Why are hosts prone to producing overzealous responses that cost proteins and may actually even cause disease? An optimal immune response requires the right type AND the right amount of activity: overzealous responses deplete host resources and can cause severe tissue damage. Immune systems can thus kill hosts as well as parasites. We are investigating the dynamics of pro- and anti-inflammatory cytokine production during infection, to assess phenotypic constraints on immunomodulation. Given the concomitant costs and benefits of immunity, we are also working to understand selection on the magnitude of antibody responses in natural populations of a range of mammalian species.

How does immunity interact with resource limitation to control parasite replication? Parasite-killing immune responses form only one part of the within-host ecosystem. Parasite population size can also be controlled by resource-based mechanisms. Malaria, for example, requires red blood cells (RBCs) in order to proliferate. To explore the potential for helminth-induced anaemia to restrict malaria replication, we are testing whether RBC limitation may outweigh immunological control of acute co-infection. We have also used meta-analysis of data on a broad taxonomic spectrum of helminth-microparasite pairings, to assess the generality of resource-based versus immunological control mechanisms during co-infection.

How does the vertebrate immune system prioritise competing cytokine responses – for example, during helminth-microparasite co-infection? Helminths (parasitic worms) and microparasites (viruses, bacteria, protozoa, or fungi) commonly co-occur and are cleared by different, mutually inhibitory suites of cytokines. Malaria and intestinal nematodes, for example, make conflicting demands on host cytokine responses. Evolutionary rationale suggests that the immune system should prioritise responses directed against the infection most damaging to host fitness – in this case, malaria. We are quantitatively testing that prediction.

What are the functional consequences of immunological complexity – for example, feedback loops within the cytokine network? Cytokines form an intricate signalling network, with positive and negative feedback loops (e.g., between pro- and anti-inflammatory cytokines) that ultimately determine how well the host fights infection. Our multiplex data – on responses to malaria in the presence and absence of helminth co-infection – allow us to test whether cytokines are additive or multiplicative in their effects upon parasite replication. Using molecular interventions, we are also assessing the robustness of the signalling network to perturbation.

At what scales can, and SHOULD, the immune system multi-task? Beyond cytokines, many different cell types and effector molecules are involved in killing parasites and repairing parasite-induced damage. Thus, during co-infection, there are many scales at which immune responses might interact. With various collaborators, we are investigating whether macrophages, T cells, and antibodies are able to multi-task efficiently, given antigenically distinct challenges. We are also keen to know whether perfect multi-tasking is in the hosts best interests.

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