Proliferation in malaria parasites: how resource limitation can prevent evolution of greater virulence.

For parasites, robust proliferation within hosts is crucial for establishing the infection and creating opportu- nities for onward transmission. While faster proliferation enhances transmission rates, it is often assumed to curtail transmission duration by killing the host (virulence), a tradeoff constraining parasite evolution. Yet in many diseases, including malaria, the preponderance of infections with mild or absent symptoms suggests that host mortality is not a sufficient constraint, raising the question of what restrains evolution towards faster proliferation. In malaria infections, the maximum rate of proliferation is determined by the burst size, the number of daughter parasites produced per infected red blood cell. Larger burst sizes should expand the pool of infected red blood cells that can be used to produce the specialized transmission forms needed to infect mosquitoes. We use a within-host model parameterized for rodent malaria parasites (Plasmodium chabaudi ) to project the transmission consequences of burst size, focusing on initial acute infection where re- source limitation and risk of host mortality are greatest. We find that resource limitation restricts evolution towards higher burst sizes below the level predicted by host mortality alone. Our results suggest resource lim- itation could represent a more general constraint than virulence-transmission tradeoffs, preventing evolution towards faster proliferation.

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.

Understanding the role of mask-wearing during COVID-19 on the island of Ireland.

Non-pharmaceutical interventions have played a key role in managing the COVID-19 pandemic, but it is challenging to estimate their impacts on disease spread and outcomes. On the island of Ireland, population mobility restrictions were imposed during the first wave, but mask-wearing was not mandated until about six months into the pandemic. We use data on mask-wearing, mobility, and season, over the first year of the pandemic to predict independently the weekly infectious contact estimated by an epidemiological model. Using our models, we make counterfactual predictions of infectious contact, and ensuing hospitalizations, under a hypothetical intervention where 90% of the population wore masks from the beginning of community spread until the dates of the mask mandates. Over periods including the first wave of the pandemic, there were 1601 hospitalizations with COVID-19 in Northern Ireland and 1521 in the Republic of Ireland. Under the counterfactual mask-wearing scenario, we estimate 512 (95% CI 400, 730) and 344 (95% CI 266, 526) hospitalizations in the respective jurisdictions during the same periods. This could be partly due to other factors that were also changing over time.

Estimating time-dependent contact: a multi-strain epidemiological model of SARS-CoV-2 on the island of Ireland.

Mathematical modelling plays a key role in understanding and predicting the epidemiological dynamics of infectious diseases. We construct a flexible discrete-time model that incorporates multiple viral strains with different transmissibilities to estimate the changing patterns of human contact that generates new infections. Using a Bayesian approach, we fit the model to longitudinal data on hospitalisation with COVID-19 from the Republic of Ireland and Northern Ireland during the first year of the pandemic. We describe the estimated change in human contact in the context of government-mandated non-pharmaceutical interventions in the two jurisdictions on the island of Ireland. We take advantage of the fitted model to conduct counterfactual analyses exploring the impact of lockdown timing and introducing a novel, more transmissible variant. We found substantial differences in human contact between the two jurisdictions during periods of varied restriction easing and December holidays. Our counterfactual analyses reveal that implementing lockdowns earlier would have decreased subsequent hospitalisation substantially in most, but not all cases, and that an introduction of a more transmissible variant - without necessarily being more severe - can cause a large impact on the health care burden.

Does exposure to different menstrual products affect the vaginal environment?

The vaginal ecosystem is a key component of women's health. It also represents an ideal system for ecologists to investigate the consequence of perturbations on species diversity and emerging properties between organizational levels. Here, we study how exposure to different types of menstrual products is linked to microbial, immunological, demographic, and behavioural measurements in a cohort of young adult women who reported using more often tampons (n = 107) or menstrual cups (n = 31). We first found that cup users were older and smoked less than tampon users. When analysing health indicators, we detected potential associations between cups use reporting and fungal genital infection. A multivariate analysis confirmed that in our cohort, reporting using cups over tampons was associated with the higher odds ratio to report a fungal genital infection diagnosis by a medical doctor within the last 3 months. We did not detect significant differences between groups in terms of their bacterial vaginal microbiota composition and found marginal differences in the level of expression of 20 cytokines. However, a multivariate analysis of these biological data identified some level of clustering based on the menstrual product type preferred (cups or tampons). These results suggest that exposure to different types of menstrual products could influence menstrual health. Larger studies and studies with a more powered setting are needed to assess the robustness of these associations and identify causal mechanisms.

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.

Linking functional and molecular mechanisms of host resilience to malaria infection.

It remains challenging to understand why some hosts suffer severe illnesses, while others are unscathed by the same infection. We fitted a mathematical model to longitudinal measurements of parasite and red blood cell density in murine hosts from diverse genetic backgrounds to identify aspects of within-host interactions that explain variation in host resilience and survival during acute malaria infection. Among eight mouse strains that collectively span 90% of the common genetic diversity of laboratory mice, we found that high host mortality was associated with either weak parasite clearance, or a strong, yet imprecise response that inadvertently removes uninfected cells in excess. Subsequent cross-sectional cytokine assays revealed that the two distinct functional mechanisms of poor survival were underpinned by low expression of either pro- or anti-inflammatory cytokines, respectively. By combining mathematical modelling and molecular immunology assays, our study uncovered proximate mechanisms of diverse infection outcomes across multiple host strains and biological scales.

Uncovering drivers of dose-dependence and individual variation in malaria infection outcomes.

To understand why some hosts get sicker than others from the same type of infection, it is essential to explain how key processes, such as host responses to infection and parasite growth, are influenced by various biotic and abiotic factors. In many disease systems, the initial infection dose impacts host morbidity and mortality. To explore drivers of dose-dependence and individual variation in infection outcomes, we devised a mathematical model of malaria infection that allowed host and parasite traits to be linear functions (reaction norms) of the initial dose. We fitted the model, using a hierarchical Bayesian approach, to experimental time-series data of acute Plasmodium chabaudi infection across doses spanning seven orders of magnitude. We found evidence for both dose-dependent facilitation and debilitation of host responses. Most importantly, increasing dose reduced the strength of activation of indiscriminate host clearance of red blood cells while increasing the half-life of that response, leading to the maximal response at an intermediate dose. We also explored the causes of diverse infection outcomes across replicate mice receiving the same dose. Besides random noise in the injected dose, we found variation in peak parasite load was due to unobserved individual variation in host responses to clear infected cells. Individual variation in anaemia was likely driven by random variation in parasite burst size, which is linked to the rate of host cells lost to malaria infection. General host vigour in the absence of infection was also correlated with host health during malaria infection. Our work demonstrates that the reaction norm approach provides a useful quantitative framework for examining the impact of a continuous external factor on within-host infection processes.

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.

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

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 (R0) 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.

Temperature-dependent variation in the extrinsic incubation period elevates the risk of vector-borne disease emergence.

Identifying ecological drivers of disease transmission is central to understanding disease risks. For vector-borne diseases, temperature is a major determinant of transmission because vital parameters determining the fitness of parasites and vectors are highly temperature-sensitive, including the extrinsic incubation period required for parasites to develop within the vector. Temperature also underlies dramatic differences in the individual-level variation in the extrinsic incubation period, yet the influence of this variation in disease transmission is largely unexplored. We incorporate empirical estimates of dengue virus extrinsic incubation period and its variation across a range of temperatures into a stochastic model to examine the consequences for disease emergence. We find that such variation impacts the probability of disease emergence because exceptionally rapid, but empirically observed incubation - typically ignored by modelling only the average - increases the chance of disease emergence even at the limits of the temperature range for dengue transmission. We show that variation in the extrinsic incubation period causes the greatest proportional increase in the risk of disease emergence at cooler temperatures where the mean incubation period is long, and associated variation is large. Thus, ignoring EIP variation will likely lead to underestimation of the risk of vector-borne disease emergence in temperate climates.

Coevolution of virulence and immunosuppression in multiple infections.

Many components of host-parasite interactions have been shown to affect the way virulence (i.e. parasite-induced harm to the host) evolves. However, coevolution of multiple parasite traits is often neglected. We explore how an immunosuppressive adaptation of parasites affects and coevolves with virulence in multiple infections. Applying the adaptive dynamics framework to epidemiological models with coinfection, we show that immunosuppression is a double-edged sword for the evolution of virulence. On one hand, it amplifies the adaptive benefit of virulence by increasing the abundance of coinfections through epidemiological feedbacks. On the other hand, immunosuppression hinders host recovery, prolonging the duration of infection and elevating the cost of killing the host (as more opportunities for transmission will be forgone if the host dies). The balance between the cost and benefit of immunosuppression varies across different background mortality rates of hosts. In addition, we find that immunosuppression evolution is influenced considerably by the precise trade-off shape determining the effect of immunosuppression on host recovery and susceptibility to further infection. These results demonstrate that the evolution of virulence is shaped by immunosuppression while highlighting that the evolution of immune evasion mechanisms deserves further research attention.

Epidemiological consequences of immune sensitisation by pre-exposure to vector saliva.

Blood-feeding arthropods-like mosquitoes, sand flies, and ticks-transmit many diseases that impose serious public health and economic burdens. When a blood-feeding arthropod bites a mammal, it injects saliva containing immunogenic compounds that facilitate feeding. Evidence from Leishmania, Plasmodium and arboviral infections suggests that the immune responses elicited by pre-exposure to arthropod saliva can alter disease progression if the host later becomes infected. Such pre-sensitisation of host immunity has been reported to both exacerbate and limit infection symptoms, depending on the system in question, with potential implications for recovery. To explore if and how immune pre-sensitisation alters the effects of vector control, we develop a general model of vector-borne disease. We show that the abundance of pre-sensitised infected hosts should increase when control efforts moderately increase vector mortality rates. If immune pre-sensitisation leads to more rapid clearance of infection, increasing vector mortality rates may achieve greater than expected disease control. However, when immune pre-sensitisation prolongs the duration of infection, e.g., through mildly symptomatic cases for which treatment is unlikely to be sought, vector control can actually increase the total number of infected hosts. The rising infections may go unnoticed unless active surveillance methods are used to detect such sub-clinical individuals, who could provide long-lasting reservoirs for transmission and suffer long-term health consequences of those sub-clinical infections. Sensitivity analysis suggests that these negative consequences could be mitigated through integrated vector management. While the effect of saliva pre-exposure on acute symptoms is well-studied for leishmaniasis, the immunological and clinical consequences are largely uncharted for other vector-parasite-host combinations. We find a large range of plausible epidemiological outcomes, positive and negative for public health, underscoring the need to quantify how immune pre-sensitisation modulates recovery and transmission rates in vector-borne diseases.

Heterogeneity in ecological and evolutionary meta-analyses: its magnitude and implications.

Meta-analysis is the gold standard for synthesis in ecology and evolution. Together with estimating overall effect magnitudes, meta-analyses estimate differences between effect sizes via heterogeneity statistics. It is widely hypothesized that heterogeneity will be present in ecological/evolutionary meta-analyses due to the system-specific nature of biological phenomena. Despite driving recommended best practices, the generality of heterogeneity in ecological data has never been systematically reviewed. We reviewed 700 studies, finding 325 that used formal meta-analysis, of which total heterogeneity was reported in fewer than 40%. We used second-order meta-analysis to collate heterogeneity statistics from 86 studies. Our analysis revealed that the median and mean heterogeneity, expressed as I2 , are 84.67% and 91.69%, respectively. These estimates are well above "high" heterogeneity (i.e., 75%), based on widely adopted benchmarks. We encourage reporting heterogeneity in the forms of I2 and the estimated variance components (e.g., τ2 ) as standard practice. These statistics provide vital insights in to the degree to which effect sizes vary, and provide the statistical support for the exploration of predictors of effect-size magnitude. Along with standard meta-regression techniques that fit moderator variables, multi-level models now allow partitioning of heterogeneity among correlated (e.g., phylogenetic) structures that exist within data.

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.

Parasites as biological tags of fish stocks: a meta-analysis of their discriminatory power.

The use of parasites as biological tags to discriminate among marine fish stocks has become a widely accepted method in fisheries management. Here, we first link this approach to its unstated ecological foundation, the decay in the similarity of the species composition of assemblages as a function of increasing distance between them, a phenomenon almost universal in nature. We explain how distance decay of similarity can influence the use of parasites as biological tags. Then, we perform a meta-analysis of 61 uses of parasites as tags of marine fish populations in multivariate discriminant analyses, obtained from 29 articles. Our main finding is that across all studies, the observed overall probability of correct classification of fish based on parasite data was about 71%. This corresponds to a two-fold improvement over the rate of correct classification expected by chance alone, and the average effect size (Zr = 0·463) computed from the original values was also indicative of a medium-to-large effect. However, none of the moderator variables included in the meta-analysis had a significant effect on the proportion of correct classification; these moderators included the total number of fish sampled, the number of parasite species used in the discriminant analysis, the number of localities from which fish were sampled, the minimum and maximum distance between any pair of sampling localities, etc. Therefore, there are no clear-cut situations in which the use of parasites as tags is more useful than others. Finally, we provide recommendations for the future usage of parasites as tags for stock discrimination, to ensure that future applications of the method achieve statistical rigour and a high discriminatory power.

What determines species richness of parasitic organisms? A meta-analysis across animal, plant and fungal hosts.

Although a small set of external factors account for much of the spatial variation in plant and animal diversity, the search continues for general drivers of variation in parasite species richness among host species. Qualitative reviews of existing evidence suggest idiosyncrasies and inconsistent predictive power for all proposed determinants of parasite richness. Here, we provide the first quantitative synthesis of the evidence using a meta-analysis of 62 original studies testing the relationship between parasite richness across animal, plant and fungal hosts, and each of its four most widely used presumed predictors: host body size, host geographical range size, host population density, and latitude. We uncover three universal predictors of parasite richness across host species, namely host body size, geographical range size and population density, applicable regardless of the taxa considered and independently of most aspects of study design. A proper match in the primary studies between the focal predictor and both the spatial scale of study and the level at which parasite species richness was quantified (i.e. within host populations or tallied across a host species' entire range) also affected the magnitude of effect sizes. By contrast, except for a couple of indicative trends in subsets of the full dataset, there was no strong evidence for an effect of latitude on parasite species richness; where found, this effect ran counter to the general latitude gradient in diversity, with parasite species richness tending to be higher further from the equator. Finally, the meta-analysis also revealed a negative relationship between the magnitude of effect sizes and the year of publication of original studies (i.e. a time-lag bias). This temporal bias may be due to the increasing use of phylogenetic correction in comparative analyses of parasite richness over time, as this correction yields more conservative effect sizes. Overall, these findings point to common underlying processes of parasite diversification fundamentally different from those controlling the diversity of free-living organisms.