Immune-mediated Competition Research Articles

Darwin review: the evolution of virulence in human pathogens.

By definition, all pathogens cause some level of harm to their hosts. If this harm occurs while the pathogen is transmitting, it can negatively affect the pathogen's fitness by shortening the duration over which transmission can occur. However, many of the factors that increase virulence (i.e. harm to host) also promote transmission, driving the pathogen population towards an optimal state of intermediate virulence. A wider spectrum of virulence may be maintained among pathogen populations which are structured into multiple discrete strains though direct resource and immune-mediated competition. These various evolutionary outcomes, and the effects of medical and public health interventions, are best understood within a framework that recognizes the complex relationship between transmission and virulence in the context of the antigenic diversity of the pathogen population.

The Enemy of my Enemy is my Friend: Immune-Mediated Facilitation Contributes to Fitness of Co-Infecting Helminths.

The conceptual understanding of immune-mediated interactions between parasites is rooted in the theory of community ecology. One of the limitations of this approach is that most of the theory and empirical evidence has focused on resource or immune-mediated competition between parasites and yet there is ample evidence of positive interactions that could be generated by immune-mediated facilitation. We developed an immuno-epidemiological model and applied it to longitudinal data of two gastrointestinal helminths in two rabbit populations to investigate, through model testing, how immune-mediated mechanisms of parasite regulation could explain the higher intensities of both helminths in rabbits with dual than single infections. The model framework was selected and calibrated on rabbit population A and then validated on the nearby rabbit population B to confirm the consistency of the findings and the generality of the mechanisms. Simulations suggested that the higher intensities in rabbits with dual infections could be explained by a weakened or low species-specific IgA response and an asymmetrical IgA cross-reaction. Simulations also indicated that rabbits with dual infections shed more free-living stages that survived for longer in the environment, implying greater transmission than stages from hosts with single infections. Temperature and humidity selectively affected the free-living stages of the two helminths. These patterns were comparable in the two rabbit populations and support the hypothesis that immune-mediated facilitation can contribute to greater parasite fitness and local persistence.

Immune-mediated competition benefits protective microbes over pathogens in a novel host species

Microbes that protect against infection inhabit hosts across the tree of life. It is unclear whether and how the host immune system may affect the formation of new protective symbioses. We investigated the transcriptomic response of Caenorhabditis elegans following novel interactions with a protective microbe (Enterococcus faecalis) able to defend against infection by pathogenic Staphylococcus aureus. We have previously shown that E. faecalis can directly limit pathogen growth within hosts. In this study, we show that colonisation by protective E. faecalis caused the differential expression of 1,557 genes in pathogen infected hosts, including the upregulation of immune genes such as lysozymes and C-type lectins. The most significantly upregulated host lysozyme gene, lys-7, impacted the competitive abilities of E. faecalis and S. aureus when knocked out. E. faecalis has an increased ability to resist lysozyme activity compared to S. aureus, suggesting that the protective microbe could gain a competitive advantage from this host response. Our finding that protective microbes can benefit from immune-mediated competition after introduction opens up new possibilities for biocontrol design and our understanding of symbiosis evolution. Crosstalk between the host immune response and microbe-mediated protection should favour the continued investment in host immunity and avoid the potentially risky evolution of host dependence.

Phylogenetic Structure and Sequential Dominance of Sub-Lineages of PRRSV Type-2 Lineage 1 in the United States.

The genetic diversity and frequent emergence of novel genetic variants of porcine reproductive and respiratory syndrome virus type-2 (PRRSV) hinders control efforts, yet drivers of macro-evolutionary patterns of PRRSV remain poorly documented. Utilizing a comprehensive database of >20,000 orf5 sequences, our objective was to classify variants according to the phylogenetic structure of PRRSV co-circulating in the U.S., quantify evolutionary dynamics of sub-lineage emergence, and describe potential antigenic differences among sub-lineages. We subdivided the most prevalent lineage (Lineage 1, accounting for approximately 60% of available sequences) into eight sub-lineages. Bayesian coalescent SkyGrid models were used to estimate each sub-lineage’s effective population size over time. We show that a new sub-lineage emerged every 1 to 4 years and that the time between emergence and peak population size was 4.5 years on average (range: 2–8 years). A pattern of sequential dominance of different sub-lineages was identified, with a new dominant sub-lineage replacing its predecessor approximately every 3 years. Consensus amino acid sequences for each sub-lineage differed in key GP5 sites related to host immunity, suggesting that sub-lineage turnover may be linked to immune-mediated competition. This has important implications for understanding drivers of genetic diversity and emergence of new PRRSV variants in the U.S.

Fitness Landscape of the Immune Compromised Favors the Emergence of Antibiotic Resistance.

Antibiotic resistance can come at a high cost, both in terms of fitness for the pathogen and poorer outcomes for patients. The fitness landscape encountered by bacterial pathogens varies greatly throughout patient populations in terms of host immunity as well as the duration and spectrum of antibiotics encountered. Severely immunocompromised patients present a favorable environment for antibiotic resistance to emerge due to lack of immune-mediated competition and increased opportunities to evolve both on-target and compensatory mutations. Such patients may present unique pathways for antibiotic resistance to emerge.

The ecological assumptions underlying type replacement

There is currently little evidence to close the question of whether the type-specific HPV vaccines will cause increased prevalence of non-targeted, oncogenic types, a scenario known as ‘type replacement’. The abundance of hypotheses in the literature about how HPV types interact (facilitation, immune-mediated competition and independence) illustrates the perplexing nature of within-host HPV type interactions. In this talk, I will present analyses of within-host mathematical models that represent multiple HPV type co-infections and that are based on ecological theory. The results suggest that co-existence found at the patient level can arise even when types are interacting. I will also show how some common assumptions being made about HPV types are in conflict with current ecological theory. Finally, I will discuss some work I am currently conducting in Montpellier where we are fitting epidemiological models to multiple infection prevalence data. These kinds of collaborations between ecologists and HPV specialists will be essential to resolving why the vaccines may or may not cause type replacement for the benefit of future vaccination programs.

Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites

Malaria infections often consist of more than one strain of the same parasitic species. Understanding the within-host competition between these various strains is essential to understanding the evolution and epidemiology of drug resistance in malarial infections. The infection process and the competition between strains involve complicated biological processes that are explained by various hypotheses. Mathematical models tested against experimental data provide quantitative measures to compare these hypotheses and enable us to discern the actual biological processes that contribute to the observed dynamics. We use a group of models against experimental data on rodent malaria to test various hypotheses. Such quantitative measures, in understanding rodent malaria, can be considered as a step towards understanding within-host parasite dynamics. Our work presented here demonstrates how confronting mathematical models with data allows the discovery of subtle and novel interactions between hosts and parasites that would be impractical to do in an experiment and allows the rejection of hypotheses that are incorrect. It is our contention that understanding the forces controlling within-host parasite dynamics in well-defined experimental model is a necessary step towards understanding these features in natural infections.

Immune-Mediated Competition in Rodent Malaria Is Most Likely Caused by Induced Changes in Innate Immune Clearance of Merozoites

Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter , the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery.

Host modulation of parasite competition in multiple infections

Parasite diversity is a constant challenge to host immune systems and has important clinical implications, but factors underpinning its emergence and maintenance are still poorly understood. Hosts typically harbour multiple parasite genotypes that share both host resources and immune responses. Parasite diversity is thus shaped not only by resource competition between co-infecting parasites but also by host-driven immune-mediated competition. We investigated these effects in an insect-trypanosome system, combining in vivo and in vitro single and double inoculations. In vivo, a non-pathogenic, general immune challenge was used to manipulate host immune condition and resulted in a reduced ability of hosts to defend against a subsequent exposure to the trypanosome parasites, illustrating the costs of immune activation. The associated increase in available host space benefited the weaker parasite strains of each pair as much as the otherwise more competitive strains, resulting in more frequent multiple infections in immune-challenged hosts. In vitro assays showed that in the absence of a host, overall parasite diversity was minimal because the outcome of competition was virtually fixed and resulted in strain extinction. Altogether, this shows that parasite competition is largely host-mediated and suggests a role for host immune condition in the maintenance of parasite diversity.

The Role of Immune‐Mediated Apparent Competition in Genetically Diverse Malaria Infections

Competitive interactions between coinfecting genotypes of the same pathogen can impose selection on virulence, but the direction of this selection depends on the mechanisms behind the interactions. Here, we investigate how host immune responses contribute to competition between clones in mixed infections of the rodent malaria parasite Plasmodium chabaudi. We studied single and mixed infections of a virulent and an avirulent clone and compared the extent of competition in immunodeficient and immunocompetent mice (nude mice and T cell-reconstituted nude mice, respectively). In immunocompetent mice, the avirulent clone suffered more from competition than did the virulent clone. The competitive suppression of the avirulent clone was alleviated in immunodeficient mice. Moreover, the relative density of the avirulent clone in mixed infections was higher in immunodeficient than in immunocompetent mice. We conclude that immune-mediated interactions contributed to competitive suppression of the avirulent clone, although other mechanisms, presumably competition for resources such as red blood cells, must also be important. Because only the avirulent clone suffered from immune-mediated competition, this mechanism should contribute to selection for increased virulence in mixed infections in this host-parasite system. As far as we are aware, this is the first direct experimental evidence of immune-mediated apparent competition in any host-parasite system.

Evolution and emergence of Bordetella in humans

Two highly infectious bordetellae, Bordetella pertussis and B. parapertussis, have emerged in historical times as co-dominant in human populations. Both of these cause acute disease (whooping cough), whereas their progenitor, B. bronchiseptica, is of variable virulence in a wide variety of animals. The remarkably close phylogenetic relatedness of these three bordetellae and the two independent jumps to humans provide a unique opportunity to examine the evolution and genetics involved in the emergence of acute human pathogens. We hypothesize that the more virulent strains in humans reflects how acutely infectious pathogens might be favored in communities with large contact networks. Furthermore, we suggest that the differential expression of the various virulence factors by the two human pathogens can be explained by immune-mediated competition between the strains. The evolutionarily favored strategies of both of the human bordetellae result in immunizing infections and acute epidemics.

A model for pathogen population structure with cross-protection depending on the extent of overlap in antigenic variant repertoires

The persistence of discrete antigenic types among pathogens with multiple immunogenic loci can be explained by the action of immune-mediated competition. It has previously been shown that pathogen populations will self-organize into non-overlapping subsets of antigenic variants if cross-protection between pathogen types sharing any variants is high. Here, we examine the critical question of whether such strain structure will emerge if the degree of immune-mediated competition is dependent on the number of variants shared between pathogen types, rather than in an all-or-nothing manner. Our analysis uncovers a progression from no strain structure through to discrete stable strain structure through intermediate partially structured states. This suggests that the number of loci or epitope regions required to detect linkage disequilibrium (as a manifestation of stable discrete strain structure) in pathogen populations correlates inversely with the strength of immune selection.