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The direct and interactive effects of climate change on host species and infectious disease dynamics are likely to initially manifest\ at latitudinal extremes. As such, Alaska represents a region in the United States for introspection on climate change and disease. Rabies is enzootic among arctic foxes ( Vulpes lagopus) throughout the northern polar region. In Alaska, arctic and red foxes (Vulpes vulpes) are reservoirs for rabies, with most domestic animal and wildlife cases reported from northern and western coastal Alaska. Based on passive surveillance, a pronounced seasonal trend in rabid foxes occurs in Alaska, with a peak in winter and spring. This study describes climatic factors that may be associated with reported cyclic rabies occurrence. Based upon probabilistic modelling, a stronger seasonal effect in reported fox rabies cases appears at higher latitudes in Alaska, and rabies in arctic foxes appear disproportionately affected by climatic factors in comparison with red foxes. As temperatures continue a warming trend, a decrease in reported rabid arctic foxes may be expected. The overall epidemiology of rabies in Alaska is likely to shift to increased viral transmission among red foxes as the primary reservoir in the region. Information on fox and lemming demographics, in addition to enhanced rabies surveillance among foxes at finer geographic scales, will be critical to develop more comprehensive models for rabies virus transmission in the region. [ABSTRACT FROM AUTHOR]

Abstract Background Brucella is a group of bacteria that causes brucellosis, which can affect population health and reproductive success in many marine mammals. We investigated the serological prevalence of antibodies against Brucella bacteria in a declining harbor seal population in Glacier Bay National Park, Alaska. Results Prevalence ranged from 16 to 74 percent for those tests detecting antibodies, indicating that harbor seals in Glacier Bay have been exposed to Brucella bacteria. However, the actual level of serological prevalence could not be determined because results were strongly assay-dependent. Conclusions This study reinforces the need to carefully consider assay choice when comparing different studies on the prevalence of anti–Brucella antibodies in pinnipeds and further highlights the need for species- or taxon-specific assay validation for both pathogen and host species.

Abstract Background Understanding mercury (Hg) distribution in blood and the importance of hair as an excretory pathway is critical for evaluating risk from long term dietary Hg exposure. The major objective of this study was to characterize changes in total Hg concentrations in specific blood compartments and hair over time due to long term piscivory. Methods Eight sled dogs (Canis lupus familiaris) were fed either a fish and kibble diet (n = 4), or a fish-free control diet (n = 4) for 12 weeks. Concentrations of Hg were monitored throughout the exposure period, and for 10 weeks post exposure, until Hg concentrations in all blood compartments of one of the exposed dogs dropped below detection limit. Additionally, foreleg hair was sampled during acclimation and weeks 0 and 12. Results Hg was detected primarily in whole blood and packed cells, although it was sporadically detected at low concentrations in plasma and serum in two of the fish fed dogs. Dogs ingested an estimated average of 13.4 ± 0.58 μg Hg per kg body weight per day. Hg was detectable in whole blood and packed cells within a week of exposure. Detected concentrations continued to rise until plateauing at approximately 3-6 weeks of exposure at a mean of 9.2 ± 1.97 ng/g (ppb) in whole blood. Hg concentration decreased post exposure following 1st order elimination. The mean half-life (t1/2) in whole blood for Hg was 7 weeks. Mean Hg in hair for the fish-fed dogs at week 12 was 540 ± 111 ppb and was significantly greater (about 7-fold) than the Hg hair concentration for the control dogs. The hair to blood ratio for Hg in fish-fed dogs was 59.0 ± 7.6:1. Conclusions This study found the sled dog model to be an effective method for investigating and characterizing blood Hg distribution (whole blood, serum, plasma, packed cells) and toxicokinetics associated with a piscivorous diet, especially for Hg-exposed fur bearing mammals (such as polar bears). Although hair excretion and hair to blood Hg ratios were not similar to human concentrations and ratios, the sled dog toxicokinetics of Hg in blood, was more similar to that of humans than traditional laboratory animals (such as the rat).

Abstract Tularemia is a serious, potentially life threatening zoonotic disease. The causative agent, Francisella tularensis, is ubiquitous in the Northern hemisphere, including Alaska, where it was first isolated from a rabbit tick (Haemophysalis leporis-palustris) in 1938. Since then, F. tularensis has been isolated from wildlife and humans throughout the state. Serologic surveys have found measurable antibodies with prevalence ranging from < 1% to 50% and 4% to 18% for selected populations of wildlife species and humans, respectively. We reviewed and summarized known literature on tularemia surveillance in Alaska and summarized the epidemiological information on human cases reported to public health officials. Additionally, available F. tularensis isolates from Alaska were analyzed using canonical SNPs and a multi-locus variable-number tandem repeats (VNTR) analysis (MLVA) system. The results show that both F. t. tularensis and F. t. holarctica are present in Alaska and that subtype A.I, the most virulent type, is responsible for most recently reported human clinical cases in the state.

Abstract Many arctic mammals are adapted to live year-round in extreme environments with low winter temperatures and great seasonal variations in key variables (e.g. sunlight, food, temperature, moisture). The interaction between hosts and pathogens in high northern latitudes is not very well understood with respect to intra-annual cycles (seasons). The annual cycles of interacting pathogen and host biology is regulated in part by highly synchronized temperature and photoperiod changes during seasonal transitions (e.g., freezeup and breakup). With a warming climate, only one of these key biological cues will undergo drastic changes, while the other will remain fixed. This uncoupling can theoretically have drastic consequences on host-pathogen interactions. These poorly understood cues together with a changing climate by itself will challenge host populations that are adapted to pathogens under the historic and current climate regime. We will review adaptations of both host and pathogens to the extreme conditions at high latitudes and explore some potential consequences of rapid changes in the Arctic.

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.

The rabies virus enters the nervous system by interacting with several molecular targets on host cells to modify behavior and trigger receptor-mediated endocytosis of the virion by poorly understood mechanisms. The rabies virus glycoprotein (RVG) interacts with the muscle acetylcholine receptor and the neuronal α4β2 subtype of the nicotinic acetylcholine receptor (nAChR) family by the putative neurotoxin-like motif. Given that the neurotoxin-like motif is highly homologous to the α7 nAChR subtype selective snake toxin α-bungarotoxin (αBTX), other nAChR subtypes are likely involved. The purpose of this study is to determine the activity of the RVG neurotoxin-like motif on nAChR subtypes that are expressed in brain regions involved in rabid animal behavior. nAChRs were expressed in Xenopus laevis oocytes, and two-electrode voltage clamp electrophysiology was used to collect concentration-response data to measure the functional effects. The RVG peptide preferentially and completely inhibits α7 nAChR ACh-induced currents by a competitive antagonist mechanism. Tested heteromeric nAChRs are also inhibited, but to a lesser extent than the α7 subtype. Residues of the RVG peptide with high sequence homology to αBTX and other neurotoxins were substituted with alanine. Altered RVG neurotoxin-like peptides showed that residues phenylalanine 192, arginine 196, and arginine 199 are important determinants of RVG peptide apparent potency on α7 nAChRs, while serine 195 is not. The evaluation of the rabies ectodomain reaffirmed the observations made with the RVG peptide, illustrating a significant inhibitory impact on α7 nAChR with potency in the nanomolar range. In a mammalian cell culture model of neurons, we confirm that the RVG peptide binds preferentially to cells expressing the α7 nAChR. Defining the activity of the RVG peptide on nAChRs expands our understanding of basic mechanisms in host-pathogen interactions that result in neurological disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 O’Brien, Thao, Weber, Danielson, Boldt, Hueffer and Weltzin.)

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 α3β2, α3β4, and α4β2 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., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

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 β1, 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., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

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., Competing Interests: The authors have declared that no competing interests exist.

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., (© 2021 The Authors. Zoonoses and Public Health published by Wiley-VCH GmbH.)

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., Competing Interests: DJ was employed by the company Nyati Health Consulting, British Columbia, Canada. DL was employed by Nunavut Tunngavik Inc., Ottawa, Canada. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AP declared a past co-authorship with one of the authors SO to the handling Editor., (Copyright © 2021 Keatts, Robards, Olson, Hueffer, Insley, Joly, Kutz, Lee, Chetkiewicz, Lair, Preston, Pruvot, Ray, Reid, Sleeman, Stimmelmayr, Stephen and Walzer.)

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)., Competing Interests: The authors have declared that no competing interests exist.

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., Competing Interests: Competing Interests: None declared., (Copyright © 2020, Ethnicity & Disease, Inc.)

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 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.

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.

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.

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., Competing Interests: Not applicableNot applicableAll authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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 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 α4β2 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.

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.

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).

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.

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.

For pathogens that infect multiple species, the distinction between reservoir hosts and spillover hosts is often difficult. In Alaska, three variants of the arctic rabies virus exist with distinct spatial distributions. We tested the hypothesis that rabies virus variant distribution corresponds to the population structure of the primary rabies hosts in Alaska, arctic foxes (Vulpes lagopus) and red foxes (Vulpes vulpes) to possibly distinguish reservoir and spillover hosts. We used mitochondrial DNA (mtDNA) sequence and nine microsatellites to assess population structure in those two species. mtDNA structure did not correspond to rabies virus variant structure in either species. Microsatellite analyses gave varying results. Bayesian clustering found two groups of arctic foxes in the coastal tundra region, but for red foxes it identified tundra and boreal types. Spatial Bayesian clustering and spatial principal components analysis identified 3 and 4 groups of arctic foxes, respectively, closely matching the distribution of rabies virus variants in the state. Red foxes, conversely, showed eight clusters comprising two regions (boreal and tundra) with much admixture. These results run contrary to previous beliefs that arctic fox show no fine-scale spatial population structure. While we cannot rule out that the red fox is part of the maintenance host community for rabies in Alaska, the distribution of virus variants appears to be driven primarily by the arctic fox. Therefore, we show that host population genetics can be utilized to distinguish between maintenance and spillover hosts when used in conjunction with other approaches., (© 2015 John Wiley & Sons Ltd.)

Disease was a listing criterion for the polar bear (Ursus maritimus) as threatened under the Endangered Species Act in 2008; it is therefore important to evaluate the current state of knowledge and identify any information gaps pertaining to diseases in polar bears. We conducted a systematic literature review focused on infectious agents and associated health impacts identified in polar bears. Overall, the majority of reports in free-ranging bears concerned serosurveys or fecal examinations with little to no information on associated health effects. In contrast, most reports documenting illness or pathology referenced captive animals and diseases caused by etiologic agents not representative of exposure opportunities in wild bears. As such, most of the available infectious disease literature has limited utility as a basis for development of future health assessment and management plans. Given that ecological change is a considerable risk facing polar bear populations, future work should focus on cumulative effects of multiple stressors that could impact polar bear population dynamics.

To address the role of bacterial infection in hatching failure of wild geese, we monitored embryo development in a breeding population of Greater white-fronted geese (Anser albifrons) on the Arctic Coastal Plain of Alaska. During 2013, we observed mortality of normally developing embryos and collected 36 addled eggs for analysis. We also collected 17 infertile eggs for comparison. Using standard culture methods and gene sequencing to identify bacteria within collected eggs, we identified a potentially novel species of Neisseria in 33 eggs, Macrococcus caseolyticus in 6 eggs, and Streptococcus uberis and Rothia nasimurium in 4 eggs each. We detected seven other bacterial species at lower frequencies. Sequences of the 16S rRNA genes from the Neisseria isolates most closely matched sequences from N. animaloris and N. canis (96 to 97% identity), but phylogenetic analysis suggested substantial genetic differentiation between egg isolates and known Neisseria species. Although definitive sources of the bacteria remain unknown, we detected Neisseria DNA from swabs of eggshells, nest contents, and cloacae of nesting females. To assess the pathogenicity of bacteria identified in contents of addled eggs, we inoculated isolates of Neisseria, Macrococcus, Streptococcus, and Rothia at various concentrations into developing chicken eggs. Seven-day mortality rates varied from 70 to 100%, depending on the bacterial species and inoculation dose. Our results suggest that bacterial infections are a source of embryo mortality in wild geese in the Arctic., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

We report here the draft genome sequence of a unique Neisseria strain that was isolated from a greater white-fronted goose (Anser albifrons) egg. The sequencing was performed with an Illumina MiSeq system, and the sequence consists of 275 contigs. The total genome is 2,397,978 bp long and has a G+C content of 46.4%., (Copyright © 2015 Hansen et al.)

The Arctic, even more so than other parts of the world, has warmed substantially over the past few decades. Temperature and humidity influence the rate of development, survival and reproduction of pathogens and thus the incidence and prevalence of many infectious diseases. Higher temperatures may also allow infected host species to survive winters in larger numbers, increase the population size and expand their habitat range. The impact of these changes on human disease in the Arctic has not been fully evaluated. There is concern that climate change may shift the geographic and temporal distribution of a range of infectious diseases. Many infectious diseases are climate sensitive, where their emergence in a region is dependent on climate-related ecological changes. Most are zoonotic diseases, and can be spread between humans and animals by arthropod vectors, water, soil, wild or domestic animals. Potentially climate-sensitive zoonotic pathogens of circumpolar concern include Brucella spp., Toxoplasma gondii, Trichinella spp., Clostridium botulinum, Francisella tularensis, Borrelia burgdorferi, Bacillus anthracis, Echinococcus spp., Leptospira spp., Giardia spp., Cryptosporida spp., Coxiella burnetti, rabies virus, West Nile virus, Hantaviruses, and tick-borne encephalitis viruses.

Intracellular pathogens and other organisms have evolved mechanisms to exploit host cells for their life cycles. Virulence genes of some intracellular bacteria responsible for these mechanisms are located in pathogenicity islands, such as secretion systems that secrete effector proteins. The Francisella pathogenicity island is required for phagosomal escape, intracellular replication, evasion of host immune responses, virulence, and encodes a type 6 secretion system. We hypothesize that some Francisella novicida pathogenicity island proteins are secreted during infection of host cells. To test this hypothesis, expression plasmids for all Francisella novicida FPI-encoded proteins with C-terminal and N-terminal epitope FLAG tags were developed. These plasmids expressed their respective epitope FLAG-tagged proteins at their predicted molecular weights. J774 murine macrophage-like cells were infected with Francisella novicida containing these plasmids. The FPI proteins expressed from these plasmids successfully restored the intramacrophage growth phenotype in mutants of the respective genes that were deficient for intramacrophage growth. Using these expression plasmids, the localization of the Francisella pathogenicity island proteins were examined via immuno-fluorescence microscopy within infected macrophage-like cells. Several Francisella pathogenicity island encoded proteins (IglABCDEFGHIJ, PdpACE, DotU and VgrG) were detected extracellularly and they were co-localized with the bacteria, while PdpBD and Anmk were not detected and thus remained inside bacteria. Proteins that were co-localized with bacteria had different patterns of localization. The localization of IglC was dependent on the type 6 secretion system. This suggests that some Francisella pathogenicity island proteins were secreted while others remain within the bacterium during infection of host cells as structural components of the secretion system and were necessary for secretion.

Endurance exercise relies on transsarcolemmal flux of substrates in order to avoid depletion of intramuscular reserves. Previous studies of endurance trained sled dogs have shown a remarkable capacity of these dogs to adapt rapidly to endurance exercise by decreasing the utilization of intramuscular reserves. The current study tested the hypothesis that the dogs' glycogen-sparing phenotype is due to increased sarcolemmal transport of glucose and fatty acids. Basal and exercise-induced transport of glucose and fatty acids into sarcolemmal vesicles was evaluated in racing sled dogs prior to and after 7 months of exercise conditioning. Sarcolemmal substrate transport capacity was measured using sarcolemmal vesicles and radiolabelled substrates, and transporter abundance was measured using Western blot quantification in whole muscle homogenates and the sarcolemmal vesicle preparations. Conditioning resulted in increased basal and exercise-induced transport of both glucose and palmitate. Neither acute exercise nor conditioning resulted in changes in muscle content of GLUT4 or FAT/CD36, but conditioning did result in decreased abundance of both transporters in the sarcolemmal vesicles used for the basal transport assays, and this decrease was further amplified in the vesicles used for the exercise-induced transport assays. These results demonstrate conditioning-induced increases in sarcolemmal transport of oxidizable substrates, as well as increased gain of exercise-induced sarcolemmal transport of these substrates. These results further indicate that increased sarcolemmal transport of oxidizable substrates may be due to either an increased intrinsic capacity of the existing transporters or to a different population of transporters from those investigated.

Whole blood (WB) is commonly used to assess mercury (Hg) exposure in mammals, but handling and shipping samples collected in remote areas can be difficult. We describe and validate use of cellulose filter paper (FP) for quantifying WB total Hg concentration. Advantec Nobuto® FP was soaked with bottlenose dolphin (Tursiops truncatus) or harbor seal (Phoca vitulina) WB (collected between March and July 2012), then air dried. Untreated blood-soaked FPs were analyzed or were eluted with phosphate-buffered saline (PBS) and the eluate and PBS-treated FP Hg concentrations were determined. Total Hg from dried blood-soaked FPs, postelution FPs, and PBS-based eluate were compared with total Hg concentrations from WB. Recovery (on a concentration basis) for soaked FP relative to WB was 0.89 ± 0.15, for postelution FP was 0.86 ± 0.13, and for eluate (with a correction factor applied) was 0.96 ± 0.23. Least-squares linear regressions were fit for soaked papers (y = 1.15x, R(2) = 0.97), postelution FPs (y = 1.22x, R(2) = 0.95), and for eluate with a correction factor applied (y = 0.91x+0.03, R(2) = 0.97) as compared with WB. These data show that FP technology can have a valuable role in monitoring blood Hg concentrations in wildlife populations and FPs have the advantage of being easy to use, store, and transport as compared with WB.

Over the last 60 years, Alaska's mean annual temperature has increased by 1.6°C, more than twice the rate of the rest of the United States. As a result, climate change impacts are more pronounced here than in other regions of the United States. Warmer temperatures may allow some infected host animals to survive winters in larger numbers, increase their population and expand their range of habitation thus increasing the opportunity for transmission of infection to humans. Subsistence hunting and gathering activities may place rural residents of Alaska at a greater risk of acquiring zoonotic infections than urban residents. Known zoonotic diseases that occur in Alaska include brucellosis, toxoplasmosis, trichinellosis, giardiasis/cryptosporidiosis, echinococcosis, rabies and tularemia. Actions for early disease detection, research and prevention and control include: (1) determining baseline levels of infection and disease in both humans and host animals; (2) conducting more research to understand the ecology of infection in the Arctic environment; (3) improving active and passive surveillance systems for infection and disease in humans and animals; (4) improving outreach, education and communication on climate-sensitive infectious diseases at the community, health and animal care provider levels; and (5) improving coordination between public health and animal health agencies, universities and tribal health organisations.

The Francisella pathogenicity island (FPI) encodes proteins thought to compose a type VI secretion system (T6SS) that is required for the intracellular growth of Francisella novicida. In this work we used deletion mutagenesis and genetic complementation to determine that the intracellular growth of F. novicida was dependent on 14 of the 18 genes in the FPI. The products of the iglABCD operon were localized by the biochemical fractionation of F. novicida, and Francisella tularensis LVS. Sucrose gradient separation of water-insoluble material showed that the FPI-encoded proteins IglA, IglB and IglC were found in multiple fractions, especially in a fraction that did not correspond to a known membrane fraction. We interpreted these data to suggest that IglA, IglB and IglC are part of a macromolecular structure. Analysis of published structural data suggested that IglC is an analogue of Hcp, which is thought to form long nano-tubes. Thus the fractionation properties of IglA, IglB and IglC are consistent with the current model of the T6SS apparatus, which supposes that IglA and IglB homologues form an outer tube structure that surrounds an inner tube composed of Hcp (IglC) subunits. Fractionation of F. novicida expressing FLAG-tagged DotU (IcmH homologue) and PdpB (IcmF homologue) showed that these proteins localize to the inner membrane. Deletion of dotU led to the cleavage of PdpB, suggesting an interaction of these two proteins that is consistent with results obtained with other T6SSs. Our results may provide a mechanistic basis for many of the studies that have examined the virulence properties of Francisella mutants in FPI genes, namely that the observed phenotypes of the mutants are the result of the disruption of the FPI-encoded T6SS structure.

The harbor seal population in Glacier Bay National Park, Alaska, has declined by over 70% since 1992. The reasons for this decline are not known. We examined serum antibodies and feces for evidence of exposure to multiple pathogens in this population. We also studied harbor seals from a reference site on Kodiak Island. In 2007, we found antibodies against Leptospira spp. in 31% of specimens from harbor seals in Glacier Bay, but no detectable serum antibodies in samples from Kodiak. In 2008, no samples had detectable antibodies against Leptospira spp. No serum antibodies against Toxoplasma gondii, morbilliviruses, or presence of Cryptosporidium in fecal samples were detected. However, Giardia was found in 6% of the fecal samples from Glacier Bay. Our results indicate that the harbor seal population in Glacier Bay National Park could be immunologically naïve to distemper viruses and therefore vulnerable to these pathogens. Given the relatively low prevalence of antibodies and low titers, pathogens likely are not the reason for the harbor seal decline in Glacier Bay.

We tested the Raboral V-RG® recombinant oral rabies vaccine for its response in Arctic foxes (Vulpes lagopus), the reservoir of rabies virus in the circumpolar North. The vaccine, which is currently the only licensed oral rabies vaccine in the United States, induced a strong antibody response and protected foxes against a challenge of 500,000 mouse intracerebral lethal dose 50% of an Arctic rabies virus variant. However, one unvaccinated control fox survived challenge with rabies virus, either indicating a high resistance of Arctic foxes to rabies infection or a previous exposure that induced immunity. This preliminary study suggested that Raboral V-RG vaccine may be efficacious in Arctic foxes.

A spotted seal harvested by subsistence hunters in Kotzebue Sound, Alaska (USA), showed a grossly enlarged uterus and associated lymph nodes. Streptococcus phocae was isolated from the purulent uterine discharge. Histopathologic examination revealed inflammation that was limited to the uterine mucosa. Lymph nodes draining the affected organ were reactive but no evidence of active infection was found in the lymph nodes. This report is the first Streptococcus phocae isolated from spotted seals as well as the first report of pyometra as the main pathologic finding associated with this pathogen. Isolation of this pathogen from Alaska expands the reported range to arctic pinnipeds. Zoonotic potential remains unknown.

Tularemia is a zoonotic disease caused by the Category A bioterrorism agent Francisella tularensis. In Scandinavia, tularemia transmission by mosquitoes has been widely cited in the literature. We tested >2,500 mosquitoes captured in Alaska and found Francisella DNA in 30% of pooled samples. To examine the potential for transmission of Francisella by mosquitoes, we developed a mosquito model of Francisella infection. Larvae of Anopheles gambiae Giles and Aedes aegypti (L.) readily ingest F. tularensis but do not efficiently transfer infective doses of the bacterium to the pupal or adult stage. After a bloodmeal containing Francisella, adult female An. gambiae and Ae. aegypti retained detectable levels of Francisella DNA for 3 d, but when they took a second bloodmeal, the mammalian host was not infected. This study suggests that although Francisella DNA can be detected in a significant portion of wild-caught mosquitoes, transmission of Francisella is either very inefficient or is species dependent for the Francisella strain or the arthropod vector.

Many bacterial pathogens and symbionts utilize type III secretion systems to deliver bacterial effector proteins into host cells. These effector proteins have the capacity to modulate a large variety of cellular functions in a highly regulated manner. Here, we report that the phosphoinositide phosphatase SopB, a Salmonella Typhimurium type III secreted effector protein, diversifies its function by localizing to different cellular compartments in a ubiquitin-dependent manner. We show that SopB utilizes the same enzymatic activity to modulate actin-mediated bacterial internalization and Akt activation at the plasma membrane and vesicular trafficking and intracellular bacterial replication at the phagosome. Thus, by exploiting the host cellular machinery, Salmonella Typhimurium has evolved the capacity to broaden the functional repertoire of a virulence factor to maximize its ability to modulate cellular functions.

Francisella tularensis, a potential bioterrorism agent, is transmitted by arthropod vectors and causes tularemia in many mammals, including humans. Francisella novicida causes disease with similar pathology in mice. We show that F. novicida invades hemocyte-like cells of the SualB cell line derived from Anopheles gambiae and replicates vigorously within these cells. We used transposon knockouts of single genes of F. novicida to show that bacterial growth within these insect cells is dependent on virulence factors encoded in a bacterial pathogenicity island that has been linked to replication in mammalian macrophages. The virulence factors MglA, IglA, IglB, IglC, and IglD as well as PdpA and PdpB were necessary for efficient growth in insect cells, but PdpC and PdpD were not required. The SualB cell line presents a valuable model to study the interactions between this important pathogen and insect vectors.

The facultative intracellular pathogen Salmonella enterica triggers programmed cell death in macrophages. The close examination of this phenomenon has revealed an unusually complex picture involving diverse mechanisms that lead to different types of programmed cell death. It appears that the outcome of the interaction of salmonella with macrophages depends on the relative contribution of two type III protein secretion systems, in conjunction with the stimulation of innate immunity outputs through conserved determinants collectively known as 'pathogen-associated molecular patterns' (PAMPs). These interactions result in a breakdown of the balance between survival and pro-apoptotic cellular pathways, which eventually leads to macrophage cell death. The relative significance for the infection process of the different types of macrophage cell death triggered by salmonella remains to be established.

Salmonella enterica, the cause of food poisoning and typhoid fever, induces actin cytoskeleton rearrangements and membrane ruffling to gain access into nonphagocytic cells, where it can replicate and avoid innate immune defenses. Here, we found that SopB, a phosphoinositide phosphatase that is delivered into host cells by a type III secretion system, was essential for the establishment of Salmonella's intracellular replicative niche. SopB mediated the formation of spacious phagosomes following bacterial entry and was responsible for maintaining high levels of phosphatidylinositol-three-phosphate [PtdIns(3)P] in the membrane of the bacteria-containing vacuoles. Absence of SopB caused a significant defect in the maturation of the Salmonella-containing vacuole and impaired bacterial intracellular growth.

The feline and canine transferrin receptors (TfRs) bind canine parvovirus to host cells and mediate rapid capsid uptake and infection. The TfR and its ligand transferrin have well-described pathways of endocytosis and recycling. Here we tested several receptor-dependent steps in infection for their role in virus infection of cells. Deletions of cytoplasmic sequences or mutations of the Tyr-Thr-Arg-Phe internalization motif reduced the rate of receptor uptake from the cell surface, while polar residues introduced into the transmembrane sequence resulted in increased degradation of transferrin. However, the mutant receptors still mediated efficient virus infection. In contrast, replacing the cytoplasmic and transmembrane sequences of the feline TfR with those of the influenza virus neuraminidase (NA) resulted in a receptor that bound and endocytosed the capsid but did not mediate viral infection. This chimeric receptor became localized to detergent-insoluble membrane domains. To test the effect of structural virus receptor interaction on infection, two chimeric receptors were prepared which contained antibody-variable domains that bound the capsid in place of the TfR ectodomain. These chimeric receptors bound CPV capsids and mediated uptake but did not result in cell infection. Adding soluble feline TfR ectodomain to the virus during that uptake did not allow infection.

Canine parvovirus (CPV) evolved as a new pathogen in dogs between 1976 and 1978 from feline panleukopenia virus (FPV). The new virus hit an unprotected population, caused a dramatic pandemic and infected virtually all populations of domestic and wild carnivores worldwide. The great similarity between the two viruses and their differences in host range, both in vivo as well as in vitro, make it a good model system for emerging diseases and host range shifts of viruses. Recent results showed that CPV expanded its host range by binding to the canine transferrin receptor (Tfr). Residues in the capsid protein that had been defined as host range controlling regions also control the binding to the canine transferrin receptor. These residues are located on a raised region of the capsid at the three-fold axis of symmetry. Interestingly, adaption of the new virus to the new host appears to correlate with an improved binding to the Tfr receptor.