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.     

Diversity emerging: from competitive exclusion to neutral coexistence in ecosystems

In this communication, we present a unifying framework to understand the emergence and maintenance of diversity in ecological systems. We do this by developing a deterministic population model including density-dependent limitation in resources and available space. Our model shows that competitive exclusion and neutral coexistence represent different regimes of the same adaptive dynamics suggesting that neutrality is the general result of an adaptive process in a finite habitat with limited energetic resources. Our model explains the emergence of biodiversity through mutation and its maintenance through neutrality. We show that this framework provides the theoretical foundations to understand the emergence and maintenance of diversity in microbial ecosystems.     

Partitioning average competition and extreme-genotype effects in genetically diverse infections

Competition between parasite genotypes in genetically diverse infections is widespread. However, experimental evidence on how genetic diversity influences total parasite load is variable. Here we use an additive partition equation to quantify the negative effect of inter-genotypic competition on total parasite load in diverse infections. Our approach controls for extreme-genotype effects, a process that can potentially neutralise, or even reverse, the negative effect of competition on total parasite load. A single extreme-genotype can have a disproportionate effect on total parasite load if it causes the highest parasite load in its single-infection, while increasing its performance in diverse relative to single infections. We show that in theory such disproportionate effects of extreme-genotypes can lead to a higher total parasite load in diverse infections than expected, even if competition reduces individual parasite performance on average. Controlling for the extreme-genotype effect is only possible if the competition effect on total parasite load is measured appropriately as the average difference between the realised number of each parasite genotype in mixed infections and the expected number based on single infection parasite loads. We apply this approach to sticklebacks that were experimentally infected with different trematode genotypes. On average, genetically diverse infections had lower parasite loads than expected from single-infection results. For the first time we demonstrate that competition between co-infecting genotypes per se caused the parasite load reduction, while extreme-genotype effects were not significant. We thus suggest that to correctly quantify the effect of competition alone on total parasite load in genetically diverse infections, the extreme-genotype effect has to be controlled for.     

Host exclusion and coexistence in apparent and direct competition: An application of bifurcation theory.

Recent empirical studies have focused attention on the interplay in multi-host systems of parasite-mediated apparent competition and direct competition between hosts. However, theoretical investigation of such systems has been hindered by the onset of algebraic intractability with the increase in system dimensionality. In this paper we circumvent this problem by using a geometric approach in which arrays of bifurcation maps are constructed, each map being structured by the set of (bifurcation) points in parameter space at which qualitative changes in system behaviour take place. From these maps can be compiled a concise catalogue of the possible modes of system behaviour, enabling an investigation of the interaction of apparent and direct competitive forces to be carried out. Of importance is the identification of those situations where increasing one or both of these competitive forces leads to a change in the stability state. The maps provide an efficient way of determining whether, and, if so, under what conditions, specific modes of behaviour are allowed by the model. Two field phenomena of particular interest, discussed in the paper, are host invasion and dominance reversal resulting from the introduction of the pathogen into a directly competitive system.     

Immunity to non-cerebral severe malaria is acquired after one or two infections

In areas of stable transmission, clinical immunity to mild malaria is acquired slowly, so it is not usually effective until early adolescence. Life-threatening disease is, however, restricted to a much younger age group, indicating that resistance to the severe clinical consequences of infection is acquired more quickly. Understanding how rapidly immunity develops to severe malaria is essential, as severe malaria should be the primary target of intervention strategies, and predicting the result of interventions that reduce host exposure will require consideration of these dynamics. Severe disease in childhood is less frequent in areas where transmission is the greatest. One explanation for this is that infants experience increased exposure to infection while they are protected from disease, possibly by maternal antibody. They therefore emerge from this period of clinical protection with considerably more immunity than those who experience lower transmission intensities. Here we use this data, assuming a period of clinical protection, to estimate the number of prior infections needed to reduce the risk of severe disease to negligible levels. Contrary to expectations, one or two successful infective bites seem to be all that is necessary across a broad range of transmission intensities.     

Competitive exclusion and coexistence of pathogens in a homosexually-transmitted disease model

A sexually-transmitted disease model for two strains of pathogen in a one-sex, heterogeneously-mixing population has been studied completely by Jiang and Chai in (J Math Biol 56:373-390, 2008). In this paper, we give a analysis for a SIS STD with two competing strains, where populations are divided into three differential groups based on their susceptibility to two distinct pathogenic strains. We investigate the existence and stability of the boundary equilibria that characterizes competitive exclusion of the two competing strains; we also investigate the existence and stability of the positive coexistence equilibrium, which characterizes the possibility of coexistence of the two strains. We obtain sufficient and necessary conditions for the existence and global stability about these equilibria under some assumptions. We verify that there is a strong connection between the stability of the boundary equilibria and the existence of the coexistence equilibrium, that is, there exists a unique coexistence equilibrium if and only if the boundary equilibria both exist and have the same stability, the coexistence equilibrium is globally stable or unstable if and only if the two boundary equilibria are both unstable or both stable.     

Pioneer exclusion in a one-hump discrete pioneer-climax competitive system

One-hump maps as single species pioneer and climax ecological models confirm the expected pioneer exclusion in an uninterrupted two dimensional discrete pioneer-climax competition model. Other dynamic situations occur in such models. In particular a mutual exclusion principle is presented as a mathematical theorem.     

Species coexistence by permanent spatial heterogeneity in a lottery model

We studied the effect of permanent spatial heterogeneity in promoting species coexistence in a lottery model. The system consisted of multiple habitats, each composed of a number of sites occupied by adults of two species. Larvae produced from different habitats were mixed in a common pool. When an adult died, the vacant site became occupied by an individual randomly chosen from the larval pool. If there were n habitats, there could be up to n-1 internal equilibria with both species in addition to two single-species equilibria. These equilibria and their local stability can be calculated from a single function, indicating the difference among species in their average lifetime reproductive success. Our main result is that between-habitat variation in the ratio of mortalities of two species promotes coexistence, while that of reproductive rates does not. This conclusion is the opposite of the role of temporal variation in the standard lottery model, in which between-year variation in the reproductive rate, but not that in the mortalities, promotes coexistence.     

General theory of competitive coexistence in spatially-varying environments

A general model of competitive and apparent competitive interactions in a spatially-variable environment is developed and analyzed to extend findings on coexistence in a temporally-variable environment to the spatial case and to elucidate new principles. In particular, coexistence mechanisms are divided into variation-dependent and variation-independent mechanisms with variation-dependent mechanisms including spatial generalizations of relative nonlinearity and the storage effect. Although directly analogous to the corresponding temporal mechanisms, these spatial mechanisms involve different life history traits which suggest that the spatial storage effect should arise more commonly than the temporal storage effect and spatial relative nonlinearity should arise less commonly than temporal relative nonlinearity. Additional mechanisms occur in the spatial case due to spatial covariance between the finite rate of increase of a local population and its local abundance, which has no clear temporal analogue. A limited analysis of these additional mechanisms shows that they have similar properties to the storage effect and relative nonlinearity and potentially may be considered as enlargements of the earlier mechanisms. The rate of increase of a species perturbed to low density is used to quantify coexistence. A general quadratic approximation, which is exact in some important cases, divides this rate of increase into contributions from the various mechanisms above and admits no other mechanisms, suggesting that opportunities for coexistence in a spatially-variable environment are fully characterized by these mechanisms within this general model. Three spatially-implicit models are analyzed as illustrations of the general findings and of techniques using small variance approximations. The contributions to coexistence of the various mechanisms are expressed in terms of simple interpretable formulae. These spatially-implicit models include a model of an annual plant community, a spatial multispecies version of the lottery model, and a multispecies model of an insect community competing for spatially-patchy and ephemeral food.     

Serology-enabled discovery of genetically diverse hepaciviruses in a new host

Genetic and biological characterization of new hepaciviruses infecting animals contributes to our understanding of the ultimate origins of hepatitis C virus (HCV) infection in humans and dramatically enhances our ability to study its pathogenesis using tractable animal models. Animal homologs of HCV include a recently discovered canine hepacivirus (CHV) and GB virus B (GBV-B), both viruses with largely undetermined natural host ranges. Here we used a versatile serology-based approach to determine the natural host of the only known nonprimate hepacivirus (NPHV), CHV, which is also the closest phylogenetic relative of HCV. Recombinant protein expressed from the helicase domain of CHV NS3 was used as antigen in the luciferase immunoprecipitation system (LIPS) assay to screen several nonprimate animal species. Thirty-six samples from 103 horses were immunoreactive, and viral genomic RNA was present in 8 of the 36 seropositive animals and none of the seronegative animals. Complete genome sequences of these 8 genetically diverse NPHVs showed 14% (range, 6.4% to 17.2%) nucleotide sequence divergence, with most changes occurring at synonymous sites. RNA secondary structure prediction of the 383-base 5' untranslated region of NPHV was refined and extended through mapping of polymorphic sites to unpaired regions or (semi)covariant pairings. Similar approaches were adopted to delineate extensive RNA secondary structures in the coding region of the genome, predicted to form 27 regularly spaced, thermodynamically stable stem-loops. Together, these findings suggest a promising new nonprimate animal model and provide a database that will aid creation of functional NPHV cDNA clones and other novel tools for hepacivirus studies.     

Host control of malaria infections: constraints on immune and erythropoeitic response kinetics

The two main agents of human malaria, Plasmodium vivax and Plasmodium falciparum, can induce severe anemia and provoke strong, complex immune reactions. Which dynamical behaviors of host immune and erythropoietic responses would foster control of infection, and which would lead to runaway parasitemia and/or severe anemia? To answer these questions, we developed differential equation models of interacting parasite and red blood cell (RBC) populations modulated by host immune and erythropoietic responses. The model immune responses incorporate both a rapidly responding innate component and a slower-responding, long-term antibody component, with several parasite developmental stages considered as targets for each type of immune response. We found that simulated infections with the highest parasitemia tended to be those with ineffective innate immunity even if antibodies were present. We also compared infections with dyserythropoiesis (reduced RBC production during infection) to those with compensatory erythropoiesis (boosted RBC production) or a fixed basal RBC production rate. Dyserythropoiesis tended to reduce parasitemia slightly but at a cost to the host of aggravating anemia. On the other hand, compensatory erythropoiesis tended to reduce the severity of anemia but with enhanced parasitemia if the innate response was ineffective. For both parasite species, sharp transitions between the schizont and the merozoite stages of development (i.e., with standard deviation in intra-RBC development time ≤2.4 h) were associated with lower parasitemia and less severe anemia. Thus tight synchronization in asexual parasite development might help control parasitemia. Finally, our simulations suggest that P. vivax can induce severe anemia as readily as P. falciparum for the same type of immune response, though P. vivax attacks a much smaller subset of RBCs. Since most P. vivax infections are nonlethal (if debilitating) clinically, this suggests that P. falciparum adaptations for countering or evading immune responses are more effective than those of P. vivax.     

Complement-like protein TEP1 is a determinant of vectorial capacity in the malaria vector Anopheles gambiae

Anopheles mosquitoes are major vectors of human malaria in Africa. Large variation exists in the ability of mosquitoes to serve as vectors and to transmit malaria parasites, but the molecular mechanisms that determine vectorial capacity remain poorly understood. We report that the hemocyte-specific complement-like protein TEP1 from the mosquito Anopheles gambiae binds to and mediates killing of midgut stages of the rodent malaria parasite Plasmodium berghei. The dsRNA knockdown of TEP1 in adults completely abolishes melanotic refractoriness in a genetically selected refractory strain. Moreover, in susceptible mosquitoes this knockdown increases the number of developing parasites. Our results suggest that the TEP1-dependent parasite killing is followed by a TEP1-independent clearance of dead parasites by lysis and/or melanization. Further elucidation of the molecular mechanisms of TEP1-mediated parasite killing will be of great importance for our understanding of the principles of vectorial capacity in insects.     

Host conditioning is a primary determinant in modulating the effect of IL-7 on murine graft-versus-host disease

Interleukin-7 has been shown to enhance T cell reconstitution after allogeneic bone marrow transplantation, in part, by expansion of mature donor T cells, but whether IL-7 also exacerbates graft-vs-host disease (GVHD) remains unresolved. To address this issue, we examined the effect of IL-7 on GVHD induction using a well-defined murine GVHD model (B6-->B6AF1/J). Administration of IL-7 to nonirradiated B6AF1/J recipients of B6 T cells resulted in expansion of splenic donor CD4(+) and CD8(+) T cells and increased GVHD mortality. In contrast, administration of IL-7 on the same schedule failed to increase GVHD mortality in either sublethally or lethally irradiated animals that received graded doses of T cells designed to induce varying degrees of GVHD severity. Moreover, IL-7 failed to increase the number of alloreactive T cells when examined in a murine model (B6-->BALB.B) that allowed for direct quantitation of graft-vs-host-reactive T cells. The combination of irradiation and transplantation of alloreactive donor T cells resulted in significantly increased levels of endogenous splenic IL-7 mRNA when compared with nonirradiated transplanted animals, providing a potential explanation for why exogenous IL-7 did not increase GVHD severity in these mice. We conclude that host conditioning modulates the ability of exogenous IL-7 to exacerbate GVHD and that this occurs through induction of endogenous IL-7 production.     

Dynamics of species coexistence: maintenance of a plant-ant competitive metacommunity

The metacommunity approach is an adequate framework to study coexistence between interacting species at different spatial scales. However, empirical evidence from natural metacommunities necessary to evaluate the predictive power of theoretical models of species coexistence remains sparse. We use two African ant species, Cataulacus mckeyi and Petalomyrmex phylax , symbiotically associated with the myrmecophyte Leonardoxa africana africana , to examine spatio-temporal dynamics of species coexistence and to investigate which environmental and life-history parameters may contribute to the maintenance of species diversity in this guild of symbiotic ants. Using environmental niche partitioning as a conceptual framework, we combined data on habitat variation, social structure of colonies, and population genetics with data from a colonisation experiment and from observation of temporal dynamics. We propose that the dynamics of ant species colonisation and replacement at local and regional scales can be explained by a set of life history traits for which the two ants exhibit hierarchies, coupled with strong environmental differences between the different patches in the level of environmental disturbances. The role of the competition–colonisation tradeoff is discussed and we propose that interspecific tradeoffs for traits related to dispersal and to reproduction are also determinant for species coexistence. We therefore suggest that species-sorting mechanisms are predominant in the dynamics of this metacommunity, but we also emphasise that there may be many ways for two symbionts in competition for the same host to coexist. The results speak in favour of a more complete integration of the various metacommunity models in a single theoretical framework.     

Co-occurrence patterns of Bornean vertebrates suggest competitive exclusion is strongest among distantly related species

Assessing the importance of deterministic processes in structuring ecological communities is a central focus of community ecology. Typically, community ecologists study a single taxonomic group, which precludes detection of potentially important biotic interactions between distantly related species, and inherently assumes competition is strongest between closely related species. We examined distribution patterns of vertebrate species across the island of Borneo in Southeast Asia to assess the extent to which inter-specific competition may have shaped ecological communities on the island and whether the intensity of inter-specific competition in present-day communities varies as a function of evolutionary relatedness. We investigated the relative extent of competition within and between species of primates, birds, bats and squirrels using species presence–absence and attribute data compiled for 21 forested sites across Borneo. We calculated for each species pair the checkerboard unit value (CU), a statistic that is often interpreted as indicating the importance of interspecific competition. The percentage of species pairs with significant CUs was lowest in within-taxon comparisons. Moreover, for invertebrate-eating species the percentage of significantly checkerboarded species pairs was highest in comparisons between primates and other taxa, particularly birds and squirrels. Our results are consistent with the interpretation that competitive interactions between distantly related species may have shaped the distribution of species and thus the composition of Bornean vertebrate communities. This research highlights the importance of taking into account the broad mammalian and avian communities in which species occur for understanding the factors that structure biodiversity.     

Intraspecific niche flexibility facilitates species coexistence in a competitive community with a fluctuating environment

We analyzed the role of niche usage flexibility (i.e. niche width) in promoting species coexistence in competitive communities in a one-dimensional niche space. We included two types of stochasticity, namely, a random sampling effect of community founding and environmental fluctuation. Fluctuation was further divided into two categories: niche-independent fluctuation (synchronized over the niche space) and niche-dependent fluctuation (variable among individual niche positions). In the analysis, two types of genetic and inheritance systems of individual niche position were considered, i.e. sexual reproduction with multiple loci and asexual reproduction with phenotypic plasticity. We found that niche usage flexibility promoted species diversity only under restricted situations when the environment was constant, but it generally promoted diversity when the environment fluctuated. In particular, under niche-independent fluctuation, niche usage flexibility significantly enhanced species diversity. In contrast, the analysis also predicted that when niche flexibility was constant, species diversity decreased with increasing environmental correlation between neighboring niches.     

Fas has a role in cerebral malaria, but not in proliferation or exclusion of the murine parasite in mice

We examined the susceptibility of murine Fas-deficient mutants to malaria infection in order to investigate the role of Fas in an experimental murine model of cerebral malaria (CM). We infected mice of B6 and CBA wild-type and mutant backgrounds with Plasmodium berghei ANKA. The incidence of CM in the mutant mice (B6-lpr, CBA-lpr^cg) was decreased by about 50% compared with wild-type control strains at 2 weeks after infection. We did not observe significant differences of parasitemia during a murine malaria infection with nonlethal Plasmodium yoelii 17XNL between wild-type and lymphoproliferative (lpr) mutant mice of C3H and MRL genetic backgrounds, although B6-lpr mice exhibited significantly higher parasitemia than did B6 mice 12 to 18 days after infection. These results suggest Fas has a possible role in CM but may not play a major role in the proliferation or exclusion of a murine malaria parasite in a nonlethal infection.     

Stability of a Ricker-type competition model and the competitive exclusion principle

Our main objective is to study a Ricker-type competition model of two species. We give a complete analysis of stability and bifurcation and determine the centre manifolds, as well as stable and unstable manifolds. It is shown that the autonomous Ricker competition model exhibits subcritical bifurcation, bubbles, period-doubling bifurcation, but no Neimark–Sacker bifurcations. We exhibit the region in the parameter space where the competition exclusion principle applies.     

Incomplete mixing promotes species coexistence in a lottery model with permanent spatial heterogeneity

For many marine organisms, the population dynamics in multiple habitats are affected by migration of planktonic larvae. We herein examine the effect of incomplete larval mixing on the condition for species coexistence. The system consists of two heterogeneous habitats, each composed of a number of sites occupied by adults of two species. Larvae produced in a habitat form a pool and migrate to the pool of the other habitat. When an adult dies, the vacant site becomes occupied by an individual randomly chosen from the larval pool. We study (1). the invasibility of a inferior species which has no advantage in either habitats, (2). the dynamics when larval migration and competition among adults are symmetric between habitats, and (3). the case with unidirectional migration. The coexistence of competitors is more likely to occur when larval migration is weak.