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Empirical immunology meets evolutionary ecology: the virulence of co-infection

Reference	BB/C508734/1
Principal Investigator / Supervisor	Professor Judith Allen
Co-Investigators / Co-Supervisors	Dr Andrea Graham, Dr Sean Nee, Professor Andrew Read
Institution	University of Edinburgh
Department	Inst for Immunology and Infection Resrch
Funding type	Research
Value (£)	313,873
Status	Completed
Type	Research Grant
Start date	01/01/2005
End date	31/12/2007
Duration	36 months

Abstract

Co-infection with parasites that make competing demands on the mammalian immune system is extremely common in agricultural, natural and human populations. The cytokine-driven feedback loops that direct development of Type 1 versus Type 2 effector pathways lead to a trade-off: only one type of response can dominate at a time and place. Co-infection by parasite species that are best cleared by different types of responses can thus pose a dilemma for the immune system. Should the immune system, for example, respond optimally to an intracellular parasite cleared by a Type 1 response OR to a nematode infection cleared by Type 2? Evolutionary rationale suggests that the immune system should preferentially optimise the response directed against the more virulent parasite ¿ that is, the one that could do most damage to the host. We propose to test this hypothesis by brining analytical techniques from evolutionary ecology and epidemiology to bear upon empirical data from mouse models of malaria-filaria co-infection. Resolution of acute malaria requires Type 1 immune effector mechanisms, while resistance to filarial nematodes is associated with Type 2 effectors. Our work to date suggests that filarial infection shifts anti-malarial responses towards Type 2, and also exacerbates anaemia. We will generate data on multiple cytokines over the course of malaria-filaria co-infection. With differential timing of malaria infection, the parasites will either compete for immunological attention in the bloodstream, or else they will remain in separate anatomical compartments. Then, by using malaria clones of differing intrinsic virulence, we will change the stakes of the dilemma that immune systems must solve. The numbers of mice we use per experimental group will allow the use of geometrical, mathematical, and statistical methods of analysis that are new to mouse cytokine biology. We will assess how cytokines individually and collectively affect whole-organism outcomes, by incorporating a broad spectrum of cytokines into quantitative summaries of the skew and magnitude of immune responses. These mathematical vectors will then be analysed in relation to anaemia and weight loss as measures of malarial virulence. Throughout, we will use statistics to partition variance into that which is explained by known factors and that which remains unknown, a powerful epidemiological tool largely neglected in murine immunology. We will also productively utilise variability among individuals to map virulence over 2-dimensional immunological heterogeneity. We will discover whether co-infection outcomes can be predicted from single-species infections, and we will also test the evolutionary prediction that the immune system should preferentially optimise responses directed against the most virulent parasites. Along the way, we will develop new, broadly applicable methodologies for the quantification and analysis of the cytokine milieu.

Summary

unavailable

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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