The impact of within-host coinfection interactions on between-host parasite transmission dynamics varies with spatial scale.

Within-host interactions among coinfecting parasites can have major consequences for individual infection risk and disease severity. However, the impact of these within-host interactions on between-host parasite transmission, and the spatial scales over which they occur, remain unknown. We developed and apply a novel spatially explicit analysis to parasite infection data from a wild wood mouse (Apodemus sylvaticus) population. We previously demonstrated a strong within-host negative interaction between two wood mouse gastrointestinal parasites, the nematode Heligmosomoides polygyrus and the coccidian Eimeria hungaryensis, using drug-treatment experiments. Here, we show this negative within-host interaction can significantly alter the between-host transmission dynamics of E. hungaryensis, but only within spatially restricted neighbourhoods around each host. However, for the closely related species E. apionodes, which experiments show does not interact strongly with H. polygyrus, we did not find any effect on transmission over any spatial scale. Our results demonstrate that the effects of within-host coinfection interactions can ripple out beyond each host to alter the transmission dynamics of the parasites, but only over local scales that likely reflect the spatial dimension of transmission. Hence there may be knock-on consequences of drug treatments impacting the transmission of non-target parasites, altering infection risks even for non-treated individuals in the wider neighbourhood.

Experimental assessment of cross-species transmission in a natural multihost-multivector-multipathogen community.

Vector-borne pathogens, many of which cause major suffering worldwide, often circulate in diverse wildlife communities comprising multiple reservoir host and/or vector species. However, the complexities of these systems make it challenging to determine the contributions these different species make to transmission. We experimentally manipulated transmission within a natural multihost-multipathogen-multivector system, by blocking flea-borne pathogen transmission from either of two co-occurring host species (bank voles and wood mice). Through genetic analysis of the resulting infections in the hosts and vectors, we show that both host species likely act together to maintain the overall flea community, but cross-species pathogen transmission is relatively rare-most pathogens were predominantly found in only one host species, and there were few cases where targeted treatment affected pathogens in the other host species. However, we do provide experimental evidence of some reservoir-spillover dynamics whereby reductions of some infections in one host species are achieved by blocking transmission from the other host species. Overall, despite the apparent complexity of such systems, we show there can be 'covert simplicity', whereby pathogen transmission is primarily dominated by single host species, potentially facilitating the targeting of key hosts for control, even in diverse ecological communities.

Genomic epidemiology of Escherichia coli: antimicrobial resistance through a One Health lens in sympatric humans, livestock and peri-domestic wildlife in Nairobi, Kenya.

BACKGROUND: Livestock systems have been proposed as a reservoir for antimicrobial-resistant (AMR) bacteria and AMR genetic determinants that may infect or colonise humans, yet quantitative evidence regarding their epidemiological role remains lacking. Here, we used a combination of genomics, epidemiology and ecology to investigate patterns of AMR gene carriage in Escherichia coli, regarded as a sentinel organism. METHODS: We conducted a structured epidemiological survey of 99 households across Nairobi, Kenya, and whole genome sequenced E. coli isolates from 311 human, 606 livestock and 399 wildlife faecal samples. We used statistical models to investigate the prevalence of AMR carriage and characterise AMR gene diversity and structure of AMR genes in different host populations across the city. We also investigated household-level risk factors for the exchange of AMR genes between sympatric humans and livestock. RESULTS: We detected 56 unique acquired genes along with 13 point mutations present in variable proportions in human and animal isolates, known to confer resistance to nine antibiotic classes. We find that AMR gene community composition is not associated with host species, but AMR genes were frequently co-located, potentially enabling the acquisition and dispersal of multi-drug resistance in a single step. We find that whilst keeping livestock had no influence on human AMR gene carriage, the potential for AMR transmission across human-livestock interfaces is greatest when manure is poorly disposed of and in larger households. CONCLUSIONS: Findings of widespread carriage of AMR bacteria in human and animal populations, including in long-distance wildlife species, in community settings highlight the value of evidence-based surveillance to address antimicrobial resistance on a global scale. Our genomic analysis provided an in-depth understanding of AMR determinants at the interfaces of One Health sectors that will inform AMR prevention and control.

Tissue tropism and transmission ecology predict virulence of human RNA viruses.

Novel infectious diseases continue to emerge within human populations. Predictive studies have begun to identify pathogen traits associated with emergence. However, emerging pathogens vary widely in virulence, a key determinant of their ultimate risk to public health. Here, we use structured literature searches to review the virulence of each of the 214 known human-infective RNA virus species. We then use a machine learning framework to determine whether viral virulence can be predicted by ecological traits, including human-to-human transmissibility, transmission routes, tissue tropisms, and host range. Using severity of clinical disease as a measurement of virulence, we identified potential risk factors using predictive classification tree and random forest ensemble models. The random forest approach predicted literature-assigned disease severity of test data with mean accuracy of 89.4% compared to a null accuracy of 74.2%. In addition to viral taxonomy, the ability to cause systemic infection was the strongest predictor of severe disease. Further notable predictors of severe disease included having neural and/or renal tropism, direct contact or respiratory transmission, and limited (0 < R0 ≤ 1) human-to-human transmissibility. We present a novel, to our knowledge, comparative perspective on the virulence of all currently known human RNA virus species. The risk factors identified may provide novel perspectives in understanding the evolution of virulence and elucidating molecular virulence mechanisms. These risk factors could also improve planning and preparedness in public health strategies as part of a predictive framework for novel human infections.

The predicted impact of resource provisioning on the epidemiological responses of different parasites.

Anthropogenic activities and natural events such as periodic tree masting can alter resource provisioning in the environment, directly affecting animals, and potentially impacting the spread of infectious diseases in wildlife. The impact of these additional resources on infectious diseases can manifest through different pathways, affecting host susceptibility, contact rate and host demography. To date however, empirical research has tended to examine these different pathways in isolation, for example by quantifying the effects of provisioning on host behaviour in the wild or changes in immune responses in controlled laboratory studies. Furthermore, while theory has investigated the interactions between these pathways, this work has focussed on a narrow subset of pathogen types, typically directly transmitted microparasites. Given the diverse ways that provisioning can affect host susceptibility, contact patterns or host demography, we may expect the epidemiological consequences of provisioning to vary among different parasite types, dependent on key aspects of parasite life history, such as the duration of infection and transmission mode. Focusing on an exemplar empirical system, the wood mouse Apodemus sylvaticus, and its diverse parasite community, we developed a suite of epidemiological models to compare how resource provisioning alters responses for a range of these parasites that vary in their biology (microparasite and macroparasite), transmission mode (direct, environmental and vector transmitted) and duration of infection (acute, latent and chronic) within the same host population. We show there are common epidemiological responses to host resource provisioning across all parasite types examined. In particular, the epidemiological impact of provisioning could be driven in opposite directions, depending on which host pathways (contact rate, susceptibility or host demography) are most altered by the addition of resources to the environment. Broadly, these responses were qualitatively consistent across all parasite types, emphasising the importance of identifying general trade-offs between provisioning-altered parameters. Despite the qualitative consistency in responses to provisioning across parasite types, we predicted notable quantitative differences between parasites, with directly transmitted parasites (those conforming to SIR and SIS frameworks) predicted to show the strongest responses to provisioning among those examined, whereas the vector-borne parasites showed negligible responses to provisioning. As such, these analyses suggest that different parasites may show different scales of response to the same provisioning scenario, even within the same host population. This highlights the importance of knowing key aspects of host-parasite biology, to understand and predict epidemiological responses to provisioning for any specific host-parasite system.

Long-term temporal trends in gastrointestinal parasite infection in wild Soay sheep.

Monitoring the prevalence and abundance of parasites over time is important for addressing their potential impact on host life histories, immunological profiles and their influence as a selective force. Only long-term ecological studies have the potential to shed light on both the temporal trends in infection prevalence and abundance and the drivers of such trends, because of their ability to dissect drivers that may be confounded over shorter time scales. Despite this, only a relatively small number of such studies exist. Here, we analysed changes in the prevalence and abundance of gastrointestinal parasites in the wild Soay sheep population of St. Kilda across 31 years. The host population density (PD) has increased across the study, and PD is known to increase parasite transmission, but we found that PD and year explained temporal variation in parasite prevalence and abundance independently. Prevalence of both strongyle nematodes and coccidian microparasites increased during the study, and this effect varied between lambs, yearlings and adults. Meanwhile, abundance of strongyles was more strongly linked to host PD than to temporal (yearly) dynamics, while abundance of coccidia showed a strong temporal trend without any influence of PD. Strikingly, coccidian abundance increased 3-fold across the course of the study in lambs, while increases in yearlings and adults were negligible. Our decades-long, intensive, individual-based study will enable the role of environmental change and selection pressures in driving these dynamics to be determined, potentially providing unparalleled insight into the drivers of temporal variation in parasite dynamics in the wild.

Supplemented nutrition decreases helminth burden and increases drug efficacy in a natural host-helminth system.

Gastrointestinal (GI) helminths are common parasites of humans, wildlife, and livestock, causing chronic infections. In humans and wildlife, poor nutrition or limited resources can compromise an individual's immune response, predisposing them to higher helminth burdens. This relationship has been tested in laboratory models by investigating infection outcomes following reductions of specific nutrients. However, much less is known about how diet supplementation can impact susceptibility to infection, acquisition of immunity, and drug efficacy in natural host-helminth systems. We experimentally supplemented the diet of wood mice (Apodemus sylvaticus) with high-quality nutrition and measured resistance to the common GI nematode Heligmosomoides polygyrus. To test whether diet can enhance immunity to reinfection, we also administered anthelmintic treatment in both natural and captive populations. Supplemented wood mice were more resistant to H. polygyrus infection, cleared worms more efficiently after treatment, avoided a post-treatment infection rebound, produced stronger general and parasite-specific antibody responses, and maintained better body condition. In addition, when applied in conjunction with anthelmintic treatment, supplemented nutrition significantly reduced H. polygyrus transmission potential. These results show the rapid and extensive benefits of a well-balanced diet and have important implications for both disease control and wildlife health under changing environmental conditions.

Experimental parasite community perturbation reveals associations between Sin Nombre virus and gastrointestinal nematodes in a rodent reservoir host.

Individuals are often co-infected with several parasite species, yet measuring within-host interactions remains difficult in the wild. Consequently, the impacts of such interactions on host fitness and epidemiology are often unknown. We used anthelmintic drugs to experimentally reduce nematode infection and measured the effects on both nematodes and the important zoonosis Sin Nombre virus (SNV) in its primary reservoir (Peromyscus spp.). Treatment significantly reduced nematode infection, but increased SNV seroprevalence. Furthermore, mice that were co-infected with both nematodes and SNV were in better condition and survived up to four times longer than uninfected or singly infected mice. These results highlight the importance of investigating multiple parasites for understanding interindividual variation and epidemiological dynamics in reservoir populations with zoonotic transmission potential.

Parasitic nematodes simultaneously suppress and benefit from coccidian coinfection in their natural mouse host.

Within-host interactions among coinfecting parasites are common and have important consequences for host health and disease dynamics. However, these within-host interactions have traditionally been studied in laboratory mouse models, which often exclude important variation and use unnatural host-parasite combinations. Conversely, the few wild studies of within-host interactions often lack knowledge of parasite exposure and infection history. Here we exposed laboratory-reared wood mice (Apodemus sylvaticus) that were derived from wild-caught animals to two naturally-occurring parasites (nematode: Heligmosomoides polygyrus, coccidia: Eimeria hungaryensis) to investigate the impact of coinfection on parasite infection dynamics, and to determine if the host immune response mediates this interaction. Coinfection led to delayed worm expulsion and prolonged egg shedding in H. polygyrus infections and lower peak E. hungaryensis oocyst burdens. By comparing antibody levels between wild and colony-housed mice, we also found that wild mice had elevated H. polygyrus-IgG1 titres even if currently uninfected with H. polygyrus. Using this unique wild-laboratory system, we demonstrate, for the first time, clear evidence for a reciprocal interaction between these intestinal parasites, and that there is a great discrepancy between antibody levels measured in the wild vs those measured under controlled laboratory conditions in relation to parasite infection and coinfection.

Are Food Animals Responsible for Transfer of Antimicrobial-Resistant Escherichia coli or Their Resistance Determinants to Human Populations? A Systematic Review.

The role of farm animals in the emergence and dissemination of both AMR bacteria and their resistance determinants to humans is poorly understood and controversial. Here, we systematically reviewed the current evidence that food animals are responsible for transfer of AMR to humans. We searched PubMed, Web of Science, and EMBASE for literature published between 1940 and 2016. Our results show that eight studies (18%) suggested evidence of transmission of AMR from food animals to humans, 25 studies (56%) suggested transmission between animals and humans with no direction specified and 12 studies (26%) did not support transmission. Quality of evidence was variable among the included studies; one study (2%) used high resolution typing tools, 36 (80%) used intermediate resolution typing tools, six (13%) relied on low resolution typing tools, and two (5%) based conclusions on co-occurrence of resistance. While some studies suggested to provide evidence that transmission of AMR from food animals to humans may occur, robust conclusions on the directionality of transmission cannot be drawn due to limitations in study methodologies. Our findings highlight the need to combine high resolution genomic data analysis with systematically collected epidemiological evidence to reconstruct patterns of AMR transmission between food animals and humans.

Multihost Bartonella parasites display covert host specificity even when transmitted by generalist vectors.

Many parasites infect multiple sympatric host species, and there is a general assumption that parasite transmission between co-occurring host species is commonplace. Such between-species transmission could be key to parasite persistence within a disease reservoir and is consequently an emerging focus for disease control. However, while a growing body of theory indicates the potential importance of between-species transmission for parasite persistence, conclusive empirical evidence from natural communities is lacking, and the assumption that between-species transmission is inevitable may therefore be wrong. We investigated the occurrence of between-species transmission in a well-studied multihost parasite system. We identified the flea-borne Bartonella parasites infecting sympatric populations of Apodemus sylvaticus (wood mice) and Myodes glareolus (bank voles) in the UK and confirmed that several Bartonella species infect both rodent species. However, counter to previous knowledge, genetic characterization of these parasites revealed covert host specificity, where each host species is associated with a distinct assemblage of genetic variants, indicating that between-species transmission is rare. Limited between-species transmission could result from rare encounters between one host species and the parasites infecting another and/or host-parasite incompatibility. We investigated the occurrence of such encounter and compatibility barriers by identifying the flea species associated with each rodent host, and the Bartonella variants carried by individual fleas. We found that the majority of fleas were host-generalists but the assemblage of Bartonella variants in fleas tended to reflect the assemblage of Bartonella variants in the host species they were collected from, thus providing evidence of encounter barriers mediated by limited between-species flea transfer. However, we also found several fleas that were carrying variants never found in the host species from which they were collected, indicating some degree of host-pathogen incompatibility when barriers to encounter are overcome. Overall, these findings challenge our default perceptions of multihost parasite persistence, as they show that despite considerable overlaps in host species ecology, separate populations of the same parasite species may circulate and persist independently in different sympatric host species. This questions our fundamental understanding of endemic transmission dynamics and the control of infection within natural reservoir communities.

Corrigendum to Streicker et al. (2013) Differential sources of host species heterogeneity influence the transmission and control of multi-host parasites.

In a recent article, we described a conceptual and analytical model to identify the key host species for parasite transmission in multi-host communities and used data from 11 gastro-intestinal parasites infecting up to five small mammal host species as an illustrative example of how the framework could be applied. A limitation of these empirical data was uncertainty in the identification of parasite species using egg/oocyst morphology, which could overestimate parasite sharing between host species. Here, we show that the key results of the original analysis, namely that (1) parasites naturally infect multiple host species, but typically rely on a small subset of infected host species for long-term maintenance, (2) that different mechanisms underlie how particular host species dominate transmission and (3) that these different mechanisms influence the predicted efficiency of disease control measures, are robust to analysis of a smaller subset of host-parasite combinations that we have greatest confidence in identifying. We further comment briefly on the need for accurate parasite identification, ideally using molecular techniques to quantify cross-species transmission and differentiate covert host specificity from true host generalism.

Are All Hosts Created Equal? Partitioning Host Species Contributions to Parasite Persistence in Multihost Communities.

Many parasites circulate endemically within communities of multiple host species. To understand disease persistence within these communities, it is essential to know the contribution each host species makes to parasite transmission and maintenance. However, quantifying those contributions is challenging. We present a conceptual framework for classifying multihost sharing, based on key thresholds for parasite persistence. We then develop a generalized technique to quantify each species' contribution to parasite persistence, allowing natural systems to be located within the framework. We illustrate this approach using data on gastrointestinal parasites circulating within rodent communities and show that, although many parasites infect several host species, parasite persistence is often driven by just one host species. In some cases, however, parasites require multiple host species for maintenance. Our approach provides a quantitative method for differentiating these cases using minimal reliance on system-specific parameters, enabling informed decisions about parasite management within poorly understood multihost communities.

Analysis of a summary network of co-infection in humans reveals that parasites interact most via shared resources.

Simultaneous infection by multiple parasite species (viruses, bacteria, helminths, protozoa or fungi) is commonplace. Most reports show co-infected humans to have worse health than those with single infections. However, we have little understanding of how co-infecting parasites interact within human hosts. We used data from over 300 published studies to construct a network that offers the first broad indications of how groups of co-infecting parasites tend to interact. The network had three levels comprising parasites, the resources they consume and the immune responses they elicit, connected by potential, observed and experimentally proved links. Pairs of parasite species had most potential to interact indirectly through shared resources, rather than through immune responses or other parasites. In addition, the network comprised 10 tightly knit groups, eight of which were associated with particular body parts, and seven of which were dominated by parasite-resource links. Reported co-infection in humans is therefore structured by physical location within the body, with bottom-up, resource-mediated processes most often influencing how, where and which co-infecting parasites interact. The many indirect interactions show how treating an infection could affect other infections in co-infected patients, but the compartmentalized structure of the network will limit how far these indirect effects are likely to spread.

Host resources and parasite traits interact to determine the optimal combination of host parasite-mitigation strategies.

Organisms have evolved diverse strategies to manage parasite infections. Broadly, hosts may avoid infection by altering behaviour, resist infection by targeting parasites or tolerate infection by repairing associated damage. The effectiveness of a strategy depends on interactions between, for example, resource availability, parasite traits (virulence, life-history) and the host itself (nutritional status, immunopathology). To understand how these factors shape host parasite-mitigation strategies, we developed a mathematical model of within-host, parasite-immune dynamics in the context of helminth infections. The model incorporated host nutrition and resource allocation to different mechanisms of immune response: larval parasite prevention; adult parasite clearance; damage repair (tolerance). We also considered a non-immune strategy: avoidance via anorexia, reducing intake of infective stages. Resources not allocated to immune processes promoted host condition, whereas harm due to parasites and immunopathology diminished it. Maximising condition (a proxy for fitness), we determined optimal host investment for each parasite-mitigation strategy, singly and combined, across different environmental resource levels and parasite trait values. Which strategy was optimal varied with scenario. Tolerance generally performed well, especially with high resources. Success of the different resistance strategies (larval prevention or adult clearance) tracked relative virulence of larval and adult parasites: slowly maturing, highly damaging larvae favoured prevention; rapidly maturing, less harmful larvae favoured clearance. Anorexia was viable only in the short term, due to reduced host nutrition. Combined strategies always outperformed any lone strategy: these were dominated by tolerance, with some investment in resistance. Choice of parasite mitigation strategy has profound consequences for hosts, impacting their condition, survival and reproductive success. We show that the efficacy of different strategies is highly dependent on timescale, parasite traits and resource availability. Models that integrate such factors can inform the collection and interpretation of empirical data, to understand how those drivers interact to shape host immune responses in natural systems.

Differential sources of host species heterogeneity influence the transmission and control of multihost parasites.

Controlling parasites that infect multiple host species often requires targeting single species that dominate transmission. Yet, it is rarely recognised that such 'key hosts' can arise through disparate mechanisms, potentially requiring different approaches for control. We identify three distinct, but not mutually exclusive, processes that underlie host species heterogeneity: infection prevalence, population abundance and infectiousness. We construct a theoretical framework to isolate the role of each process from ecological data and to explore the outcome of different control approaches. Applying this framework to data on 11 gastrointestinal parasites in small mammal communities across the eastern United States reveals variation not only in the magnitude of transmission asymmetries among host species but also in the processes driving heterogeneity. These differences influence the efficiency by which different control strategies reduce transmission. Identifying and tailoring interventions to a specific type of key host may therefore enable more effective management of multihost parasites.

Stability of within-host-parasite communities in a wild mammal system.

Simultaneous infection by multiple parasite species is ubiquitous in nature. Interactions among co-infecting parasites may have important consequences for disease severity, transmission and community-level responses to perturbations. However, our current view of parasite interactions in nature comes primarily from observational studies, which may be unreliable at detecting interactions. We performed a perturbation experiment in wild mice, by using an anthelminthic to suppress nematodes, and monitored the consequences for other parasite species. Overall, these parasite communities were remarkably stable to perturbation. Only one non-target parasite species responded to deworming, and this response was temporary: we found strong, but short-lived, increases in the abundance of Eimeria protozoa, which share an infection site with the dominant nematode species, suggesting local, dynamic competition. These results, providing a rare and clear experimental demonstration of interactions between helminths and co-infecting parasites in wild vertebrates, constitute an important step towards understanding the wider consequences of similar drug treatments in humans and animals.

Anthelmintic treatment alters the parasite community in a wild mouse host.

Individuals are often co-infected with several parasite species, yet the consequences of drug treatment on the dynamics of parasite communities in wild populations have rarely been measured. Here, we experimentally reduced nematode infection in a wild mouse population and measured the effects on other non-target parasites. A single oral dose of the anthelmintic, ivermectin, significantly reduced nematode infection, but resulted in a reciprocal increase in other gastrointestinal parasites, specifically coccidial protozoans and cestodes. These results highlight the possibility that drug therapy may have unintended consequences for non-target parasites and that host-parasite dynamics cannot always be fully understood in the framework of single host-parasite interactions.

Defining schistosomiasis hotspots based on literature and shareholder interviews.

The World Health Organization (WHO) recently proposed a new operational definition which designates communities with ≥10% prevalence of Schistosoma spp. infection as a persistent hotspot, when, after at least two rounds of high-coverage annual preventive chemotherapy, there is a lack of appropriate reduction. However, inconsistencies and challenges from both biological and operational perspectives remain, making the prescriptive use of this definition difficult. Here, we present a comprehensive analysis of the use of the term 'hotspot' across schistosomiasis research over time, including both literature searches and opinions from a range of stakeholders, to assess the utility and generalisability of the new WHO definition of a persistent hotspot. Importantly, we propose an updated definition based on our analyses.