Assessing the stability of parasite communities through perturbation experiments

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Biological Sciences

Abstract

In the past twenty years, there has been a surge of interest in the role of disease on individual health and its effects on host populations. These studies and, indeed, the majority of disease control programmes of humans and domestic animals tend to consider individual infections in isolation. However, hosts are typically infected by many parasite species at any one time. For example, humans, particularly in the developing world, can be simultaneously co-infected with a variety of parasites: around 40.3 million people are currently infected with HIV/AIDS, over one third of the population worldwide has TB, and over one fourth has soil transmitted helminths. Importantly, these co-infecting parasites are unlikely to occur in isolation within each host, indeed there may be a vast network of interactions between them. These interactions may arise through direct competition between parasites within each host. However, they may also be indirect, possibly through competition for shared resources (bottom-up interactions) or via the host's immune system (top-down interactions). In this case, immune responses raised against one parasite may also affect other co-infecting parasite species. Alternatively, if the host is combating one parasite type it may not be able to mount an effective response against another. Therefore there may be a complex network of subtle, and difficult to detect interactions between parasite species that result in a diverse, interactive community within each individual host. Clearly, understanding how these communities are shaped is vital for the design of truly effective and sustainable disease control programs. If control approaches only consider one parasite species there may be unpredictable consequences for disease caused by other, co-infecting parasites. However, current approaches to measure parasite interactions are purely observational and, so far, have produced unclear information about their strength or existence. We propose to adopt a new, direct way of measuring interactions using classical community ecology perturbation experiments, by removing certain parasites from wild wood mice and measuring what happens to the remaining parasite species - if they increase after the target parasites have been removed then this suggests that the target species was previously suppressing their abundance. By repeating this process for all main parasite groups in the wood mice, we can build a more complete picture of how these parasite communities are shaped by the interactions between species. Putting all these interactions into a mathematical model will allow us to predict how such parasite communities will respond to more complex treatments, such as the removal of two species at the same time. If our model predictions prove accurate for more complex co-treatment strategies, then these within host network approaches may provide a vital tool for developing long-term disease control strategies in other host species, such as humans, domestic animals or wildlife threatened to extinction by infectious diseases. It is gradually being realised that parasite co-infections play an important role in the occurrence and management of many diseases of human concern. Given the increasing concerns about emerging infectious diseases around the globe, it has never been more pressing to develop a genuine understanding of the factors affecting parasite invasion, transmission, persistence, and control. This project will be a major step in that direction.

Publications

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Clerc M (2019) Age affects antibody levels and anthelmintic treatment efficacy in a wild rodent in International Journal for Parasitology: Parasites and Wildlife

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Clerc M (2018) Antibodies and coinfection drive variation in nematode burdens in wild mice. in International journal for parasitology

 
Description We have made several key findings:

1) When anthelmintic drugs were used to reduce nematode infections, their effects were short-lived, lasting less than 4 weeks, and resulted in a significant increase in other non-target parasites, specifically coccidia protozoans (Knowles et al. in review). In addition, we found that parasite communities were remarkable stable to these drug-based perturbations, with the parasite community returning to its pre-treatment levels within 4 weeks of drug treatment.

2) By comparing the results of these experimental perturbations to those obtained from classical, observation-based studies we demonstrated, for the first time, the lack of reliability of standard approaches in detecting interspecific parasite interactions. In fact, most standard methods for observing within host parasite interactions were unable to detect this strong negative interaction between nematodes and protozoans demonstrated in our experiments (Fenton et al. in prep).

3) Based on our findings above, we empirically tested the efficacy and outcome of co-treatment experiments in which multiple parasite taxa are targeted for control. We combined several anthelmintics with different modes of action, as well as combination therapies of anthelmintics and anti-protozoal drugs and found that, in some but not all cases, added therapies improved host health through reductions in several parasite species. However, we found in some cases, that these drugs blocked efficacies, and had no additional benefits to the host (Knowles et al. in prep).

4) We examined how host parasite community structure and treatment affects individual host health. We found that, on average, nematodes were harmful to their hosts fitness. However, and importantly, this was not always the case. We found strong effects of parasite burden (intensity of infection) and these effects were not always linearly related to host survival. In addition, male and female mice differed significantly in the effect of nematodes on their survival. We found that treating a subset of mice, specifically males with low worm burdens, actually reduced their survival by >40% (Pedersen et al. in prep).

5) In addition, the effect of worm infection and intensity had other larger scale effects, determining the outcome of the shape between worm burden and survival, the benefits or costs of treatment, and the level of within host parasite interactions (Knowles et al. in prep).

6) To generalize these results we developed a simple theoretical framework of how different interactions between helminths and pathogens affect (1) host lifespan, (2) pathogen spread and (3) the evolution of pathogen virulence. It was shown that there is considerable context dependency in the net impact of helminths on these factors, and hence the outcome of deworming programmes, depending both on the mechanisms of parasite interaction and the burden of worms at the time of treatment (Fenton et al. in review).

7) We built a general model of the within-host human parasite communities, and tested for positive or negative interactions between parasites, as well as how the outcome of these interactions varied dependent on whether the interactions were direct, top-down (via the immune response) or bottom up (via shared resources). This model was then used to test how different disease control strategies were affected, sometimes unexpectedly by these interactions (Griffiths et al. in prep).

8) We used community ecology theory and network tools to identify patterns of coinfections from humans, specifically we found that most parasites likely interact through bottom up, or shared resource, mechanisms, and that there is strong evidence of modularity in the coinfection network, suggesting that there are groups of parasites, immune components and resources that associate closely with each other in the network (Griffiths et al. in review).

9) We collated a large data set of coinfection in humans and found that most coinfections result in increased parasite abundance of the coinfecting parasites, and reduced health in the human hosts (Griffiths et al. 2011).

10) Lastly, we translated these findings to human mortality data from the UK, to see if coinfected invididuals had higher mortality rates, and if so, what types of coinfections were likely to contribute to higher death rates (Griffiths et al. in prep).
Exploitation Route This work shows how coinfecting parasites and pathogens can affect each other, host health and the success of control strategies. Importantly, even if interactions between parasites can be hard to detect from population-level data (as is most commonly available), that does not mean those interactions are not playing an important role in driving disease dynamics. These interactions can have complex consequences for host health and the success of treatment. By raising awareness of these factors, and highlighting the potential contexts where such coinfections may (or may not) affect disease progression and control success, this work may help guide the design of individual and population-level treatments in the face of coinfection.
Sectors Environment,Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://www.biology.ed.ac.uk/research/groups/apedersen/
 
Description NERC Biomolecular Analysis Facility (NBAF)
Amount £7,822 (GBP)
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 01/2011 
End 12/2011
 
Description NERC Standard Grant
Amount £552,710 (GBP)
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 09/2012 
End 08/2015
 
Description NERC Standard Grant
Amount £880,736 (GBP)
Funding ID NE/I026367/1 
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 05/2012 
End 04/2015
 
Description National Science Foundation Postdoctoral Research Fellowship in Biology
Amount $170,000 (USD)
Organisation National Science Foundation (NSF) 
Sector Public
Country United States
Start 10/2013 
End 09/2015
 
Description Standard Discovery Grant
Amount £789,000 (GBP)
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 06/2018 
End 05/2021
 
Description The ecology within: the impact of gut ecosystem dynamics on host fitness in the wild
Amount £3,570,094 (GBP)
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 03/2019 
End 02/2025
 
Description The impact of resource availability on parasite transmission: insights from a natural multi-parasite community
Amount £641,701 (GBP)
Funding ID NE/R011397/1 
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 06/2018 
End 06/2021
 
Description University of Edinburgh Moray Endowment Fund
Amount £1,992 (GBP)
Organisation University of Edinburgh 
Department Moray Endowment Fund
Sector Academic/University
Country United Kingdom
Start 01/2017 
End 12/2017
 
Description Wellcome Trust Institutional Strategic Support Fund (WT ISSF)
Amount £36,718 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Institutional Strategic Support Fund
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 12/2013
 
Description Wellcome Trust Institutional Strategic Support Fund (WT ISSF)
Amount £24,810 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Institutional Strategic Support Fund
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 12/2014
 
Description Wellcome Trust Institutional Strategic Support Fund Grant
Amount £29,640 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Institutional Strategic Support Fund
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 02/2017
 
Description Wellcome Trust Institutional Strategic Support Fund Grant
Amount £30,400 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2017 
End 06/2018
 
Title Wild derived parasite isolates 
Description We have collected wild isolates of several important murine pathogens and parasites that can then be used in laboratory experiments to test natural host - parasite combinations. 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2019 
Provided To Others? Yes  
Impact These wild derived parasites have been a part of a recently published paper (Clerc et al. 2019), contributed to the preliminary data that was used in a successful NERC Standard Grant application (2018) and will be shared with other groups working on these systems. 
 
Title Wild-caught wood mouse colony 
Description The development and maintenance of a formerly wild-caught, laboratory wood mouse (Apodemus sylvaticus) colony. To further test the findings and results that were emerging from our wild infection and immunity experiments, I acquired and maintain a now lab-reared colony of wood mice, and their naturally occurring parasites, in order to test how parasites and the immune response interact, but in a controlled environment. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2011 
Provided To Others? Yes  
Impact Mice, and samples from this colony, from this colony have been used in order to (i) measure the oral microbiome and test for associated bone disease and loss (that are not found in the standard lab mouse model (grant in review), (ii) understand the vast diversity seen in gut microbiomes compared to lab mice (published in ESME J), (iii) measure microbiome - immune response interactions and how that may be different than seen in lab mice (paper in review) and several other collaborations that are in progress. 
 
Title Wild small rodent parasite and pathogen database 
Description We have accumulated a spatially explicitly database from two consecutive NERC grants, totally 6-years of captures of individually marked individuals caught throughout their life, were at each capture significant demographic, physiological and infection histories are recorded. We monitor >30 species of parasites and pathogens. This data base currently involves wood mice and bank voles, captured 1- 20 times, and totally >8000 individually-tagged mice captured >12,000 times. We have spatially-explicit information of reach capture location on our sampling grids (rangingin size from 50x50m-70mx70m; with 6x6 -8x8 trap locations at 10m intervals with 2 traps/location,spanning 4 different woodlands, 2-8 grids/woodland, each grid replicated across 2-4 years). In addition to this data, we also have extracted DNA samples for the vast majority of captures, and immune gene polymorphism data for around 1000 mice. 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact We are just building these external collaboration now. 
 
Description During a Centre for Immunity, infection & evolution & ASCUS Art & Science Collaboration called 'Transmission' (2015), I engaged with artists working on an installation piece called 'Art, design and antimicrobial resistance' which focused on how contemporary society is challenged by microscopic organisms, and I was interviewed by film director Ann Milne as part of a piece aiming to put scientists themselves under the microscope to better understand their motivations. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact During a Centre for Immunity, infection & evolution & ASCUS Art & Science Collaboration called 'Transmission' (2015), I engaged with artists working on an installation piece called 'Art, design and antimicrobial resistance' which focused on how contemporary society is challenged by microscopic organisms, and I was interviewed by film director Ann Milne as part of a piece aiming to put scientists themselves under the microscope to better understand their motivations.
Year(s) Of Engagement Activity 2015
URL http://www.ascus.org.uk/ciie-micro-residency-2/
 
Description Edinburgh International Science Festival 2015 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We created a stall for the Edinburgh International Science Festival which was held at the Scottish Natural History Museum in April highlighting our research and having several interactive activities for the general public. Hundreds of adults and children visited our stall.
Year(s) Of Engagement Activity 2015
 
Description Edinburgh Open Days 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Public were engaged in the presentation, leading to enthusiastic discussions.

There was general interest in the wild rodent research, specifically the community of parasites and pathogens that infect wild rodents.
Year(s) Of Engagement Activity 2012,2013,2014
 
Description Popular Press and science communication: I actively engage in communicating science to the public and my career and research have featured in the following: Bioscience, Nature, Lab Times, The Daily Telegraph, The Santa Barbara Independent, The Metro, Google News, Herald Scotland, Science Daily, Science, Newsline, News about Planet Earth, and Forth Radio and the South African Broadcast Company Radio. 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Popular Press and science communication: I actively engage in communicating science to the public and my career and research have featured in the following: Bioscience, Nature, Lab Times, The Daily Telegraph, The Santa Barbara Independent, The Metro, Google News, Herald Scotland, Science Daily, Science, Newsline, News about Planet Earth, and Forth Radio and the South African Broadcast Company Radio.
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015
 
Description Popular science lecture at the Edinburgh International Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Edinburgh International Science Festival (2018): I presented and participated in a panel discussion that was aimed at the general public, titled 'Bad Ways to Die'; where I was introducing the audience to the diversity and biology of human animal parasites.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/events/festivals/highlights/all-events/2018/science-festival-interview-with-dr-...
 
Description Soapbox Science Edinburgh 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Soapbox Science Edinburgh 2018. As part of a women in science & public engagement initiative I stood on a soapbox in city centre Edinburgh for 1 hour to openly discuss my research with passerby (estimate of 600 people came to the event).
Year(s) Of Engagement Activity 2018
URL http://soapboxscience.org/soapbox-science-2017-edinburgh/