The next 20 years of ecology and evolution.
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Animals↗
Biomedical subjects
Andrew F Read
Publications and source records attributed to Andrew F Read.
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.
Animals↗
The past 20 years of ecology and evolution.
Explore the source record for details and available documents.
Biological Evolution↗
Within-host competition in genetically diverse malaria infections: parasite virulence and competitive success.
Humans and animals often become coinfected with pathogen strains that differ in virulence. The ensuing interaction between these strains can, in theory, be a major determinant of the direction of selection on virulence genes in pathogen populations. Many mathematical analyses of this assume that virulent pathogen lineages have a competitive advantage within coinfected hosts and thus predict that pathogens will evolve to become more virulent where genetically diverse infections are common. Although the implications of these studies are relevant to both fundamental biology and medical science, direct empirical tests for relationships between virulence and competitive ability are lacking. Here we use newly developed strain-specific real-time quantitative polymerase chain reaction protocols to determine the pairwise competitiveness of genetically divergent Plasmodium chabaudi clones that represent a wide range of innate virulences in their rodent host. We found that even against their background of widely varying genotypic and antigenic properties, virulent clones had a competitive advantage in the acute phase of mixed infections. The more virulent a clone was relative to its competitor, the less it suffered from competition. This result confirms our earlier work with parasite lines derived from a single clonal lineage by serial passage and supports the virulence-competitive ability assumption of many theoretical models. To the extent that our rodent model captures the essence of the natural history of malaria parasites, public health interventions which reduce the incidence of mixed malaria infections should have beneficial consequences by reducing the selection for high virulence.
Animals↗
Poor maternal environment enhances offspring disease resistance in an invertebrate.
Natural populations vary tremendously in their susceptibility to infectious disease agents. The factors (environmental or genetic) that underlie this variation determine the impact of disease on host population dynamics and evolution, and affect our capacity to contain disease outbreaks and to enhance resistance in agricultural animals and disease vectors. Here, we show that changes in the environmental conditions under which female Daphnia magna are kept can more than halve the susceptibility of their offspring to bacterial infection. Counter-intuitively, and unlike the effects typically observed in vertebrates for transfer of immunity, mothers producing offspring under poor conditions produced more resistant offspring than did mothers producing offspring in favourable conditions. This effect occurred when mothers who were well provisioned during their own development then found themselves reproducing in poor conditions. These effects likely reflect adaptive optimal resource allocation where better quality offspring are produced in poor environments to enhance survival. Maternal exposure to parasites also reduced offspring susceptibility, depending on host genotype and offspring food levels. These maternal responses to environmental conditions mean that studies focused on a single generation, and those in which environmental variation is experimentally minimized, may fail to describe the crucial parameters that influence the spread of disease. The large maternal effects we report here will, if they are widespread in nature, affect disease dynamics, the level of genetic polymorphism in populations, and likely weaken the evolutionary response to parasite-mediated selection.
Animals↗
Rodent malaria parasites Plasmodium chabaudi and P. vinckei do not increase their rates of gametocytogenesis in response to mosquito probing.
Several vector-borne infectious agents facultatively alter their life history strategies in response to local vector densities. Some evidence suggests that malaria parasites invest more heavily in transmission stage production (gametocytogenesis) when vectors are present. Such a strategy could rapidly increase malaria transmission rates, particularly when adult mosquitoes begin to appear after dry seasons. However, in contrast to a recent experiment with a rodent malaria (Plasmodium chabaudi), we found no change in gametocytogenesis in either P. chabaudi or in another rodent malaria, P. vinckei, when their mouse hosts were exposed to mosquitoes. Positive results in the earlier study may have been because mosquito-feeding caused anaemia in hosts, a known promoter of gametocytogenesis. The substantial evidence that malaria and a variety of other parasites facultatively alter transmission strategies in response to a variety of environmental influences makes our results surprising.
Animals↗
Plasmodium chabaudi: reverse transcription PCR for the detection and quantification of transmission stage malaria parasites.
We have developed two reverse transcription polymerase chain reaction (RT-PCR) techniques to detect and quantify the transmission stages (gametocytes) of Plasmodium chabaudi malaria parasites. Both the qualitative and quantitative techniques are based on the amplification of mRNA coding for the P. chabaudi protein Pcs230, which is expressed exclusively in gametocytes. The quantitative RT-PCR (qRT-PCR) technique was developed and validated by examining serial dilutions of known gametocyte densities. The method generated a high correlation between calibration curves of blind samples (R(2)=0.86). The technique was found to be specific, reproducible, and time efficient for quantification of both patent and sub-patent gametocytemia with a sensitivity level 100-1000 times greater than microscopy. The qualitative RT-PCR (RT-PCR) technique was used to monitor the persistence and dynamics of P. chabaudi gametocytes following acute infection. Mice in two independent experiments were sampled for up to 87 days post-infection. RT-PCR showed that gametocytes can persist for up to 8 weeks, post-infection, whereas microscopy could only detect gametocytes up to 6 weeks. Potential applications of the above techniques for studying the ecology, evolution, and epidemiology of malaria transmission are discussed.
Animals↗
Dynamics of multiple infection and within-host competition in genetically diverse malaria infections.
Within-host competition between coinfecting parasite strains shapes the evolution of parasite phenotypes such as virulence and drug resistance. Although this evolution has a strong theoretical basis, within-host competition has rarely been studied experimentally, particularly in medically relevant pathogens with hosts that have pronounced specific and nonspecific immune responses against coinfecting strains. We investigated multiple infection in malaria, using two pairs of genetically distinct clones of the rodent malaria Plasmodium chabaudi in mice. Clones were inoculated into mice simultaneously or 3 or 11 days apart, and population sizes were tracked using immunofluorescence or quantitative polymerase chain reaction. In all experiments, at least one of the two clones suffered strong competitive suppression, probably through both resource- and immune-mediated (apparent) competition. Clones differed in intrinsic competitive ability, but prior residency was also an important determinant of competitive outcome. When clones infected mice first, they did not suffer from competition, but they did when infecting mice at the same time or after their competitor, more so the later they infected their host. Consequently, clones that are competitively inferior in head-to-head competition can be competitively superior if they infect hosts first. These results are discussed in the light of strain-specific immunity, drug resistance, and virulence evolution theory.
Animals↗
Fungal pathogen reduces potential for malaria transmission.
Using a rodent malaria model, we found that exposure to surfaces treated with fungal entomopathogens following an infectious blood meal reduced the number of mosquitoes able to transmit malaria by a factor of about 80. Fungal infection, achieved through contact with both solid surfaces and netting for durations well within the typical post-feed resting periods, was sufficient to cause >90% mortality. Daily mortality rates escalated dramatically around the time of sporozoite maturation, and infected mosquitoes showed reduced propensity to blood feed. Residual sprays of fungal biopesticides might replace or supplement chemical insecticides for malaria control, particularly in areas of high insecticide resistance.
Animals↗
Virulence and competitive ability in genetically diverse malaria infections.
Explaining parasite virulence is a great challenge for evolutionary biology. Intuitively, parasites that depend on their hosts for their survival should be benign to their hosts, yet many parasites cause harm. One explanation for this is that within-host competition favors virulence, with more virulent strains having a competitive advantage in genetically diverse infections. This idea, which is well supported in theory, remains untested empirically. Here we provide evidence that within-host competition does indeed select for high parasite virulence. We examine the rodent malaria Plasmodium chabaudi in laboratory mice, a parasite-host system in which virulence can be easily monitored and competing strains quantified by using strain-specific real-time PCR. As predicted, we found a strong relationship between parasite virulence and competitive ability, so that more virulent strains have a competitive advantage in mixed-strain infections. In transmission experiments, we found that the strain composition of the parasite populations in mosquitoes was directly correlated with the composition of the blood-stage parasite population. Thus, the outcome of within-host competition determined relative transmission success. Our results imply that within-host competition is a major factor driving the evolution of virulence and can explain why many parasites harm their hosts.
Animals↗
Host cell preference and variable transmission strategies in malaria parasites.
Malaria and other haemosporin parasites must undergo a round of sexual reproduction in their insect vector in order to produce stages that can be transmitted to vertebrate hosts. Consequently, it is crucial that parasites produce the sex ratio (proportion of male sexual stages) that will maximize the number of fertilization and thus, transmission to new vertebrate hosts. There is some evidence to show that, consistent with evolutionary theory, the sex ratios of malaria parasites are negatively correlated to their inbreeding rate. However, recent theory has shown that when fertilization success is compromised, parasites should respond by increasing their investment in sexual stages or by producing a less female biased ration than predicted by their inbreeding rate alone. Here, we show that two species of rodent malaria, Plasmodium chabaudi and Plasmodium vinckei petteri, adopt different strategies in response to host anaemia, a factor though to compromise transmission success: P. chabaudi increases investment in sexual stages, whereas P. vinckei produces a less female biased sex ratio. We suggest that these different transmission strategies may be due to marked differences in host cell preference.
Anemia↗
Probabilistic order in antigenic variation of Trypanosoma brucei.
Antigenic variation in African trypanosomes displays a degree of order that is usually described as 'semi-predictable' but which has not been analysed in statistical detail. It has been proposed that, during switching, the variable antigen type (VAT) being inactivated can influence which VAT is subsequently activated. Antigenic variation proceeds by the differential activation of members of the large archive of distinct variable surface glycoprotein (VSG) genes. The most popular model for ordered expression of VATs invokes differential activation probabilities for individual VSG genes, dictated in part by which of the four types of genetic locus they occupy. We have shown, in pilot experiments in cattle, correlation between the timing of appearance of VSG-specific mRNA and of lytic antibodies corresponding to seven VSGs encoded by single-copy genes. We have then determined the times of appearance of VAT-specific antibodies, as a measure of appearance of the VATs, in a statistically significant number of mouse infections (n=22). There is a surprisingly high degree of order in temporal appearance of the VATs, indicating that antigenic variation proceeds through order in the probability of activation of each VAT. In addition, for the few examples of each available, the locus type inhabited by the silent 'donor' VSG plays a significant role in determination of order. We have analysed in detail previously published data on VATs appearing in first relapse peaks, and find that the variant being switched off does not influence which one is being switched on. This differs from what has been reported for Plasmodium falciparum var antigenic variation. All these features of trypanosome antigenic variation can be explained by a one-step model in which, following an initial deactivation event, the switch process and the imposition of order early in infection arise from the inherent activation probabilities of the specific VSG being switched on.
Animals↗
Invertebrate immunity and the limits of mechanistic immunology.
Rapid progress is being made in elucidating the molecular mechanisms involved in invertebrate immunity. This search for molecules runs the risk of missing important phenomena. In vertebrates, acquired protection and pathogen-specific responses were demonstrated experimentally long before the mechanisms responsible were elucidated. Without analogous experiments, mechanism-driven work may not demonstrate the full richness of invertebrate immunity.
Animals↗
Host-parasite and genotype-by-environment interactions: temperature modifies potential for selection by a sterilizing pathogen.
Parasite-mediated selection is potentially of great importance in modulating genetic diversity. Genetic variation for resistance, the fuel for natural selection, appears to be common in host-parasite interactions, but responses to selection are rarely observed. In the present study, we tested whether environmental variation could mediate infection and determine evolutionary outcomes. Temperature was shown to dramatically alter the potential for parasite-mediated selection in two independent laboratory infection experiments at four temperatures. The bacterial parasite, Pasteuria ramosa, was extremely virulent at 20 degrees C and 25 degrees C, sterilizing its host, Daphnia magna, so that females often never produced a single brood. However, at 10 degrees C and 15 degrees C, the host-parasite interaction was much more benign, as nearly all females produced broods before becoming sterile. This association between virulence and temperature alone could stabilize coexistence and lead to the maintenance of diversity, because it would weaken parasite-mediated selection during parts of the season. Additionally, highly significant genotype-by-environment interactions were found, with changes in clone rank order for infection rates at different temperatures. Our results clearly show that the outcome of parasite-mediated selection in this system is strongly context dependent.
Animals↗
The presence of Plasmodium falciparum gametocytes in human blood increases the gravidity of Anopheles gambiae mosquitoes.
We conducted a field study in an area of endemic malaria transmission in western Kenya to determine whether mosquitoes that feed on gametocyte-infected blood but do not become infected have reduced or enhanced fecundity in comparison to mosquitoes fed on uninfected blood. Fifteen paired membrane-feeding experiments were conducted in which two strains of Anopheles gambiae mosquitoes were simultaneously fed on either Plasmodium falciparum-infected blood from children or uninfected control blood from adults. The presence of noninfecting gametocytes in blood increased the probability that An. gambiae would produce eggs after one blood meal by sixfold (odds ratio for control relative to infected blood group 0.16; 95% CI 0.10-0.23). This result could not be explained by variation in blood meal size or hemoglobin content between hosts. When children cleared their infections, the difference in gravidity between mosquitoes fed on their blood and uninfected adults disappeared, suggesting this phenomenon is due to the presence of Plasmodium gametocytes in blood and not to host-specific factors such as age. This result was observed in two mosquito strains that differ in their innate fecundity, suggesting it may apply generally. To our knowledge, this is the first time that Plasmodium has been implicated as enhancing vector gravidity.
Adult↗
Malaria-filaria coinfection in mice makes malarial disease more severe unless filarial infection achieves patency.
Coinfections are common in natural populations, and the literature suggests that helminth coinfection readily affects how the immune system manages malaria. For example, type 1-dependent control of malaria parasitemia might be impaired by the type 2 milieu of preexisting helminth infection. Alternatively, immunomodulatory effects of helminths might affect the likelihood of malarial immunopathology. Using rodent models of lymphatic filariasis (Litomosoides sigmodontis) and noncerebral malaria (clone AS Plasmodium chabaudi chabaudi), we quantified disease severity, parasitemia, and polyclonal splenic immune responses in BALB/c mice. We found that coinfected mice, particularly those that did not have microfilaremia (Mf(-)), had more severe anemia and loss of body mass than did mice with malaria alone. Even when controlling for parasitemia, malaria was most severe in Mf(-) coinfected mice, and this was associated with increased interferon- gamma responsiveness. Thus, in Mf(-) mice, filariasis upset a delicate immunological balance in malaria infection and exacerbated malaria-induced immunopathology.
Anemia↗
Competitive release of drug resistance following drug treatment of mixed Plasmodium chabaudi infections.
BACKGROUND: Malaria infections are often genetically diverse, potentially leading to competition between co-infecting strains. Such competition is of key importance in the spread of drug resistance. METHODS: The effects of drug treatment on within-host competition were studied using the rodent malaria Plasmodium chabaudi. Mice were infected simultaneously with a drug-resistant and a drug-sensitive clone and were then either drug-treated or left untreated. Transmission was assessed by feeding mice to Anopheles stephensi mosquitoes. RESULTS: In the absence of drugs, the sensitive clone competitively suppressed the resistant clone; this resulted in lower asexual parasite densities and also reduced transmission to the mosquito vector. Drug treatment, however, allowed the resistant clone to fill the ecological space emptied by the removal of the sensitive clone, allowing it to transmit as well as it would have done in the absence of competition. CONCLUSION: These results show that under drug pressure, resistant strains can have two advantages: (1) they survive better than sensitive strains and (2) they can exploit the opportunities presented by the removal of their competitors. When mixed infections are common, such effects could increase the spread of drug resistance.
Animals↗
Virulence in malaria: an evolutionary viewpoint.
Malaria parasites cause much morbidity and mortality to their human hosts. From our evolutionary perspective, this is because virulence is positively associated with parasite transmission rate. Natural selection therefore drives virulence upwards, but only to the point where the cost to transmission caused by host death begins to outweigh the transmission benefits. In this review, we summarize data from the laboratory rodent malaria model, Plasmodium chabaudi, and field data on the human malaria parasite, P. falciparum, in relation to this virulence trade-off hypothesis. The data from both species show strong positive correlations between asexual multiplication, transmission rate, infection length, morbidity and mortality, and therefore support the underlying assumptions of the hypothesis. Moreover, the P. falciparum data show that expected total lifetime transmission of the parasite is maximized in young children in whom the fitness cost of host mortality balances the fitness benefits of higher transmission rates and slower clearance rates, thus exhibiting the hypothesized virulence trade-off. This evolutionary explanation of virulence appears to accord well with the clinical and molecular explanations of pathogenesis that involve cytoadherence, red cell invasion and immune evasion, although direct evidence of the fitness advantages of these mechanisms is scarce. One implication of this evolutionary view of virulence is that parasite populations are expected to evolve new levels of virulence in response to medical interventions such as vaccines and drugs.
Age Factors↗