in biomedical research. METHODS: We collected data from the 2016-2017 Higher Education Research Institute survey of faculty and NIH progress reports for the first four years of the program (2015-2018). We then conducted descriptive analyses of data from the nine BUILD institutions that had collected data and evaluated which activities were associated with research productivity. We used Poisson regression and rate ratios of the numbers of BUILD pilots funded, students included, abstracts, presentations, publications, and submitted and funded grant proposals. RESULTS: Teaching workshops were associated with more abstracts (RR 4.04, 95% CI 2.21-8.09). Workshops on grant writing were associated with more publications (RR 2.64, 95% CI 1.64-4.34) and marginally with marginally more presentations. Incentives to develop courses were associated with more abstracts published (RR 4.33, 95% CI 2.56-7.75). Workshops on research skills and other incentives were not associated with any positive effects. CONCLUSIONS: Pilot interventions show promise in supporting diversity in NIH-level research. Longitudinal modeling that considers time lags in career development in moving from project development to grants submissions can provide more direction for future diversity pilot interventions.

Interactions between the rabies virus and nicotinic acetylcholine receptors: A potential role in rabies virus induced behavior modifications.

Rabies causes approximately 60,000 casualties annually and has a case fatality rate approaching 100% once clinical signs occur. The glycoprotein on the surface of the virion is important for the host immune response and facilitates interaction of the virion with host cell receptors. Nicotinic acetylcholine receptors were the first receptors identified as a molecular target for the rabies virus. Additional targets, including neural cell adhesion molecule, p75 neurotrophin receptor, metabotropic glutamate receptor subtype 2, and integrin ß1, have been added to the list, all of which can mediate viral entry into the cell. Multiple receptors and different subtypes of nicotinic acetylcholine receptors result in a complex picture of virus-receptor interactions. In addition, some data suggest that the rabies virus glycoprotein inhibits cell signaling events mediated by various nicotinic receptor subtypes that have been implicated in altering behavior in unaffected animals. This review focuses on interactions between the rabies virus glycoprotein and nicotinic receptors and proposes possible functional consequences, including behavioral modifications and therapeutic approaches for future research.

Genetic structure of immunologically associated candidate genes suggests arctic rabies variants exert differential selection in arctic fox populations.

Patterns of local adaptation can emerge in response to the selective pressures diseases exert on host populations as reflected in increased frequencies of respective, advantageous genotypes. Elucidating patterns of local adaptation enhance our understanding of mechanisms of disease spread and the capacity for species to adapt in context of rapidly changing environments such as the Arctic. Arctic rabies is a lethal disease that largely persists in northern climates and overlaps with the distribution of its natural host, arctic fox. Arctic fox populations display little neutral genetic structure across their North American range, whereas phylogenetically unique arctic rabies variants are restricted in their geographic distributions. It remains unknown if arctic rabies variants impose differential selection upon host populations, nor what role different rabies variants play in the maintenance and spread of this disease. Using a targeted, genotyping-by-sequencing assay, we assessed correlations of arctic fox immunogenetic variation with arctic rabies variants to gain further insight into the epidemiology of this disease. Corroborating past research, we found no neutral genetic structure between sampled regions, but did find moderate immunogenetic structuring between foxes predominated by different arctic rabies variants. FST outliers associated with host immunogenetic structure included SNPs within interleukin and Toll-like receptor coding regions (IL12B, IL5, TLR3 and NFKB1); genes known to mediate host responses to rabies. While these data do not necessarily reflect causation, nor a direct link to arctic rabies, the contrasting genetic structure of immunologically associated candidate genes with neutral loci is suggestive of differential selection and patterns of local adaptation in this system. These data are somewhat unexpected given the long-lived nature and dispersal capacities of arctic fox; traits expected to undermine local adaptation. Overall, these data contribute to our understanding of the co-evolutionary relationships between arctic rabies and their primary host and provide data relevant to the management of this disease.

Implications of Zoonoses From Hunting and Use of Wildlife in North American Arctic and Boreal Biomes: Pandemic Potential, Monitoring, and Mitigation.

The COVID-19 pandemic has re-focused attention on mechanisms that lead to zoonotic disease spillover and spread. Commercial wildlife trade, and associated markets, are recognized mechanisms for zoonotic disease emergence, resulting in a growing global conversation around reducing human disease risks from spillover associated with hunting, trade, and consumption of wild animals. These discussions are especially relevant to people who rely on harvesting wildlife to meet nutritional, and cultural needs, including those in Arctic and boreal regions. Global policies around wildlife use and trade can impact food sovereignty and security, especially of Indigenous Peoples. We reviewed known zoonotic pathogens and current risks of transmission from wildlife (including fish) to humans in North American Arctic and boreal biomes, and evaluated the epidemic and pandemic potential of these zoonoses. We discuss future concerns, and consider monitoring and mitigation measures in these changing socio-ecological systems. While multiple zoonotic pathogens circulate in these systems, risks to humans are mostly limited to individual illness or local community outbreaks. These regions are relatively remote, subject to very cold temperatures, have relatively low wildlife, domestic animal, and pathogen diversity, and in many cases low density, including of humans. Hence, favorable conditions for emergence of novel diseases or major amplification of a spillover event are currently not present. The greatest risk to northern communities from pathogens of pandemic potential is via introduction with humans visiting from other areas. However, Arctic and boreal ecosystems are undergoing rapid changes through climate warming, habitat encroachment, and development; all of which can change host and pathogen relationships, thereby affecting the probability of the emergence of new (and re-emergence of old) zoonoses. Indigenous leadership and engagement in disease monitoring, prevention and response, is vital from the outset, and would increase the success of such efforts, as well as ensure the protection of Indigenous rights as outlined in the United Nations Declaration on the Rights of Indigenous Peoples. Partnering with northern communities and including Indigenous Knowledge Systems would improve the timeliness, and likelihood, of detecting emerging zoonotic risks, and contextualize risk assessments to the unique human-wildlife relationships present in northern biomes.

The ecological niche of reported rabies cases in Canada is similar to Alaska.

The ecology of rabies in the circumpolar North is still not well understood. We use machine learning, a geographic information system and data explicit in time and space obtained for reported rabies cases and predictors in Canada to develop an ecological niche model for the distribution of reported rabies cases in the American north (Alaska and Canada). The ecological niche model based on reported rabies cases in Canada predicted reported rabies cases in Alaska, suggesting a rather robust inference and even similar drivers on a continental scale. As found in Alaska, proximity to human infrastructure-specifically along the coast-was a strong predictor in the detection of rabies cases in Canada. Also, this finding highlights the need for a more systematic landscape sampling for rabies infection model predictions to better understand and tackle the ecology of this important zoonotic disease on a landscape scale at some distance from human infrastructure in wilderness areas.

The role of a mechanistic host in maintaining arctic rabies variant distributions: Assessment of functional genetic diversity in Alaskan red fox (Vulpes vulpes).

Populations are exposed to different types and strains of pathogens across heterogeneous landscapes, where local interactions between host and pathogen may present reciprocal selective forces leading to correlated patterns of spatial genetic structure. Understanding these coevolutionary patterns provides insight into mechanisms of disease spread and maintenance. Arctic rabies (AR) is a lethal disease with viral variants that occupy distinct geographic distributions across North America and Europe. Red fox (Vulpes vulpes) are a highly susceptible AR host, whose range overlaps both geographically distinct AR strains and regions where AR is absent. It is unclear if genetic structure exists among red fox populations relative to the presence/absence of AR or the spatial distribution of AR variants. Acquiring these data may enhance our understanding of the role of red fox in AR maintenance/spread and inform disease control strategies. Using a genotyping-by-sequencing assay targeting 116 genomic regions of immunogenetic relevance, we screened for sequence variation among red fox populations from Alaska and an outgroup from Ontario, including areas with different AR variants, and regions where the disease was absent. Presumed neutral SNP data from the assay found negligible levels of neutral genetic structure among Alaskan populations. The immunogenetically-associated data identified 30 outlier SNPs supporting weak to moderate genetic structure between regions with and without AR in Alaska. The outliers included SNPs with the potential to cause missense mutations within several toll-like receptor genes that have been associated with AR outcome. In contrast, there was a lack of genetic structure between regions with different AR variants. Combined, we interpret these data to suggest red fox populations respond differently to the presence of AR, but not AR variants. This research increases our understanding of AR dynamics in the Arctic, where host/disease patterns are undergoing flux in a rapidly changing Arctic landscape, including the continued northward expansion of red fox into regions previously predominated by the arctic fox (Vulpes lagopus).

Baseline Characteristics of the 2015-2019 First Year Student Cohorts of the NIH Building Infrastructure Leading to Diversity (BUILD) Program.

Objective: The biomedical/behavioral sciences lag in the recruitment and advancement of students from historically underrepresented backgrounds. In 2014 the NIH created the Diversity Program Consortium (DPC), a prospective, multi-site study comprising 10 Building Infrastructure Leading to Diversity (BUILD) institutional grantees, the National Research Mentoring Network (NRMN) and a Coordination and Evaluation Center (CEC). This article describes baseline characteristics of four incoming, first-year student cohorts at the primary BUILD institutions who completed the Higher Education Research Institute, The Freshmen Survey between 2015-2019. These freshmen are the primary student cohorts for longitudinal analyses comparing outcomes of BUILD program participants and non-participants. Design: Baseline description of first-year students entering college at BUILD institutions during 2015-2019. Setting: Ten colleges/universities that each received <$7.5mil/yr in NIH Research Project Grants and have high proportions of low-income students. Participants: First-year undergraduate students who participated in BUILD-sponsored activities and a sample of non-BUILD students at the same BUILD institutions. A total of 32,963 first-year students were enrolled in the project; 64% were female, 18% Hispanic/Latinx, 19% African American/Black, 2% American Indian/Alaska Native and Native Hawaiian/Pacific Islander, 17% Asian, and 29% White. Twenty-seven percent were from families with an income <$30,000/yr and 25% were their family's first generation in college. Planned Outcomes: Primary student outcomes to be evaluated over time include undergraduate biomedical degree completion, entry into/completion of a graduate biomedical degree program, and evidence of excelling in biomedical research and scholarship. Conclusions: The DPC national evaluation has identified a large, longitudinal cohort of students with many from groups historically underrepresented in the biomedical sciences that will inform institutional/national policy level initiatives to help diversify the biomedical workforce.

Factors Contributing to Anthrax Outbreaks in the Circumpolar North.

A 2016 outbreak of anthrax on the Yamal Peninsula in Siberia that led to the culling of more than two hundred thousand reindeer and killed one human, resulted in significant media interests and in the reporting was often linked to thawing permafrost and ultimately climate change. Here, we review the historic context of anthrax outbreaks in the circumpolar North and explore alternative explanations for the anthrax outbreak in Western Siberia. Further, we propose a convergence model where multiple factors likely contributed to the outbreak of anthrax, including an expanded population and discontinued vaccination.

The Research, Advising, and Mentoring Professional: A Unique Approach to Supporting Underrepresented Students in Biomedical Research.

As a pilot intervention strategy to support undergraduate students, especially rural and Alaska Native students who are pursuing biomedical science research and career trajectories, we have developed a unique, mid-level Research, Advising, and Mentoring Professional (RAMP) position. In this article we outline the reasons for creating this position, RAMP qualifications, training, duties, and differences between RAMP and other positions typically found in higher education. Additionally, we discuss the evolution of the position and why it may be of interest to other institutions as they address similar issues involving students from underrepresented groups. Preliminary survey and focus group data from students mentored directly by RAMPs indicated that the holistic advising approach of RAMPs has had a positive impact on student experiences by supporting persistence in degree programs and providing psychosocial support of both personal and professional development.

One health in the circumpolar North.

The North faces significant health disparities, especially among its many Indigenous peoples. In this article we discuss historical, environmental, and cultural variables that contribute to these disparities and propose a One Health approach to address them in a holistic and culturally appropriate manner. The One Health paradigm recognizes the interdependence among the health and well-being of people, animals and the environment. As such, the framework aligns well with many Indigenous world views. This proactive, interdisciplinary, constructivist, and collaborative approach promise earlier detection of risks and threats, as well as more effective responses, in part by engaging community level stakeholders in all stages of the process. In the far North, humans, especially Indigenous peoples, continue to live closely connected to their environment, in settings that exert significant impacts on health. In recent decades, rapid warming and elevated contaminant levels have heightened environmental risks and increased uncertainty, both of which threaten individual and community health and well-being. Under these circumstances especially, One Health's comprehensive approach may provide mitigating and adaptive strategies to enhance resilience. While many of the examples used in this manuscript focus on Alaska and Canada, the authors believe similar conditions exist among the indigenous and rural residents across the entire Circumpolar North.

Rabies in Alaska, from the past to an uncertain future.

Rabies is a serious zoonotic disease with significant public health consequences in the circumpolar North. Recent studies have advanced our understanding of the disease ecology in Alaska. In this paper, we review historical records of rabies in Alaska ranging from the late nineteenth century to the present, analyse the public health impact in the state and review studies on disease ecology before assessing challenges and anticipated altered disease dynamics in the face of a rapidly changing North. Rabies is a disease that has been present in Alaska continuously for over 100 years. It is maintained in bats and foxes with the arctic fox likely playing a bigger role in maintaining the virus, although a multi-host system with both red and arctic foxes cannot be excluded. Some modelling evidence suggest a possible decrease in rabies due to a changing climate, although uncertainty is high around these predictions for rabies distribution in Alaska into the future.

Development of a genotype-by-sequencing immunogenetic assay as exemplified by screening for variation in red fox with and without endemic rabies exposure.

Pathogens are recognized as major drivers of local adaptation in wildlife systems. By determining which gene variants are favored in local interactions among populations with and without disease, spatially explicit adaptive responses to pathogens can be elucidated. Much of our current understanding of host responses to disease comes from a small number of genes associated with an immune response. High-throughput sequencing (HTS) technologies, such as genotype-by-sequencing (GBS), facilitate expanded explorations of genomic variation among populations. Hybridization-based GBS techniques can be leveraged in systems not well characterized for specific variants associated with disease outcome to "capture" specific genes and regulatory regions known to influence expression and disease outcome. We developed a multiplexed, sequence capture assay for red foxes to simultaneously assess ~300-kbp of genomic sequence from 116 adaptive, intrinsic, and innate immunity genes of predicted adaptive significance and their putative upstream regulatory regions along with 23 neutral microsatellite regions to control for demographic effects. The assay was applied to 45 fox DNA samples from Alaska, where three arctic rabies strains are geographically restricted and endemic to coastal tundra regions, yet absent from the boreal interior. The assay provided 61.5% on-target enrichment with relatively even sequence coverage across all targeted loci and samples (mean = 50×), which allowed us to elucidate genetic variation across introns, exons, and potential regulatory regions (4,819 SNPs). Challenges remained in accurately describing microsatellite variation using this technique; however, longer-read HTS technologies should overcome these issues. We used these data to conduct preliminary analyses and detected genetic structure in a subset of red fox immune-related genes between regions with and without endemic arctic rabies. This assay provides a template to assess immunogenetic variation in wildlife disease systems.

Rabies virus modifies host behaviour through a snake-toxin like region of its glycoprotein that inhibits neurotransmitter receptors in the CNS.

Rabies virus induces drastic behaviour modifications in infected hosts. The mechanisms used to achieve these changes in the host are not known. The main finding of this study is that a region in the rabies virus glycoprotein, with homologies to snake toxins, has the ability to alter behaviour in animals through inhibition of nicotinic acetylcholine receptors present in the central nervous system. This finding provides a novel aspect to virus receptor interaction and host manipulation by pathogens in general. The neurotoxin-like region of the rabies virus glycoprotein inhibited acetylcholine responses of α4ß2 nicotinic receptors in vitro, as did full length ectodomain of the rabies virus glycoprotein. The same peptides significantly altered a nicotinic receptor induced behaviour in C. elegans and increased locomotor activity levels when injected into the central nervous system of mice. These results provide a mechanistic explanation for the behavioural changes in hosts infected by rabies virus.

Investigation of a Canine Parvovirus Outbreak using Next Generation Sequencing.

Canine parvovirus (CPV) outbreaks can have a devastating effect in communities with dense dog populations. The interior region of Alaska experienced a CPV outbreak in the winter of 2016 leading to the further investigation of the virus due to reports of increased morbidity and mortality occurring at dog mushing kennels in the area. Twelve rectal-swab specimens from dogs displaying clinical signs consistent with parvoviral-associated disease were processed using next-generation sequencing (NGS) methodologies by targeting RNA transcripts, and therefore detecting only replicating virus. All twelve specimens demonstrated the presence of the CPV transcriptome, with read depths ranging from 2.2X - 12,381X, genome coverage ranging from 44.8-96.5%, and representation of CPV sequencing reads to those of the metagenome background ranging from 0.0015-6.7%. Using the data generated by NGS, the presence of newly evolved, yet known, strains of both CPV-2a and CPV-2b were identified and grouped geographically. Deep-sequencing data provided additional diagnostic information in terms of investigating novel CPV in this outbreak. NGS data in addition to limited serological data provided strong diagnostic evidence that this outbreak most likely arose from unvaccinated or under-vaccinated canines, not from a novel CPV strain incapable of being neutralized by current vaccination efforts.

Ecological niche modeling of rabies in the changing Arctic of Alaska.

BACKGROUND: Rabies is a disease of global significance including in the circumpolar Arctic. In Alaska enzootic rabies persist in northern and western coastal areas. Only sporadic cases have occurred in areas outside of the regions considered enzootic for the virus, such as the interior of the state and urbanized regions. RESULTS: Here we examine the distribution of diagnosed rabies cases in Alaska, explicit in space and time. We use a geographic information system (GIS), 20 environmental data layers and provide a quantitative non-parsimonious estimate of the predicted ecological niche, based on data mining, machine learning and open access data. We identify ecological correlates and possible drivers that determine the ecological niche of rabies virus in Alaska. More specifically, our models show that rabies cases are closely associated with human infrastructure, and reveal an ecological niche in remote northern wilderness areas. Furthermore a model utilizing climate modeling suggests a reduction of the current ecological niche for detection of rabies virus in Alaska, a state that is disproportionately affected by a changing climate. CONCLUSIONS: Our results may help to better inform public health decisions in the future and guide further studies on individual drivers of rabies distribution in the Arctic.

Neisseria arctica sp. nov., isolated from nonviable eggs of greater white-fronted geese (Anser albifrons) in Arctic Alaska.

During the summers of 2013 and 2014, isolates of a novel Gram-stain-negative coccus in the genus Neisseriawere obtained from the contents of nonviable greater white-fronted goose (Anseralbifrons) eggs on the Arctic Coastal Plain of Alaska. We used a polyphasic approach to determine whether these isolates represent a novel species. 16S rRNA gene sequences, 23S rRNA gene sequences, and chaperonin 60 gene sequences suggested that these Alaskan isolates are members of a distinct species that is most closely related to Neisseria canis, Neisseriaanimaloris and Neisseriashayeganii. Analysis of the rplF gene additionally showed that the isolates are unique and most closely related to Neisseriaweaveri. Average nucleotide identity of the whole genome sequence of the type strain was between 71.5 and 74.6 % compared to close relatives, further supporting designation as a novel species. Fatty acid methyl ester analysis showed a predominance of C14 : 0, C16 : 0 and C16 : 1ω7c fatty acids. Finally, biochemical characteristics distinguished the isolates from other species of the genus Neisseria. On the basis of these combined data, the isolates are proposed to represent a novel species of the genus Neisseria, with the name Neisseria arctica sp. nov. The type strain is KH1503T (=ATCC TSD-57T=DSM 103136T).

BUILDing BLaST: promoting rural students' biomedical research careers using a culturally responsive, one health approach.

BACKGROUND AND PURPOSE: Most postsecondary institutions in the state of Alaska (USA) have a broad mission to serve diverse students, many of whom come from schools in rural villages that are accessible only by plane, boat, or snowmobile. The major research university, the University of Alaska in Fairbanks (UAF), serves a population whereby 40% are from groups recognized as underrepresented in the biomedical workforce. The purpose of this article is to describe the Building Infrastructure Leading to Diversity (BUILD)-supported program in the state of Alaska that seeks to engage students from rural areas with a culturally relevant approach that is centered on the One Health paradigm, integrating human, animal, and environmental health. PROGRAM AND KEY HIGHLIGHTS: The Biomedical Learning and Student Training (BLaST) program distinguished by broad themes that address recruitment, retention, and success of students in biomedical programs, especially for students from rural backgrounds. Targeted rural outreach emphasizes that biomedical research includes research on the integration of human, animal, and environmental health. This One Health perspective gives personal relevance and connection to biomedical research. This outreach is expected to benefit student recruitment, as well as foster family and community support for pursuit of college degrees. BLaST promotes integration of research into undergraduate curricula through curriculum development, and by creating a new class of instructors, laboratory research and teaching technicians, who provide research mentorship, course instruction, and comprehensive advising. Finally, BLaST facilitates early and sustained undergraduate research experiences in collaborations with graduate students and faculty. IMPLICATIONS: BLaST's approach is highly adapted to the Alaskan educational and physical environment, but components and concepts could be adapted to other rural areas as a means to engage students from rural backgrounds, who often have a closer relationship with the natural environment than urban students.

Spatio-temporal Analysis of the Genetic Diversity of Arctic Rabies Viruses and Their Reservoir Hosts in Greenland.

There has been limited knowledge on spatio-temporal epidemiology of zoonotic arctic fox rabies among countries bordering the Arctic, in particular Greenland. Previous molecular epidemiological studies have suggested the occurrence of one particular arctic rabies virus (RABV) lineage (arctic-3), but have been limited by a low number of available samples preventing in-depth high resolution phylogenetic analysis of RABVs at that time. However, an improved knowledge of the evolution, at a molecular level, of the circulating RABVs and a better understanding of the historical perspective of the disease in Greenland is necessary for better direct control measures on the island. These issues have been addressed by investigating the spatio-temporal genetic diversity of arctic RABVs and their reservoir host, the arctic fox, in Greenland using both full and partial genome sequences. Using a unique set of 79 arctic RABV full genome sequences from Greenland, Canada, USA (Alaska) and Russia obtained between 1977 and 2014, a description of the historic context in relation to the genetic diversity of currently circulating RABV in Greenland and neighboring Canadian Northern territories has been provided. The phylogenetic analysis confirmed delineation into four major arctic RABV lineages (arctic 1-4) with viruses from Greenland exclusively grouping into the circumpolar arctic-3 lineage. High resolution analysis enabled distinction of seven geographically distinct subclades (3.I - 3.VII) with two subclades containing viruses from both Greenland and Canada. By combining analysis of full length RABV genome sequences and host derived sequences encoding mitochondrial proteins obtained simultaneously from brain tissues of 49 arctic foxes, the interaction of viruses and their hosts was explored in detail. Such an approach can serve as a blueprint for analysis of infectious disease dynamics and virus-host interdependencies. The results showed a fine-scale spatial population structure in Greenland arctic foxes based on mitochondrial sequences, but provided no evidence for independent isolated evolutionary development of RABV in different arctic fox lineages. These data are invaluable to support future initiatives for arctic fox rabies control and elimination in Greenland.