Ecological immunology and immunopathologies : evolutionary perspectives on the inflammation and its regulation. – EVOREGIM

To address this issue, we assessed the shape of the selection operating on pro- and anti-inflammatory effectors following an inflammatory challenge in laboratory mice.

We found that selection acts on the combination of these two traits as individuals that produced large amount of pro-inflammatory cytokines could achieve relatively high fitness (survival) only if also producing a large amount of anti-inflammatory effectors.
To our knowledge, this is the first study providing evidence for correlational selection on immunity.

- We will start a first set of long term experiments on mice. First, on the effects, on host fitness components, of a parasite known to down-regulate inflammation. Second, on the effects of the disruption of immune regulation in a population of mice with enhanced inflammatory responses, UCP2 KO mice.

- Following previous results, we plan to build a review on how alterations of inflammation and its regulation in host populations, may affect evolution of parasite virulence.

P1 - Guerreiro R., Besson A.A., Bellenger J., Ragot K., Lizard G., Faivre B. & Sorci G. (2012). Correlational selection on pro- and anti-inflammatory effectors. Evolution 66 : 3615-3623.

Immune defences are probably the most sophisticated function evolved by hosts to fend off parasites and limit the fitness costs of infection. We should keep in mind that they are under strong selection pressures exerted (i) by parasites which evolved strategies to elude this weapon that endows the hosts and (ii) by costs due to their activation or the investment they require. Studies in ecological immunology consider the host immune response as a trait whose expression should be optimized by natural selection as to maximize fitness. Therefore, the central paradigm of ecological immunology follows an economical sense and postulates that immune defences are beneficial, but also costly, and then natural selection should maximize the benefits/costs ratio. Costs occur when investment into immunes defences is afforded at the expense of other fitness-related functions, and this generates trade-offs between competing traits. In most studies, costs of immune defences were seen in terms of resources consumption at the expense of other traits. In this context, the paradigm of ecological immunology has generally neglected resource-independent costs, and also how parasites may affect the benefits/costs ratio of immunity.

Evolutionary ecology studies exploring resource-independent costs of immunity among selective forces are recent and scarce. However, physiological works have now provided a large body of evidence that mis-directed or over-reacting immune responses may strongly damage host-structures independently of resource consumption, and then inflict severe costs. This is particularly true for inflammation which is now recognized as a major determinant of immune-mediated damage at the origin of widespread diseases. In several infectious diseases, the severity of symptoms relies more on the over-expression of the inflammation, then on direct effects of the parasite itself. To keep immune response at bound and dampen its negative effects, hosts have evolved regulation processes that should be considered when focusing on selective pressure shaping immune defences. Indeed, variation in regulation efficiency may strongly modulate the negative outcomes of immune activation, with expectable consequences on fitness.

Although crucial for organism homeostasis, immune regulation also offers an opportunity for pathogens to manipulate the host’s immune system for their own persistence and spread within the infected organism. Indeed, strategies aiming at evading the host immunity by down-regulating the immune response are known among pathogens. This may have important consequences on host exposure to the risk of immunopathologies. Therefore, both “natural” variation in regulation abilities, and evasion strategies evolved by parasites should be considered to have a better insight on selective forces which act on immune defences.

The current proposal explores this issue by following an evolutionary approach focused on both mechanisms (immune effectors) and host fitness to investigate the role of two neglected forces which are likely to play a critical role for the evolutionary shaping of immunity: immune regulation and immune evasion strategies developed by pathogens. We propose to investigate the fitness consequences of immune regulation, in captive mice, following a set of 4 tasks: first, experimental disruption of the regulatory function in mice; second, down-regulation of the inflammation by a helminth species; third, experimental evolution of the regulatory functions; fourth, exploration of the inflammatory response and its regulation as an example of antagonistic pleiotropy. In addition, because inflammation increases with age, and causes many age-related disorders in humans and animal models, potential age effects will be emphasized (i) by including different age groups in experiments to investigate the relative costs and benefits of immune regulation, and (ii) by monitoring immune regulation of individuals during their lifespan.