Clayton E. Cressler

Antimicrobial resistance is an emergent property of ecological interactions within complex microbial communities. Environmental perturbations, such as high-dose antimicrobial treatment, can alter competitive interactions in ways that either promote or suppress drug-resistant pathogens. Leveraging these competitive interactions shows promise in managing drug resistance in cancer, malaria, and bacteria. However, the broader utility of this approach remains limited by an incomplete understanding of how selective pressures imposed by antimicrobials interact with other environmental factors to shape the emergence and persistence of resistance. Here, we develop a general mathematical framework for investigating how environmental context, including homogenization, resource availability, and growth-efficiency trade-offs that are relevant for bacterial competition shape resistance dynamics. Anthropogenic changes can modify each of these factors in systems such as the gut and soil microbiomes, which are increasingly recognized as critical reservoirs of antimicrobial-resistant bacteria. Our results suggest that environmental structure determines not only whether resistance can be suppressed, but which competitive mechanisms can do so. Environmental homogenization creates a narrow set of conditions under which faster-growing drug-sensitive strains can suppress resistant competitors. In contrast, environmental heterogeneity combined with resource limitation can enable efficient drug-sensitive strains to competitively suppress drug-resistant strains and prevent the evolution of drug resistance. Together, these results join mounting evidence that ecological interactions can be leveraged alongside traditional interventions to more effectively limit antimicrobial resistance. More broadly, our results indicate that anthropogenic pressures that homogenize environments and eliminate competitors may increase the risk of promoting the evolution of drug resistance. Author summary: Managing antimicrobial resistance will require strategies that extend beyond reliance on new or existing antimicrobials. An emerging paradigm is that harnessing ecological interactions may enable us to constrain or event prevent the emergence of drug resistance, rather than continually chasing it. We show that rather than relying on directly killing resistant bacteria, resistance can be limited by via competitive interactions between drug-sensitive and drug-resistant strains, but the best strategy depends on environmental conditions. Environmental homogenization and nutrient enrichment can promote the persistence and evolution of antimicrobial resistance because they limit opportunities for competitive suppression. In contrast, environmental heterogeneity favors drug-sensitive strains that use resources more efficiently. Under these conditions, resistant strains are suppressed before they can spread or evolve. These results may help explain why drug-resistant pathogens persist in some patients of environmental hot spots. Additionally, these results help mechanistically explain why promoting more diverse and heterogeneous microbiomes through, for example, probiotics or regenerative agricultural practices, can provide a powerful strategy to manage antimicrobial resistance.

Due to long co-evolutionary histories, many zoonotic pathogens are thought to exert little or no negative effects on their wildlife reservoir hosts. However, there remains a lack of rigorous investigations in natural settings. We conducted a 3-year factorial field experiment to investigate how survival of the Puumala hantavirus (PUUV) reservoir, the bank vole, is impacted by PUUV infection, nematode infections, and food availability. We hypothesized that PUUV would not impact survival, but that coinfection with nematodes would negatively impact survival, and that increased food availability would mitigate the negative effects of coinfection. Surprisingly, we demonstrated that PUUV infected voles had substantially reduced survival when compared to uninfected voles, and this strong negative effect manifested in young voles. Nematode removal increased survival of young voles and food supplementation interacted with movement rather than survival. Our results provide empirical evidence in a natural system for infection reducing survival of its reservoir host.

Anthropogenic food subsidies can have profound influences on wildlife behavior and health, including exposure to parasites. In many host–macroparasite systems, parasite exposure is tied to foraging behavior, but how different distributions of food subsidy shape macroparasite encounter and population‐level impacts is poorly understood. Here we modify a mathematical model of macroparasite transmission to explore how food subsidies could change parasite encounter rates and between‐host variation in parasite burdens, reflecting changes in host foraging and conspecific overlap. Hosts experience the highest average parasite abundance and associated reductions in population size when food subsidies increase and homogenize parasite encounter rates, for example when hosts center their home ranges on a point food source and overlap with many conspecifics. Conversely, hosts experience the lowest parasite abundance and impacts when subsidies result in lower and more heterogeneous parasite encounter rates, for example when multiple patchily distributed subsidies subdivide host populations and increase host commute times to food at the expense of time spent foraging. Even when resources affect other processes such as improving host immunity or fecundity, the overall effect of subsidies on infection is more strongly driven by changes in parasite encounter rates through altered foraging behavior. These patterns are robust to different effect sizes of resource subsidy on foraging and nonforaging parameters. Our findings demonstrate that resource‐driven shifts in host foraging behavior could play an integral role in determining infection dynamics for parasites with environmental (free‐living) infectious stages, with consequences for wildlife provisioning in recreational, conservation, and management contexts.

Anthropogenic changes to the environment, including altered food resource availability, influence host physiology, behaviour, and population dynamics, which can have strong downstream consequences on wildlife disease dynamics. Additionally, some individuals within a population contribute disproportionately to infection as ‘super-shedders’ of infection, but the extent to which food availability alters the likelihood of super-shedding and overall parasite infection patterns is poorly understood. We conducted a three-year field experiment in southern Finland to investigate how food supplementation and parasite removal affect nematode infection measures and the relationship between nematode infection and fitness of wild bank voles ( Clethrionomys glareolus ). Using a factorial design across 12 populations, we manipulated food availability and administered anthelmintic treatments to assess effects on nematode infection status, intensity, and two measures of super-shedding (abundance super-shedding, intensity super-shedding). We also examined parasite impacts on host fitness, including apparent survival probability and reproductive status. Food supplementation did not affect likelihood of infection, intensity or intensity super-shedding, but did reduce the likelihood of abundance super-shedding, suggesting an effect of food availability on infection heterogeneity. We also identified an interaction between nematode infection status and host age on fitness. Notably, infected younger individuals had reduced survival and reproduction, but infected older individuals had greater survival and reproduction compared to their uninfected counterparts. Our study provides novel empirical evidence on how anthropogenic changes in food availability can influence parasite transmission dynamics and the fitness consequences of these sub-lethal parasites in a wildlife system.

1. Anthropogenic food subsidies can have profound influences on wildlife behavior and health, including exposure to parasites. In many host-macroparasite systems, parasite exposure is tied to foraging behavior, but how different distributions of food subsidy shape macroparasite encounter and population-level impacts is poorly understood. 2. Here we modify a mathematical model of macroparasite transmission to explore how food subsidies could change parasite encounter rates and between-host variation in parasite burdens, reflecting changes in host foraging and conspecific overlap. 3. Hosts experience the highest average parasite abundance, and associated reductions in population size, when food subsidies increase and homogenize parasite encounter rates, for example when hosts center their home ranges on a point food source and overlap with many conspecifics. Conversely, hosts experience the lowest parasite abundance and impacts when subsidies result in lower and more heterogeneous parasite encounter rates, for example when multiple, patchily-distributed subsidies subdivide host populations and increase host commute times to food at the expense of time spent foraging. Even when resources affect other processes such as improving host immunity or fecundity, the overall effect of subsidies on infection is more strongly driven by changes in parasite encounter rates through altered foraging behavior. These patterns are robust to different effect sizes of resource subsidy on foraging and non-foraging parameters. 4. The finding that host foraging behavior strongly influences infection outcomes in environmentally-acquired parasites has implications for the provisioning of wildlife for recreation, conservation, and management. We advocate for distributing food subsidies in ways that reduce artificial aggregation of hosts and the time animals spend at feeding stations, or that reduce environmental parasite encounters while feeding.

Most parasites are able to infect several host species, yet generalism is anticipated to be a costly strategy. Parasite abundance provides an important indicator of fitness because it is promoted by longevity and fecundity, which are correlated with a parasite’s basic reproductive number. Using a global database of parasitic helminths of terrestrial mammals, we show that the abundance of parasitic helminths is phylogenetically structured across helminth species. High parasite abundance can be achieved through three separate components: infecting abundant host species, having a high infection success (prevalence) or achieving high parasite abundance withinhost individuals (infection intensity). Both phylogenetically specialist and generalist strategies can reach high abundances but through different strategies. Relatively specialist parasites achieve higher abundance than generalists on their principal host species but rely on host relatedness to infect multiple species. For generalist parasites, geographic overlap with and diet similarity to principal host species are better predictors of parasite abundance than host relatedness. This study characterizes constraints on parasite host range and provides novel context to evaluate the potential for parasites to establish in new host species.

Experiments have shown that predation‐risk effects on prey fitness can be highly contingent on environmental conditions, suggesting a potential difficulty in generalizing risk effects on prey abundance in natural settings. Rather than study the influence of a particular controlled factor, we examine the problem with a novel approach. We examined the influence of risk effects in multiple experiments performed under similar study conditions. Any differences in the experiments would typically be deemed incidental, that is, they would not be given attention in methodology, nor be presented as factors affecting results or inferences. Therefore, any differences in the magnitude and direction of risk effects among experiments would indicate that risk effects on prey population abundance are strongly influenced by context in natural communities. The multiple experiments were conducted under similar conditions, objectives, measurables and implementation, and captured much of the complexity of natural systems (e.g., they were performed with diverse prey assemblages (≥ 11 taxa) over multiple prey generations). Our results highlight the potentially profound context dependence of risk effects: risk effects on the density of some zooplankton species varied between a significant negative effect in one experiment to a significant positive effect in another, whereas other species showed significant negative or positive effects in one experiment and no effect in another. We review mechanisms that could underlie risk effects having opposite effects on the same prey. Our findings illustrate that risk effects observed in one study may not hold, even for the same species in the same system.

Infection duration affects individual host fitness and between-host transmission. Whether an infection is cleared or becomes chronic depends on the complex interaction between host immune responses and parasite growth. Empirical and theoretical studies have suggested that there are critical thresholds of parasite dose that can determine clearance versus chronicity, driven by the ability of the parasite to manipulate host immunity. However, the mammalian immune response is characterized by strong positive and negative feedback loops that could generate duration thresholds even in the absence of direct immunomodulation. Here, we derive and analyse a simple model for the interaction between T-cell subpopulations and parasite growth. We show that whether an infection is cleared or not is very sensitive to the initial immune state, parasite dose and strength of immunological feedbacks. In particular, chronic infections are possible even when parasites provoke a strong and effective immune response and lack any ability to immunomodulate. Our findings indicate that the initial immune state, which often goes unmeasured in empirical studies, is a critical determinant of infection duration. This work also has implications for epidemiological models, as it implies that infection duration will be highly variable among individuals, and dependent on each individual’s infection history.

Spatial overlap between animals in wildlife populations can have important implications for pathogen transmission. Ecological factors and animal demographic traits can influence animal space use and spatial overlap, but it is unclear how these interactions drive pathogen transmission. We experimentally manipulated wild bank vole populations via resource supplementation and anthelmintic treatment. Using network analysis, we investigated the relationship between spatial overlap and infection likelihood of an endemic zoonotic hantavirus, including how vole sex and reproductive status interact with spatial behaviour to affect infection likelihood. Spatial overlap in a previous month drove the likelihood of current hantavirus infection, and food supplementation and anthelmintic treatment altered the effects of spatial overlap on infection likelihood. Vole sex and reproductive status were important factors determining whether spatial overlap increased or decreased the likelihood of hantavirus infection and interacted with resource supplementation and anthelmintic treatment, generating different infection dynamics in each treatment. Our research provides rare empirical evidence linking previous spatial overlap to current infection status in wildlife populations, with implications for understanding disease dynamics and persistence as well as developing effective management efforts. We further highlight the importance of incorporating variation in ecological factors and host demography when studying pathogen transmission in wildlife systems.