Food availability leads to more connected contact networks among peridomestic zoonotic reservoir hosts.

The North American deermouse (Peromyscus maniculatus) is a reservoir host for many zoonotic pathogens. Deermice have been well studied, but few studies have attempted to understand social interactions within the species despite these interactions being key to understanding disease transmission. We performed an experiment to determine if supplemental food or nesting material affected social interactions of deermice and tested if interactions increased with increasing population density. We constructed three simulated buildings that received one of three treatments: food, nesting material, or control. Mice were tagged with passive integrated transponder (PIT) tags, and their movement in and out of buildings was monitored with PIT tag readers. PIT tag readings were used to create contact networks, assuming a contact if two deermice were in the same building at the same time. We found that buildings with food led to contact networks that were approximately 10 times more connected than buildings with nesting material or control buildings. We also saw a significant effect of population density on the average number of contacts per individual. These results suggest that food supplementation which is common in peridomestic settings, can significantly increase contacts between reservoir hosts, potentially leading to increased transmission of zoonotic viruses within the reservoir host and from reservoir hosts to humans.

Species diversity concurrently dilutes and amplifies transmission in a zoonotic host-pathogen system through competing mechanisms.

In this era of unprecedented biodiversity loss and increased zoonotic disease emergence, it is imperative to understand the effects of biodiversity on zoonotic pathogen dynamics in wildlife. Whether increasing biodiversity should lead to a decrease or increase in infection prevalence, termed the dilution and amplification effects, respectively, has been hotly debated in disease ecology. Sin Nombre hantavirus, which has an ∼35% mortality rate when it spills over into humans, occurs at a lower prevalence in the reservoir host, the North American deermouse, in areas with higher small mammal diversity-a dilution effect. However, the mechanism driving this relationship is not understood. Using a mechanistic mathematical model of infection dynamics and a unique long-term, high-resolution, multisite dataset, it appears that the observed dilution effect is a result of increasing small-mammal diversity leading to decreased deermouse population density and, subsequently, prevalence (a result of density-dependent transmission). However, once density is taken into account, there is an increase in the transmission rate at sites with higher diversity-a component amplification effect. Therefore, dilution and amplification are occurring at the same time in the same host-pathogen system; there is a component amplification effect (increase in transmission rate), but overall a net dilution because the effect of diversity on reservoir host population density is stronger. These results suggest we should focus on how biodiversity affects individual mechanisms that drive prevalence and their relative strengths if we want to make generalizable predictions across host-pathogen systems.

INTERSPECIFIC COMPARISON OF HANTAVIRUS PREVALENCE IN PEROMYSCUS POPULATIONS FROM A FRAGMENTED AGRO-ECOSYSTEM IN INDIANA, USA.

Comparatively little is known about hantavirus prevalence within rodent populations from the Midwestern US, where two species of native mice, the prairie deer mouse ( Peromyscus maniculatus bairdii) and the white-footed mouse ( Peromyscus leucopus noveboracensis), are dominant members of rodent communities. We sampled both species in central Indiana and tested individuals for presence of hantavirus antibodies to determine whether seroprevalence (percent of individuals with antibodies reactive to Sin Nombre virus antigen) differed between species, or among different habitat types within fragmented agro-ecosystems. Prevalence of hantavirus antibodies varied significantly between species, with seroprevalence in prairie deer mice (21.0%) being nearly four times higher than in white-footed mice (5.5%). Seroprevalence was almost eight times higher within the interior of row-crop fields (37.7%) occupied solely by prairie deer mouse populations, relative to field edges (5.2%) or adjacent forest habitat (6.1%). In the fragmented Midwestern agro-ecosystem of this study, prairie deer mice appear to be the dominant hantavirus reservoir, with particularly high seroprevalence in populations within the interior of row-crop fields.

Toward a Mechanistic Understanding of Environmentally Forced Zoonotic Disease Emergence: Sin Nombre Hantavirus.

Understanding the environmental drivers of zoonotic reservoir and human interactions is crucial to understanding disease risk, but these drivers are poorly predicted. We propose a mechanistic understanding of human-reservoir interactions, using hantavirus pulmonary syndrome as a case study. Crucial processes underpinning the disease's incidence remain poorly studied, including the connectivity among natural and peridomestic deer mouse host activity, virus transmission, and human exposure. We found that disease cases were greatest in arid states and declined exponentially with increasing precipitation. Within arid environments, relatively rare climatic conditions (e.g., El Niño) are associated with increased rainfall and reservoir abundance, producing more frequent virus transmission and host dispersal. We suggest that deer mice increase their occupancy of peridomestic structures during spring-summer, amplifying intraspecific transmission and human infection risk. Disease incidence in arid states may increase with predicted climatic changes. Mechanistic approaches incorporating reservoir behavior, reservoir-human interactions, and pathogen spillover could enhance our understanding of global hantavirus ecology, with applications to other directly transmitted zoonoses.

Increased detection of Sin Nombre hantavirus RNA in antibody-positive deer mice from Montana, USA: evidence of male bias in RNA viremia.

Hantaviruses are widespread emergent zoonotic agents that cause unapparent or limited disease in their rodent hosts, yet cause acute, often fatal pulmonary or renal infections in humans. Previous laboratory experiments with rodent reservoir hosts indicate that hantaviruses can be cleared from host blood early in the infection cycle, while sequestered long term in various host organs. Field studies of North American deer mice (Peromyscus maniculatus), the natural reservoir of Sin Nombre hantavirus, have shown that viral RNA can be transiently detected well past the early acute infection stage, but only in the minority of infected mice. Here, using a non-degenerate RT-PCR assay optimized for SNV strains known to circulate in Montana, USA, we show that viral RNA can be repeatedly detected on a monthly basis in up to 75% of antibody positive deer mice for periods up to 3-6 months. More importantly, our data show that antibody positive male deer mice are more than twice as likely to have detectable SNV RNA in their blood as antibody positive females, suggesting that SNV-infected male deer mice are more likely to shed virus and for longer periods of time.

Human exposure to particulate matter potentially contaminated with sin nombre virus.

The most common mechanism for human exposure to hantaviruses throughout North America is inhalation of virally contaminated particulates. However, risk factors associated with exposure to particulates potentially contaminated with hantaviruses are generally not well understood. In North America, Sin Nombre virus (SNV) is the most common hantavirus that infects humans, causing hantavirus pulmonary syndrome, which has a significant mortality rate (approximately 35%). We investigated human exposure to particulate matter and evaluated the effects of season, location (sylvan and peridomestic environment), and activity (walking and sweeping) on generation of particulates at the breathing zone (1.5 m above the ground). We found greater volumes of small inhalable particulates during the spring and summer compared to the fall and winter seasons and greater volumes of small inhalable particulates produced in peridomestic, compared to sylvan, environments. Also, greater volumes of particulates were generated at the breathing zone while walking compared to sweeping. Results suggest that more aerosolized particles were generated during the spring and summer months. Our findings suggest that simply moving around in buildings is a significant source of human exposure to particulates, potentially contaminated with SNV, during spring and summer seasons. These findings could be advanced by investigation of what particle sizes SNV is most likely to attach to, and where in the respiratory tract humans become infected.

Transmission ecology of Sin Nombre hantavirus in naturally infected North American deermouse populations in outdoor enclosures.

Sin Nombre hantavirus (SNV), hosted by the North American deermouse (Peromyscus maniculatus), causes hantavirus pulmonary syndrome (HPS) in North America. Most transmission studies in the host were conducted under artificial conditions, or extrapolated information from mark-recapture data. Previous studies using experimentally infected deermice were unable to demonstrate SNV transmission. We explored SNV transmission in outdoor enclosures using naturally infected deermice. Deermice acquiring SNV in enclosures had detectable viral RNA in blood throughout the acute phase of infection and acquired significantly more new wounds (indicating aggressive encounters) than uninfected deermice. Naturally-infected wild deermice had a highly variable antibody response to infection, and levels of viral RNA sustained in blood varied as much as 100-fold, even in individuals infected with identical strains of virus. Deermice that infected other susceptible individuals tended to have a higher viral RNA load than those that did not infect other deermice. Our study is a first step in exploring the transmission ecology of SNV infection in deermice and provides new knowledge about the factors contributing to the increase of the prevalence of a zoonotic pathogen in its reservoir host and to changes in the risk of HPS to human populations. The techniques pioneered in this study have implications for a wide range of zoonotic disease studies.

Population density and seasonality effects on Sin Nombre virus transmission in North American deermice (Peromyscus maniculatus) in outdoor enclosures.

Surveys of wildlife host-pathogen systems often document clear seasonal variation in transmission; conclusions concerning the relationship between host population density and transmission vary. In the field, effects of seasonality and population density on natural disease cycles are challenging to measure independently, but laboratory experiments may poorly reflect what happens in nature. Outdoor manipulative experiments are an alternative that controls for some variables in a relatively natural environment. Using outdoor enclosures, we tested effects of North American deermouse (Peromyscus maniculatus) population density and season on transmission dynamics of Sin Nombre hantavirus. In early summer, mid-summer, late summer, and fall 2007-2008, predetermined numbers of infected and uninfected adult wild deermice were released into enclosures and trapped weekly or bi-weekly. We documented 18 transmission events and observed significant seasonal effects on transmission, wounding frequency, and host breeding condition. Apparent differences in transmission incidence or wounding frequency between high- and low-density treatments were not statistically significant. However, high host density was associated with a lower proportion of males with scrotal testes. Seasonality may have a stronger influence on disease transmission dynamics than host population density, and density effects cannot be considered independent of seasonality.

Prediction of Peromyscus maniculatus (deer mouse) population dynamics in Montana, USA, using satellite-driven vegetation productivity and weather data.

Deer mice (Peromyscus maniculatus) are the main reservoir host for Sin Nombre virus, the primary etiologic agent of hantavirus pulmonary syndrome in North America. Sequential changes in weather and plant productivity (trophic cascades) have been noted as likely catalysts of deer mouse population irruptions, and monitoring and modeling of these phenomena may allow for development of early-warning systems for disease risk. Relationships among weather variables, satellite-derived vegetation productivity, and deer mouse populations were examined for a grassland site east of the Continental Divide and a sage-steppe site west of the Continental Divide in Montana, USA. We acquired monthly deer mouse population data for mid-1994 through 2007 from long-term study sites maintained for monitoring changes in hantavirus reservoir populations, and we compared these with monthly bioclimatology data from the same period and gross primary productivity data from the Moderate Resolution Imaging Spectroradiometer sensor for 2000-06. We used the Random Forests statistical learning technique to fit a series of predictive models based on temperature, precipitation, and vegetation productivity variables. Although we attempted several iterations of models, including incorporating lag effects and classifying rodent density by seasonal thresholds, our results showed no ability to predict rodent populations using vegetation productivity or weather data. We concluded that trophic cascade connections to rodent population levels may be weaker than originally supposed, may be specific to only certain climatic regions, or may not be detectable using remotely sensed vegetation productivity measures, although weather patterns and vegetation dynamics were positively correlated.

Delayed density-dependent prevalence of Sin Nombre virus infection in deer mice (Peromyscus maniculatus) in central and western Montana.

Understanding how transmission of zoonoses takes place within reservoir populations, such as Sin Nombre virus (SNV) among deer mice (Peromyscus maniculatus), is important in determining the risk of exposure to other hosts, including humans. In this study, we examined the relationship between deer mouse populations and the prevalence of antibodies to SNV, a system where the effect of host population abundance on transmission is debated. We examined the relationship between abundance of deer mice in late summer-early autumn and SNV antibody prevalence the following spring-early summer (termed delayed density-dependent [DDD] prevalence of infection) at both regional and local scales, using 12 live-trapping grids for 11-14 yr, across central and western Montana. When all trapping grids were combined (regional scale), there was a significant DDD relationship for individual months and when months within seasons were averaged. However, within individual grids (local scale), evidence of DDD prevalence of infection was observed consistently at only one location. These findings suggest that, although there is evidence of DDD prevalence of infection at regional scales, it is not always apparent at local scales, possibly because the regional pattern of DDD infection prevalence is driven by differences in abundance and prevalence among sites, rather than in autumn-spring delays. Transmission of SNV may be more complex than the original hypothesis of autumn-spring delayed density dependence suggests. This complexity is also supported by recent modeling studies. Empirical investigations are needed to determine the duration and determinants of time-lagged abundance and antibody prevalence. Our study suggests predicting local, human exposure risk to SNV in spring, based on deer mouse abundance in autumn, is unlikely to be a reliable public health tool, particularly at local scales.

A temporal dilution effect: hantavirus infection in deer mice and the intermittent presence of voles in Montana.

The effect of intermittently occurring, non-reservoir host species on pathogen transmission and prevalence in a reservoir population is poorly understood. We investigated whether voles, Microtus spp., which occur intermittently, influenced estimated standing antibody prevalence (ESAP) to Sin Nombre hantavirus (SNV, Bunyaviridae: Hantavirus) among deer mice, Peromyscus maniculatus, whose populations are persistent. We used 14 years of data from central Montana to investigate whether ESAP among deer mice was related to vole presence or abundance while controlling for the relationship between deer mouse abundance and ESAP. We found a reduction in deer mouse ESAP associated with the presence of voles, independent of vole abundance. A number of studies have documented that geographic locations which support a higher host diversity can be associated with reductions in pathogen prevalence by a hypothesized dilution effect. We suggest a dilution effect may also occur in a temporal dimension at sites where host richness fluctuates. Preservation of host diversity and optimization of environmental conditions which promote occurrence of ephemeral species, such as voles, may result in a decreased ESAP to hantaviruses among reservoir hosts. Our results may extend to other zoonotic infectious diseases.

Grazing Effects on Deer Mice with Implications to Human Exposure to Sin Nombre Virus.

We examined the effects of grazing on deer mouse (Peromyscus maniculatus) movements into buildings using passive integrated transponder (PIT) technology and small simulated buildings located on 0.6-ha treatment (grazing) and control (no grazing) plots. Twelve experimental 9-day trials were conducted over the course of the study. During these trials, mouse movements into buildings were monitored during three time periods (each 3 days in length). In the treatment plots these time periods corresponded to pre-grazing, grazing, and post grazing by horses. The number of individual deer mice entering buildings over time decreased in both the grazed and control plots during the 9 days of each experiment. The number of entrances per/individual among the pre-grazing, grazing and post grazing periods was different between control and treated plots for both males and females. The distribution of entrances/individual among the three periods differed between males and females in both grazed and control plots. The habitat modification caused by grazing appeared to reduce deer mouse activity (entrances/individual) in buildings but does not affect the number of mice entering buildings. Reducing vegetative cover by grazing or mowing may not affect the number of mice investigating small structures but grazing creates different activity patterns in the structures for neighboring deer mice.

Effect of Rock Cover on Small Mammal Abundance in a Montana Grassland.

We examined the influence of rock cover, as an indicator of presumable retreat site availability on the abundance of deer mice (Peromyscus maniculatus) and prevalence of Sin Nombre virus (SNV) using long-term live trapping and habitat data from three live trapping grids and a short-term (three month), spatially replicated study across three slopes in Cascade County, Montana. In our long-term study, we found that deer mice were more abundant at a live-trapping grid with greater rock cover, than two grids with less rock cover. There was a non-significant trend(P = 0.053) for deer mice to be more abundant in rocky sites in the short term study. In the long-term study, average SNV antibody prevalence among deer mice was slightly greater (5.0 vs. 3.5 % on average) at the live trapping grid with more rock cover, than the grid with less rock cover. We were unable to demonstrate differences in SNV antibody prevalence among treatments in the short-term study. Further studies are needed to elucidate the multiple determinants of deer mouse abundance and SNV prevalence in grassland ecosystem and other habitat types.

Environmental monitoring to enhance comprehension and control of infectious diseases.

In a world of emerging and resurging infectious diseases, dominated by zoonoses, environmental monitoring plays a vital role in our understanding their dynamics and their spillover to humans. Here, we critically review the ecology, epidemiology and need for monitoring of a variety of directly transmitted (Sin Nombre virus, Avian Influenza) and vector-borne (Ross River virus, West Nile virus, Lyme disease, anaplasmosis and babesiosis) zoonoses. We focus on the valuable role that existing monitoring plays in the understanding of these zoonoses, the demands for new monitoring, and how improvements can be made to existing monitoring. We also identify the fruitful outcomes which would result from implementation of the monitoring demands we have highlighted. This review aims to promote improvements in our understanding of zoonoses, their management, and public health by encouraging discussion among researchers and public health officials.

Sampling frequency differentially influences interpretation of zoonotic pathogen and host dynamics: Sin Nombre virus and deer mice.

Reports of novel emerging and resurging wildlife and zoonotic diseases have increased. Consequently, integration of pathogen sampling into wildlife monitoring programs has grown. Sampling frequency influences interpretations of coupled host-pathogen dynamics, with direct implication to human exposure risk, but has received little empirical attention. To address this, a 15-year study, based on monthly sampling, of deer mouse (Peromyscus maniculatus) populations and Sin Nombre virus (SNV; a virulent disease in humans) dynamics was evaluated. Estimates of deer mouse abundance, number infected with SNV, and SNV prevalence from sampling less frequently than each month (achieved by deletion of months and recalculation of these parameters) were compared to monthly sampling frequencies. Deer mouse abundance was underestimated (10%-20%), SNV prevalence was overestimated when prevalence was high (>15%), and fewer annual extremes of abundance and infection were detected when sampling frequency was less than monthly. Effort necessary to detect temporal dynamics of SNV differed from effort to detect demographic patterns in deer mouse abundance. Findings here are applicable to sampling strategies for other host-pathogen dynamics and have direct implications for allocation of public health resources and intervention programs.

Hantavirus transmission in sylvan and peridomestic environments.

We developed a compartmental model for hantavirus infection in deer mice (Peromyscus maniculatus) with the goal of comparing relative importance of direct and indirect transmission in sylvan and peridomestic environments. A direct transmission occurs when the infection is mediated by the contact of an infected and an uninfected mouse, while an indirect transmission occurs when the infection is mediated by the contact of an uninfected mouse with, for instance, infected soil. Based on population dynamics data and estimates of hantavirus decay in the two types of environments, our model predicts that direct transmission dominates in the sylvan environment, while both pathways are important in peridomestic environments. The model allows us to compute a basic reproduction number R(0), which indicates whether the virus will be endemic or eradicated from the mouse population, in both an autonomous and a time-periodic model. Our analysis can be used to evaluate various eradication strategies.

Seasonal dispersal patterns of sylvan deer mice (Peromyscus maniculatus) within Montana rangelands.

We examined seasonal dispersal patterns and timing of new infections of Sin Nombre virus (SNV), as determined by recent acquisition of antibodies (seroconversion), in deer mice (Peromyscus maniculatus) at two Montana rangeland study sites over three years, 2004-2007. One study site was located in grassland habitat, and the other was located in shrub-steppe. In Montana, both of these habitats are commonly associated with peridomestic environments (in and around buildings). Peridomestic environments are where most reported human cases of hantavirus pulmonary syndrome (HPS) likely originate. Furthermore, deer mice dispersing from sylvan habitats colonize peridomestic environments. Thus, a thorough understanding of deer mouse dispersal is needed to help predict when humans are most at risk for exposure to SNV. We trapped mice at each study site twice a month, accumulating 85,200 trap nights of effort and capturing 6,185 individual deer mice a total of 22,654 times. We documented 980 dispersing individuals over 3 yr. We found positive correlations between the number of dispersing mice and number captured at each site, but there were no statistically significant seasonal differences in the number of dispersing mice. However, we did find a spring/summer bias in mice that seroconverted and dispersed, suggesting that recently infected deer mice are most likely to enter settings where humans may be exposed to SNV during spring and summer.

An Experimental Test of Factors Attracting Deer Mice into Buildings.

Deer mice (Peromyscus maniculatus) are the principal reservoir host of Sin Nombre virus (SNV). Deer mice use a wide variety of habitats including peridomestic settings in and around human dwellings, their presence in and around homes has been implicated as a risk factor for acquiring Hantavirus Pulmonary Syndrome. Deer mice are believed to enter buildings in order to gain access to a variety of resources including food, bedding material, and better thermal microclimates. However, no one has experimentally tested which factors influence mice use of buildings. We conducted experiments using small simulated buildings to determine the effects of two factors, i.e., food and bedding material, on mouse activity in these buildings. We also examined if these effects varied with time of year. We found that deer mice entered our buildings regardless of the presence or absence of food or bedding. However, the amount of activity in buildings was affected by what they contained. We found significantly higher indices of activity in buildings containing food compared to both empty buildings (control) and buildings containing bedding material. Time of year did not affect activity in buildings.

Seroprevalence against Sin Nombre virus in resident and dispersing deer mice.

Through dispersal, deer mice (Peromyscus maniculatus) enter peridomestic settings (e.g., outbuildings, barns, cabins) and expose humans and other deer mouse populations to Sin Nombre virus (SNV). In June 2004, research on deer mouse dispersal was initiated at 2 locations in Montana. During the course of the study, over 6000 deer mouse movements were recorded, and more than 1000 of these movements were classified as dispersal movements. More than 1700 individual deer mice were captured and tested for SNV, revealing an average SNV antibody prevalence of approximately 11%. Most of the dispersing and antibody-positive individuals were adult males. Among the few subadult dispersing mice discovered during the study, none were seropositive for SNV. Our results suggest that dispersal rates are higher in high abundance populations of deer mice and that during peak times of dispersal, human exposure to SNV, which commonly occurs in peridomestic settings, could increase.