The impact of innate immunity on malaria parasite infection dynamics in rodent models

Decades of research have probed the molecular and cellular mechanisms that control the immune response to malaria. Yet many studies offer conflicting results on the functional impact of innate immunity for controlling parasite replication early in infection. We conduct a meta-analysis to seek consensus on the effect of innate immunity on parasite replication, examining three different species of rodent malaria parasite. Screening published studies that span four decades of research we collate, curate, and statistically analyze infection dynamics in immune-deficient or -augmented mice to identify and quantify general trends and reveal sources of disagreement among studies. Additionally, we estimate whether host factors or experimental methodology shape the impact of immune perturbations on parasite burden. First, we detected meta-analytic mean effect sizes (absolute Cohen’s h) for the difference in parasite burden between treatment and control groups ranging from 0.1475 to 0.2321 across parasite species. This range is considered a small effect size and translates to a modest change in parasitaemia of roughly 7-12% on average at the peak of infection. Second, we reveal that variation across studies using P. chabaudi or P. yoelii is best explained by stochasticity (due to small sample sizes) rather than by host factors or experimental design. Third, we find that for P. berghei the impact of immune perturbation is increased when young or female mice are used and is greatest when effector molecules (as opposed to upstream signalling molecules) are disrupted (up to an 18% difference in peak parasitaemia). Finally, we find little evidence of publication bias suggesting that our results are robust. The small effect sizes we observe, across three parasite species, following experimental perturbations of the innate immune system may be explained by redundancy in a complex biological system or by incomplete (or inappropriate) data reporting for meta-analysis. Alternatively, our findings might indicate a need to re-evaluate the efficiency with which innate immunity controls parasite replication early in infection. Testing these hypotheses is necessary to translate understanding from model systems to human malaria

Targeting malaria parasites inside mosquitoes:Ecoevolutionary consequences

Proof-of-concept studies demonstrate that antimalarial drugs designed for human treatment can also be applied to mosquitoes to interrupt malaria transmission. Deploying a new control tool is ideally undertaken within a stewardship programme that maximises a drug’s lifespan by minimising the risk of resistance evolution and slowing its spread once emerged. We ask: what are the epidemiological and evolutionary consequences of targeting parasites within mosquitoes? Our synthesis argues that targeting parasites inside mosquitoes (i) can be modelled by readily expanding existing epidemiological frameworks; (ii) provides a functionally novel control method that has potential to be more robust to resistance evolution than targeting parasites in humans; and (iii) could extend the lifespan and clinical benefit of antimalarials used exclusively to treat humans

Coevolutionary feedback elevates constitutive immune defence: a protein network model

Background: Organisms have evolved a variety of defence mechanisms against natural enemies, which are typically used at the expense of other life history components. Induced defence mechanisms impose minor costs when pathogens are absent, but mounting an induced response can be time-consuming. Therefore, to ensure timely protection, organisms may partly rely on constitutive defence despite its sustained cost that renders it less economical. Existing theoretical models addressing the optimal combination of constitutive versus induced defence focus solely on host adaptation and ignore the fact that the efficacy of protection depends on genotype-specific host-parasite interactions. Here, we develop a signal-transduction network model inspired by the invertebrate innate immune system, in order to address the effect of parasite coevolution on the optimal combination of constitutive and induced defence. Results: Our analysis reveals that coevolution of parasites with specific immune components shifts the host's optimal allocation from induced towards constitutive immunity. This effect is dependent upon whether receptors (for detection) or effectors (for elimination) are subjected to parasite counter-evolution. A parasite population subjected to a specific immune receptor can evolve heightened genetic diversity, which makes parasite detection more difficult for the hosts. We show that this coevolutionary feedback renders the induced immune response less efficient, forcing the hosts to invest more heavily in constitutive immunity. Parasites diversify to escape elimination by a specific effector too. However, this diversification does not alter the optimal balance between constitutive and induced defence: the reliance on constitutive defence is promoted by the receptor's inability to detect, but not the effectors' inability to eliminate parasites. If effectors are useless, hosts simply adapt to tolerate, rather than to invest in any defence against parasites. These contrasting results indicate that evolutionary feedback between host and parasite populations is a key factor shaping the selection regime for immune networks facing antagonistic coevolution. Conclusion: Parasite coevolution against specific immune defence alters the prediction of the optimal use of defence, and the effect of parasite coevolution varies between different immune components

Evolutionary consequences of feedbacks between within-host competition and disease control

Lay Summary: Competition often occurs among diverse parasites within a single host, but control efforts could change its strength. We examined how the interplay between competition and control could shape the evolution of parasite traits like drug resistance and disease severity

Ecology of Vector-borne Diseases at the Interface of Theory and Data

Infectious diseases continue to impact human lives. However, surprisingly little is known about the fundamental biology of disease-causing organisms and their interactions with the host. This thesis focuses on vector-borne diseases which account for 17% of all known human infections and put more than half of the global population at risk of infection. An overarching focus of the work presented is heterogeneity within species, which is ubiquitous and fundamental to biology, yet has often been neglected outside of evolutionary biology. In infectious disease biology, a better understanding of individual heterogeneity is needed across scales. At the within-host level, infection dynamics and health outcomes are highly variable between hosts. Therefore, a single clinical intervention strategy will likely not achieve the desired cure in all individuals infected with the same parasite. At the between-host level, it is important to map the consequences of heterogeneity because a small fraction of the host population contributes disproportionately to disease transmission and determines the fate of an epidemic. By combining mathematical modelling and empirical data, this thesis develops conceptual and methodological frameworks that are rooted in ecology, but shift away from the strict focus on the average often found in biological sciences, dubbed the “tyranny of the golden mean”. This thesis uncovers within-host origins, and explores the between-host consequences, of heterogeneities in vector-borne diseases. In the first half, I outline how differences in within-host ecological processes generate variation in parasite population dynamics and health outcomes of malaria infection across inoculum sizes and host genetic backgrounds. In the latter half, I present host population-level consequences of variation generated by tri-trophic interactions be- tween parasites, hosts, and arthropod disease vectors, and of temperature-dependent heterogeneity in within-vector processes that govern the timing of infectivity. Overall, this thesis showcases the synergistic benefit of combining mathematical and computational modelling with empirical data to achieve better understanding and management of infectious diseases.Ph.D

Data from: Caste ratios affect the reproductive output of social trematode colonies

Intraspecific phenotypic diversification in social organisms often leads to formation of physical castes which are morphologically specialised for particular tasks within the colony. The optimal caste allocation theory argues that specialised morphological castes are efficient at specific tasks, and hence different caste ratios should affect the ergonomic efficiency, hence reproductive output of the colony. However, the reproductive output of different caste ratios has been documented only in few species of insects with equivocal support for the theory. The present study investigated whether the ratios of non-reproductive and reproductive morphs affect the reproductive output of a recently discovered social trematode, Philophthalmus sp., in which the non-reproductive members are hypothesized to be defensive specialists. Census of natural infections and a manipulative in-vitro experiment demonstrated a positive association between the reproductive output of trematode colonies and the ratio of non-reproductive to reproductive morphs in the presence of an intra-host trematode competitor, Maritrema novaezealandensis. On the contrary, without the competitor, reproductive output was negatively associated with the proportion of non-reproductive castes in colonies. Our findings demonstrate for the first time a clear fitness benefit associated with the non-reproductive castes in the presence of a competitor while illustrating the cost of maintaining such morphs in non-competitive situations. Although the proximate mechanisms controlling caste ratio remain unclear in this trematode system, the present study supports the prediction that the fitness of colonies is influenced by the composition of specialized functional morphs in social organisms, suggesting a potential for adaptive shifts of caste ratios over evolutionary time

In-vivo

Dataset used for the in-vivo component of the stud

Evolution, phylogenetic distribution and functional ecology of division of labour in trematodes

Abstract Division of labour has evolved in many social animals where colonies consist of clones or close kin. It involves the performance of different tasks by morphologically distinct castes, leading to increased colony fitness. Recently, a form of division of labour has been discovered in trematodes: clonal rediae inside the snail intermediate host belong either to a large-bodied reproductive caste, or to a much smaller and morphologically distinct ‘soldier’ caste which defends the colony against co-infecting trematodes. We review recent research on this phenomenon, focusing on its phylogenetic distribution, its possible evolutionary origins, and how division of labour functions to allow trematode colonies within their snail host to adjust to threats and changing conditions. To date, division of labour has been documented in 15 species from three families: Himasthlidae, Philophthalmidae and Heterophyidae. Although this list of species is certainly incomplete, the evidence suggests that division of labour has arisen independently more than once in the evolutionary history of trematodes. We propose a simple scenario for the gradual evolution of division of labour in trematodes facing a high risk of competition in a long-lived snail host. Starting with initial conditions prior to the origin of castes (size variation among rediae within a colony, size-dependent production of cercariae by rediae, and a trade-off between cercarial production and other functions, such as defence), maximising colony fitness (R 0) can lead to caste formation or the age-structured division of labour observed in some trematodes. Finally, we summarise recent research showing that caste ratios, i.e. relative numbers of reproductive and soldier rediae per colony, become more soldier-biased in colonies exposed to competition from another trematode species sharing the same snail, and also respond to other stressors threatening the host’s survival or the colony itself. In addition, there is evidence of asymmetrical phenotypic plasticity among individual caste members: reproductives can assume defensive functions against competitors in the absence of soldiers, whereas soldiers are incapable of growing into reproductives if the latter’s numbers are reduced. We conclude by highlighting future research directions, and the advantages of trematodes as model systems to study social evolution

In-vitro

Dataset used for the in-vitro componen