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Immune responses benefit organismal fitness by clearing parasites but also exact costs associated with immunopathology and energetic investment. Hosts manage these costs by tightly regulating the induction of immune signaling to curtail excessive responses and restore homeostasis. Despite the theoretical importance of turning off the immune response to mitigate these costs, experimentally connecting variation in the negative regulation of immune responses to organismal fitness remains a frontier in evolutionary immunology. In this study, we used a dose-response approach to manipulate the RNAi-mediated knockdown efficiency of cactus (IκBα), a central regulator of Toll pathway signal transduction in flour beetles (Tribolium castaneum). By titrating cactus activity across four distinct levels, we derived the shape of the relationship between immune response investment and traits associated with host fitness, including infection susceptibility, lifespan, fecundity, body mass, and gut homeostasis. Cactus knock-down increased the overall magnitude of inducible immune responses and delayed their resolution in a dsRNA dose-dependent manner, promoting survival and resistance following bacterial infection. However, these benefits were counterbalanced by dsRNA dose-dependent costs to lifespan, fecundity, body mass, and gut integrity. Our results allowed us to move beyond the qualitative identification of a trade-off between immune investment and fitness to actually derive its functional form. This approach paves the way to quantitatively compare the evolution and impact of distinct regulatory elements on life-history trade-offs and fitness, filling a crucial gap in our conceptual and theoretical models of immune signaling network evolution and the maintenance of natural variation in immune systems. Author summary: The immune system provides defense against infection but demands substantial energy and can inadvertently harm the host. To limit these costly side effects, hosts use regulatory proteins that dampen immune responses after they respond to infection. Despite the importance of these regulating proteins, we do not understand how their variation influences infection defense and the broader effects on an organism's health, reproduction, and fitness. We used a novel approach to vary the expression of the regulatory protein cactus, thereby adjusting the magnitude of Toll pathway activation in the red flour beetle. We found that while increasing the intensity of immune pathway activation enhances immune output and survival to bacterial infection, it comes at a disproportionally severe cost to female egg production, gut health, body mass, and lifespan. This reveals that even small variations in negative regulation and immune pathway activation can have disproportionate health and reproductive consequences, helping us better understand how immune systems evolved and the diversity of rules governing their regulation in nature. [ABSTRACT FROM AUTHOR]

1. Trans-generational immune priming is a phenomenon in insects in which the offspring of mothers previously challenged with a focal microbe exhibit a survival advantage when challenged with that microbe. 2. Maternal egg provisioning with immune factors such as antimicrobial peptides (AMPs) is widely believed to contribute to the primed phenotype. However, other 'socially mediated' environmental factors secreted or excreted by the mother and others in the community, such as the gut microbiota or pheromones, may also affect offspring immune phenotype. 3. The relative contributions of maternal egg provisioning and socially mediated environmental factors to the primed larval phenotype were assessed by performing a cross-fostering survival experiment with Tribolium castaneum, in which the eggs of primed or naïve mothers were sterilised, treated with the frass of primed or naïve beetles, and challenged as larvae with the maternal pathogen, Bacillus thuringiensis. 4. Larvae from primed mothers showed greater survival than unprimed larvae, regardless of frass treatment; maternal treatment therefore showed a substantially greater contribution to larval priming than frass treatment. 5. Planned contrast tests to quantify the contributions of maternal and environmental matching revealed that maternal treatment mattered more for larvae exposed to primed, rather than unprimed, frass. This suggests that the effects of maternal egg provisioning may be exacerbated or mitigated by environmental factors. 6. Thus, although maternal egg provisioning plays a predominant role in producing the primed phenotype, environmental matching may matter for priming in some contexts. [ABSTRACT FROM AUTHOR]

Energetic resources fuel immune responses and parasite growth within organisms, but it is unclear whether energy allocation is sufficient to explain changes in infection outcomes under the threat of multiple parasites. We manipulated diet in flour beetles ( Tribolium confusum ) infected with two natural parasites to investigate the role of resources in shifting metabolic and immune responses after single and co-infection. Our results suggest that gregarine parasites alter the within-host energetic environment, and by extension juvenile development time, in a diet-dependent manner. Gregarines do not affect host resistance to acute bacterial infection but do stimulate the expression of an alternative set of immune genes and promote damage to the gut, ultimately contributing to reduced survival regardless of diet. Thus, energy allocation is not sufficient to explain the immunological contribution to coinfection outcomes, emphasizing the importance of mechanistic insight for predicting the impact of coinfection across levels of biological organization.

Many genes and signalling pathways within plant and animal taxa drive the expression of multiple organismal traits. This form of genetic pleiotropy instigates trade-offs among life-history traits if a mutation in the pleiotropic gene improves the fitness contribution of one trait at the expense of another. Whether or not pleiotropy gives rise to conflict among traits, however, likely depends on the resource costs and timing of trait deployment during organismal development. To investigate factors that could influence the evolutionary maintenance of pleiotropy in gene networks, we developed an agent-based model of co-evolution between parasites and hosts. Hosts comprise signalling networks that must faithfully complete a developmental programme while also defending against parasites, and trait signalling networks could be independent or share a pleiotropic component as they evolved to improve host fitness. We found that hosts with independent developmental and immune networks were significantly more fit than hosts with pleiotropic networks when traits were deployed asynchronously during development. When host genotypes directly competed against each other, however, pleiotropic hosts were victorious regardless of trait synchrony because the pleiotropic networks were more robust to parasite manipulation, potentially explaining the abundance of pleiotropy in immune systems despite its contribution to life history trade-offs.

Insect metamorphosis promotes the exploration of different ecological niches, as well as exposure to different parasites, across life stages. Adaptation should favour immune responses that are tailored to specific microbial threats, with the potential for metamorphosis to decouple the underlying genetic or physiological basis of immune responses in each stage. However, we do not have a good understanding of how early-life exposure to parasites influences immune responses in subsequent life stages. Is there a developmental legacy of larval infection in holometabolous insect hosts? To address this question, we exposed flour beetle (Tribolium castaneum) larvae to a protozoan parasite that inhabits the midgut of larvae and adults despite clearance during metamorphosis. We quantified the expression of relevant immune genes in the gut and whole body of exposed and unexposed individuals during the larval, pupal and adult stages. Our results suggest that parasite exposure induces the differential expression of several immune genes in the larval stage that persist into subsequent stages. We also demonstrate that immune gene expression covariance is partially decoupled among tissues and life stages. These results suggest that larval infection can leave a lasting imprint on immune phenotypes, with implications for the evolution of metamorphosis and immune systems. This article is part of the theme issue 'The evolution of complete metamorphosis'.