Pathogens, Vol. 12, Pages 28: Tularemia above the Treeline: Climate and Rodent Abundance Influences Exposure of a Sentinel Species, the Arctic Fox (Vulpes lagopus), to Francisella tularensis

1. IntroductionTularemia is a zoonotic disease of the northern hemisphere caused by the Gram-negative intracellular bacterium, Francisella tularensis [1]. Transmission occurs through several routes, including direct contact with infected host fluids, vector bites (mechanical or biological transmission), and through ingestion of contaminated food and water [2]. Francisella tularensis is renowned for its high infectivity (as little as 10 colony-forming units) and wide range of hosts and vectors [1]. The source of exposure typically determines clinical symptoms of tularemia that are observed for humans, while the subspecies determines the severity of disease [3]. Ulceroglandular and glandular tularemia, represented by an ulcer and/or swelling of lymph nodes, are the most common forms of disease and occur after bacteria are introduced in the skin via a cut or insect bite. Other forms of the disease include oculoglandular (introduction of bacteria in the eyes), oropharyngeal (ingestion), typhoidal (systemic infection), and pneumonic tularemia (inhalation) [1]. The number of subspecies of F. tularensis is debated, but two are known to occur throughout North America. Type A (subsp. tularensis) is highly virulent and is associated with terrestrial rodents and lagomorphs, while type B (subsp. holarctica) has a circumpolar distribution and is associated with water-dwelling rodents and arthropod transmission (such as mosquitoes, biting flies, and ticks) [1,2,4]. Rodents and lagomorphs (hares and rabbits) are the main reservoirs for aquatic and terrestrial cycles of tularemia transmission, and infection often results in high-mortality events [5,6]. Life history traits, such as population turnover and reproductive output, influence the ability of a reservoir to maintain a pathogen, and those with high population turnover often act as reservoirs for more virulent pathogens [7]. Both rodents and lagomorphs are r-selected species, with high reproduction rates and short lifespans, making them optimal hosts for F. tularensis [7].Across the circumpolar Arctic, rodents and lagomorphs exhibit cyclical population irruptions [8]. These cycles are not fully understood, though mechanisms behind these cycles may include (i) predation (top-down regulation), (ii) social interactions and dispersal (bottom-up regulation), and (iii) effects of climate variability [9]. As the Canadian Arctic is experiencing unprecedented climate change, both increasing temperature and precipitation are likely to create ideal scenarios for tularemia outbreaks in the north [10,11]. Snow depth and the quality of vegetation during the summer and winter months are linked with rodent survival and highlight the influence of weather changes on population irruptions [10,12]. In addition, warming temperatures and increasing precipitation trends provide more opportunities for insect-borne and water-borne transmission by increasing the availability of aquatic habitats and breeding sites for mosquitoes, along with extending the season of mosquito activity [11,13]. Francisella tularensis is known to occur in wild animals from most provinces and territories in Canada, yet no studies have documented exposure in wildlife above the treeline [14]. However, one human case (thought to have originated from an insect bite) has been reported in Nunavut, and DNA from F. tularensis has been detected in wild-caught mosquitoes from Alaska (Fairbanks), indicating that F. tularensis is likely endemic in the north and present in the Canadian Arctic [15,16].In addition to the potential effects of climate volatility on F. tularensis transmission in the North American Arctic, this region also receives millions of migratory birds that may play a role in dissemination of the bacteria when they make their way to breeding colonies from southern overwintering grounds [17,18]. There are at least 26 species of birds known to be susceptible to F. tularensis infection, and cases of direct transmission from birds to humans has been documented [19,20]. Transportation of F. tularensis-infected arthropods has also been documented on migratory birds [21]. Thus, bird migrations to Arctic breeding grounds may provide opportunities for the dispersal of infected arthropods and the introduction of new subspecies from southern latitudes. As high mortality is often observed in rodents and lagomorphs during tularemia outbreaks, we hypothesized that scavengers and predators, such as the arctic fox (Vulpes lagopus), may serve as important sentinels for F. tularensis in tundra ecosystems [22] (Figure 1). Foxes are also important predators of migratory birds and their eggs during summer months [18]. Our study provides baseline information about F. tularensis exposure in arctic foxes sampled (lived-trapped or harvested) between 2011 and 2021 within a vast area of the Northwest Territories (NT) and Nunavut (NU) in the Canadian Arctic. Locally intensive vector, rodent, and fox sampling at a long-term field site (Karrak Lake, NU) uniquely allowed us to answer specific questions about F. tularensis epidemiology in the Arctic. Our overall project objectives included: (i) determining seroprevalence of F. tularensis in arctic foxes from the Canadian Arctic, (ii) determining whether F. tularensis DNA was present in insects, migratory geese, and rodents at our long-term study site (Karrak Lake, NU) to identify sources of transmission, (iii) establishing whether climate variables, such as spring snow cover and summer precipitation, and prey variables, such as rodent and goose density, influenced F. tularensis exposure of adult and juvenile live-captured foxes at Karrak Lake, and (iv) comparing maternal serostatus with serological results from pups (6–9 weeks of age) to determine if juvenile foxes may serve as seasonal indicators of F. tularensis transmission during summer months. 4. DiscussionWe provide the first description of F. tularensis in wildlife above the treeline in northern Canada and the factors that impact transmission in tundra ecosystems, which are primarily climate and rodent abundance. Our long-term study of arctic foxes at Karrak Lake presented a unique opportunity to monitor this population over a nine-year period. During 2011–2013, no antibodies for F. tularensis were detected in live-captured foxes. However, from 2014–2019, both adult and juvenile foxes were identified with positive titers, ranging from 1:128 to >1:2048. The year with the highest estimated seroprevalence was 2018, following a peak in vole abundance in 2017. This year appeared to be an outbreak year, with high prevalence and antibody titers in both adult foxes and pups (Table 1). In 2019, blood was successfully collected twice from pups at two den sites (n = 11; once at six weeks of age and once at eight weeks of age). During the time between first and second blood collection, three pups developed antibodies for F. tularensis, which again supports that the bacteria were actively circulating within the environment during the summer months. The observation of seronegative pups in litters from seropositive breeding females suggests that maternal antibodies did not interfere with test results (Figure S1). In addition, litters often had both negative and positive pups, which indicates that transmission via insects or rodents may be more likely than a common contaminated water source (Figure 1). No visibly ill or dead foxes were observed, even in 2018 and 2019, suggesting that there may have been nonlethal exposure of foxes through rapid consumption of rodents that may have died acutely due to tularemia. Indeed, fox pups might preferentially feed on easy prey such as septicaemic rodents and scavenge their carcasses.More snow cover in May during the year of live capture of foxes at Karrak Lake was associated with increased F. tularensis exposure (Model 2; Table 2). This makes sense, as rodent survival is influenced by spring temperatures, and longer periods of snow cover can reduce predation, leading to higher population density of rodents during the summer [12]. Ironically, warmer temperatures in May during the year prior to sampling was also associated with increased exposure for foxes, potentially due to reduced rodent survival during the spring, which may have created higher resource availability and provided the opportunity for more reproductive success the following winter. Finally, prevalence of F. tularensis increased with increasing precipitation in the same year that foxes were captured. Both temperature and precipitation impact vegetation growth, which in turn influences rodent population cycles [9]. For example, higher summer precipitation may lead to higher abundance of berry crops, which is an important food source for northern red-backed voles [35,36]. The availability of food plants with high nutritive value perhaps contributed to high rodent population density over the summer months. When adult foxes were excluded from the regression analyses, only colder temperatures in May during the year of sampling remained as an important climate correlate of pup exposure (Model 4; Table 2). This is logical, as colder temperatures should lead to longer snow cover in spring, limiting stress and predation, which should favor reproduction and contribute to higher rodent population density during the summer [37,38,39]. Furthermore, colder springs can induce earlier onset of reproduction for voles and may contribute to a higher population density during the summer months [40].When examining associations between prey variables (abundance measures collected in June and July) and the presence of F. tularensis antibodies, lower abundance of lemmings and higher abundance of voles during the year prior to sampling was associated with higher seroprevalence for both the model that included adult and pup serology results (Model 1; Table 2) and the model that only included pup results (Model 3; Table 2). This corresponds with previous reports of density-dependent effects for F. tularensis and rodent populations [41] and highlights that vole abundance may play an important role in the dissemination of F. tularensis in this tundra ecosystem. It also supports our hypothesis that higher temperatures in May and potentially lower rodent survival during spring in the year prior to fox exposure (Model 2; Table 2) may have provided an opportunity for increased reproduction during the following summer for northern red-backed voles. Both lemmings and voles often coexist by using different microhabitats in tundra environments, with lemmings inhabiting drier habitats and voles inhabiting wetter habitats [42]. The use of different microhabitats limits competition between these rodents, which could minimize transmission risk from one species to another. Given that water-borne transmission has been well-documented for F. tularensis and that it can remain viable in cold water (8°C) for at least 70 days, it is therefore not surprising that rodents that occupy wetter environments may play a larger role in transmission of the bacteria [43]. None of the lemmings and voles sampled during this study were actively infected with F. tularensis. High mortality in rodents following infection suggests that it is unlikely that infected animals would be collected during snap trapping, as foraging rodents should generally be healthy animals [5]. Our sample size was also quite small (n=21), probably sampling an insignificant proportion of the population. Rodent mortality events may go undetected in tundra ecosystems (large geographic area with little human activity), highlighting the importance of identifying sentinel species for F. tularensis that will scavenge carcasses of these small mammals. It is important to note that there are no studies that have investigated lethality following F. tularensis infection in Arctic rodents. One study found that rats infected with subsp. tularensis (type A) did not survive past 72 h [44]. Documenting mortality for small mammals in the wild is complicated by the fact that scavengers are likely to consume carcasses before humans notice these events, especially in remote locations. However, during population peaks, mortality may be so high that scavengers cannot keep up with the number of dead animals. For example, this was seen during an outbreak of subsp. holarctica (type B) in deer mice from Canada [45]. Thus, it is not possible to estimate lemming or vole mortality due to tularemia without studies in controlled environments, and outbreaks may go unnoticed (depending on population density).Weaned juvenile foxes appear to be ideal sentinels for summer prevalence, and surveillance at den sites around communities may be a useful indicator of seasonal risk for rodent-borne diseases (Table 1). Foxes rely heavily on voles and lemmings as a food source, and they are important predictors for litter size, breeding density, and annual variation in fox abundance [46,47]. Thus, monitoring reproductive success of arctic foxes and identifying years with a higher density of young foxes may provide important information with regards to F. tularensis risk in the environment. Our study site at Karrak Lake is home to one of the largest white goose colonies in the Canadian Arctic, and foxes in this region rely heavily on the goose population as a dietary source during the summer months [47]. Despite this seasonal superabundance of migratory prey, we identified associations between F. tularensis exposure and rodent abundance, suggesting that foxes can still be useful sentinels in regions where they have a diversified diet. Lower goose density during the year prior to fox sampling was associated with F. tularensis exposure in the first model that included serology results for all foxes from Karrak Lake (Model 1; Table 2), which is logical, as lower numbers of lemmings and geese during the summer prior to the outbreak year in 2018 would have led to higher consumption of voles and potentially more exposure to the bacteria. Birds can be infected with F. tularensis, migratory birds have been implicated in the spread of the bacteria via the transportation of ectoparasites, and direct bird-to-human transmission has been documented [20]. Although birds may play a role in the transmission of F. tularensis at Karrak Lake (Figure 1), none of the nest fleas or goose spleens contained F. tularensis DNA. In fact, an interesting research question for the future would be if years with higher goose density in the colony might dilute transmission of F. tularensis by providing a significant food source for foxes, thus reducing consumption of rodents.A variety of insects were collected and tested for F. tularensis DNA during this study, and none were positive. While sample size was relatively small for fleas and black flies, the sample size was large for mosquitoes (n = 1163). Mosquitoes were collected during the summer of 2018, when we observed the highest seroprevalence of F. tularensis in both adult and juvenile foxes. DNA of F. tularensis has been identified in mosquitoes from North America (Fairbanks, Alaska); however, these were all collected below the treeline [16]. Our study suggests that vectors may not be significantly involved in the transmission of F. tularensis in the Canadian Arctic, though further studies are needed to identify whether insects play a role in transmission of the bacteria above the treeline. Serum samples collected from live-captured foxes were significantly more likely to be positive than whole blood collected from carcasses, which may be attributed to three potential reasons. First, this may be due to sample quality, as carcasses are often frozen and thawed several times during skinning and necropsy. Second, this may reflect spatial variation between sample locations, as live trapping at Karrak Lake occurred on the mainland of Nunavut and fox carcasses were collected from trappers in communities around the Arctic Archipelago. Though foxes can disperse across long distances and over the Arctic Sea ice [48], the absence of voles on the islands may have contributed to the low seroprevalence observed in fox carcasses. Lemmings are generally the only rodents collected during snap-trapping efforts on these islands (Dicrostonyx and Lemmus), while both lemmings and voles are present in ecosystems further south, such as Karrak Lake [18,49]. There are differences between these two groups of rodents in their habitat use (voles are often associated with aquatic habitats) and other life history traits that influence their reservoir potential for F. tularensis [7]. Third, the timing of the trapping season may also impact the number of positives observed, as trappers typically wait until foxes have a full winter coat before setting out traplines (from November to March). As F. tularensis can be transmitted via arthropods or ingestion of contaminated water sources, freezing temperatures during the trapping season in the Arctic minimizes these sources of transmission (Figure 1) [2]. The potential for transmission via contact with rodents continues in the winter, though dense snow cover and freezing conditions may reduce the ability of foxes to scavenge rodent carcasses during the high-mortality events that are associated with tularemia epizootics [5]. Serum samples from live-captured foxes at Karrak Lake were collected during late spring and summer (May–July) of each year, which would provide a more favorable environment for transmission. Thus, foxes may be more effective sentinels if samples are collected in the summer vs. winter, especially if antibody production is short-lived.

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