Ann T. Tate

Tracking Resilience to Infections by Mapping Disease Space

Infected hosts differ in their responses to pathogens; some hosts are resilient and recover their original health, whereas others follow a divergent path and die. To quantitate these differences, we propose mapping the routes infected individuals take through “disease space.” We find that when plotting physiological parameters against each other, many pairs have hysteretic relationships that identify the current location of the host and predict the future route of the infection. These maps can readily be constructed from experimental longitudinal data, and we provide two methods to generate the maps from the cross-sectional data that is commonly gathered in field trials. We hypothesize that resilient hosts tend to take small loops through disease space, whereas nonresilient individuals take large loops. We support this hypothesis with experimental data in mice infected with Plasmodium chabaudi, finding that dying mice trace a large arc in red blood cells (RBCs) by reticulocyte space as compared to surviving mice. We find that human malaria patients who are heterozygous for sickle cell hemoglobin occupy a small area of RBCs by reticulocyte space, suggesting this approach can be used to distinguish resilience in human populations. This technique should be broadly useful in describing the in-host dynamics of infections in both model hosts and patients at both population and individual levels.

How Many Parameters Does It Take to Describe Disease Tolerance

The study of infectious disease has been aided by model organisms, which have helped to elucidate molecular mechanisms and contributed to the development of new treatments; however, the lack of a conceptual framework for unifying findings across models, combined with host variability, has impeded progress and translation. Here, we fill this gap with a simple graphical and mathematical framework to study disease tolerance, the dose response curve relating health to microbe load; this approach helped uncover parameters that were previously overlooked. Using a model experimental system in which we challenged Drosophila melanogaster with the pathogen Listeria monocytogenes, we tested this framework, finding that microbe growth, the immune response, and disease tolerance were all well represented by sigmoid models. As we altered the system by varying host or pathogen genetics, disease tolerance varied, as we would expect if it was indeed governed by parameters controlling the sensitivity of the system (the number of bacteria required to trigger a response) and maximal effect size according to a logistic equation. Though either the pathogen or host immune response or both together could theoretically be the proximal cause of pathology that killed the flies, we found that the pathogen, but not the immune response, drove damage in this model. With this new understanding of the circuitry controlling disease tolerance, we can now propose better ways of choosing, combining, and developing treatments.

Trans‐generational priming of resistance in wild flour beetles reflects the primed phenotypes of laboratory populations and is inhibited by co‐infection with a common parasite

Summary Trans-generational priming renders offspring of immune-challenged parents less susceptible to disease-induced mortality, and has been demonstrated in a variety of arthropod taxa under controlled laboratory conditions. However, relatively little is known about the applicability of these laboratory results to priming in wild populations, especially in the context of environmental variables like maternal co-infection and potential trade-offs with other life history traits. We performed nearly parallel trans-generational priming experiments on laboratory and wild strains of Tribolium beetles against the bacterial pathogen Bacillus thuringiensis (Bt). We investigated the impact of maternal immune challenge on offspring survival and development time, as well as the correlation between development and survival by priming status. Furthermore, we manipulated wild beetle parental co-infection with a gregarine parasite that was prevalent in the wild population in order to determine the impact of co-infection on the efficacy of trans-generational priming. Trans-generational priming resulted in a large but birth order-dependent acceleration of offspring development time, and enhanced offspring survival against infection, in both laboratory and wild populations. However, adult parental co-infection with gut protozoa severely curtailed primed offspring survival against Bt infection. These results suggest that shifts in life history traits associated with trans-generational priming in laboratory model systems extend to wild populations. These traits, including survival, development, and interference from co-infection, are important parameters for predicting the impact of priming on disease dynamics in the wild.

The within-host dynamics of infection in trans-generationally primed flour beetles

Many taxa exhibit plastic immune responses initiated after primary microbial exposure that provide increased protection against disease‐induced mortality and the fitness costs of infection. In several arthropod species, this protection can even be passed from parents to offspring through a phenomenon called trans‐generational immune priming. Here, we first demonstrate that trans‐generational priming is a repeatable phenomenon in flour beetles (Tribolium castaneum) primed and infected with Bacillus thuringiensis (Bt). We then quantify the within‐host dynamics of microbes and host physiological responses in infected offspring from primed and unprimed mothers by monitoring bacterial density and using mRNA‐seq to profile host gene expression, respectively, over the acute infection period. We find that priming increases inducible resistance against Bt around a critical temporal juncture where host septicaemic trajectories, and consequently survival, may be determined in unprimed individuals. Our results identify a highly differentially expressed biomarker of priming, containing an EIF4‐e domain, in uninfected individuals, as well as several other candidate genes. Moreover, the induction and decay dynamics of gene expression over time suggest a metabolic shift in primed individuals. The identified bacterial and gene expression dynamics are likely to influence patterns of bacterial fitness and disease transmission in natural populations.

Dynamic Patterns of Parasitism and Immunity across Host Development Influence Optimal Strategies of Resource Allocation

The integration of physiological mechanisms into life-history theory is an emerging frontier in our understanding of the constraints and drivers of life-history evolution. Dynamic patterns of antagonism between developmental and immunological pathways in juvenile insects illustrate the importance of mechanisms for determining life-history strategy optima in the face of trade-offs. For example, developmental interference occurs when developmental processes transiently take priority over resources or pathway architecture, preventing allocation to immunity or other traits. We designed a within-host model of infected larval development to explore the impact of developmental dynamics on optimal resource mobilization and allocation strategies as well as on larval resistance and tolerance phenotypes. The model incorporates mechanism-inspired functional forms of developmental interference with immunity against parasites that attack specific larval stages. We find that developmental interference generally increases optimal investment in constitutive immunity and decreases optimal resource mobilization rates, but the results are sensitive to the developmental stage at first infection. Moreover, developmental interference reduces resistance but generally increases tolerance of infection. We demonstrate the potential impact of these dynamics on empirical estimates of host susceptibility and discuss the general implications of incorporating realistic physiological mechanisms and developmental dynamics for life-history theory in insects and other organisms.

Demographically framing trade-offs between sensitivity and specificity illuminates selection on immunity

A fundamental challenge faced by the immune system is to discriminate contexts meriting activation from contexts in which activation would be harmful. Selection pressures on this ability are likely to be acute: the penalty of mis-identification of pathogens (therefore failure to attack them) is mortality or morbidity linked to infectious disease, which could reduce fitness by reducing lifespan or fertility; the penalty associated with mis-identification of host (therefore self-attack) is immunopathology, whose fitness costs can also be extreme. Here we use classic epidemiological tools to frame this trade-off between sensitivity and specificity of immune activation, exploring implications for evolution of immune discrimination. We capture the expected increase in the evolutionarily optimal sensitivity under higher pathogen mortality risk, and a decrease in sensitivity with increased immunopathology mortality risk; but a number of non-intuitive predictions also emerge. All else being equal, optimal sensitivity decreases with increasing lifespan; and, where sensitivity can vary over age, decreases at late ages not solely attributable to immunosenescence are predicted. These results both enrich and challenge previous predictions concerning the relationship between life expectancy and optimal evolved defenses, highlighting the need to account for epidemiological setting, lifestage-specific immune priorities, and immune discrimination in future investigations.Immune systems face a trade-off between sensitivity and specificity when challenged by pathogens. Here, the authors use epidemiological tools to explore the evolution of optimal immune discrimination in relation to life-history strategy.

Dissecting the contributions of time and microbe density to variation in immune gene expression

Widespread differential expression of immunological genes is a hallmark of the response to infection in almost all surveyed taxa. However, several challenges remain in the attempt to connect differences in gene expression with functional outcomes like parasite killing and host survival. For example, temporal gene expression patterns are not always monotonic (unidirectional slope), yielding results that qualitatively depend on the time point selected for analysis. They may also be correlated to microbe density, confounding the strength of an immune response and resistance to parasites. In this study, we analyse these relationships in an mRNA-seq time series of Tribolium castaneum infected with Bacillus thuringiensis. Our results suggest that many extracellular immunological components with known roles in immunity, like antimicrobial peptides and recognition proteins, are highly correlated to microbe load. On the other hand, intracellular components of immunological signalling pathways overwhelmingly show non-monotonic temporal patterns of gene expression, despite the underlying assumption of monotonicity in most ecological and comparative transcriptomics studies that rely on cross-sectional analyses. Our results raise a host of new questions, including to what extent variation in host resistance, infection tolerance and immunopathology can be explained by variation in the slope or sensitivity of these newly characterized patterns.

The Interaction of Immune Priming with Different Modes of Disease Transmission

Immune priming in invertebrates is most commonly described as an increase in survival (Roth et al., 2010) or the strength of an immune response (Moret, 2006) against a microbe to which the host has been previously exposed. Because priming alters epidemiologically relevant parameters like disease-induced mortality and recovery, priming is likely to impact the spread, and persistence of diseases in invertebrate populations. Early modeling efforts have explicitly incorporated priming into disease transmission frameworks by allowing exposed (Tidbury et al., 2012) or previously infected but recovered (Tate and Rudolf, 2012) individuals to transition into a primed compartment. There, they are less likely to become infected and infectious upon subsequent exposure, but may suffer reproductive or developmental costs stemming from the physiological costs of maintaining a primed immune response. Conflating infected and infectious states, however, obscures the impact of priming on the correlative and dynamical relationships (Day, 2003; Berenos et al., 2009) between parasite replication, pathology, and transmission.

Innate Immune Memory: Activation of Macrophage Killing Ability by Developmental Duties.

Innate immune systems in many taxa exhibit hallmarks of memory in response to previous microbial exposure. A new study demonstrates that innate immune memory in Drosophila embryonic macrophages can also be induced by the successful engulfment of apoptotic cells, highlighting the importance of early exposure events for developing responsive immune systems.

Vector Immunity and Evolutionary Ecology: The Harmonious Dissonance

Recent scientific breakthroughs have significantly expanded our understanding of arthropod vector immunity. Insights in the laboratory have demonstrated how the immune system provides resistance to infection, and in what manner innate defenses protect against a microbial assault. Less understood, however, is the effect of biotic and abiotic factors on microbial-vector interactions and the impact of the immune system on arthropod populations in nature. Furthermore, the influence of genetic plasticity on the immune response against vector-borne pathogens remains mostly elusive. Herein, we discuss evolutionary forces that shape arthropod vector immunity. We focus on resistance, pathogenicity and tolerance to infection. We posit that novel scientific paradigms should emerge when molecular immunologists and evolutionary ecologists work together.