Parasite evolution in response to sex‐based host heterogeneity in resistance and tolerance

Heterogenity between sexes in terms of both the level and the type of immune response to infection is documented in many species, but its role on parasite evolution is only beginning to be explored. We adopt an evolutionary epidemiology approach to study how the ability of a host to respond to infection through active immunity (resistance) or through minimizing deleterious effects of a given parasite load (tolerance) affects the evolution of parasite virulence. Consistently with earlier models, we find that increases in host resistance and tolerance both favour more virulent parasite strains. However, we show that qualitatively different results can be obtained if dimorphism between the sexes occurs through resistance or through tolerance depending on the contact pattern between the sexes. Finally, we find that variations in host sex ratio can amplify the consequences of heterogeneity for parasite evolution. These results are analysed in the light of several examples from the literature to illustrate the prevalence of sexually dimorphic immune responses and the potential for further study of the role of sexual dimorphism on parasite evolution. Such studies are likely to be highly relevant for improving treatment of chronic infections and control of infectious diseases, and understanding the role of sex in immune function.     

Parasites and immune responses: memory illusion?

Immunological memory responses to intracellular protozoa and extracellular helminths govern host resistance and susceptibility to reinfection. Humans and livestock living in parasitic disease endemic regions face continuous exposure from a very early age that often leads to asymptomatic chronic infection over their entire lifespan. Fundamental immunological studies suggest that the generation of T-cell memory is driven by tightly coordinated innate and adaptive cellular immune responses rapidly triggered following initial host infection. A key distinguishing feature of immune memory maintenance between the majority of parasitic diseases and most bacterial or viral diseases is long-term antigen persistence. Consequently, functional parasite immune memory is in a continuous, dynamic flux between activation and deactivation producing functional parasite killing or functional memory cell death. In this sense, T-cell immune memory can be regarded as "memory illusion." Furthermore, due to the finite capacity of memory lymphocytes to proliferate, continuous parasite antigen stimulation may exceed a threshold level at some point in the chronically infected host. This may result in suboptimal effector immune memory leading to host susceptibility to reinfection, or immune dysregulation yielding disease reactivation or immune pathology. The goal of this review is to highlight, through numerous examples, what is currently known about T-cell immune memory to parasites and to provide compelling hypotheses on the survival and maintenance of parasite "memory illusion." These novel concepts are discussed in the context of rationale parasite vaccine design strategies.     

The effect of challenge and trickle Trichuris muris infections on the polarisation of the immune response

In the field, determination of mechanisms of immunity to geohelminths are problematic due to the variation in infection exposure, host genetics, nutrition and co-infection. This study uses a well defined laboratory model, Trichuris muris in the mouse to study immune responses to challenge and trickle infections. The rationale is thus to study parasite acquisition under more natural antigen dose exposure. Antigen dose has previously been shown in this system to affect the outcome of infection with low antigen doses favouring type 1 responses (and susceptibility) and high antigen doses favouring type 2 responses (and resistance). A high level challenge infection could be established in a normally resistant host but only following priming of the immune response by a low level infection. Once type 2 responses were initiated it was impossible to switch an ongoing type 2 response even using IL-12 which is a potent stimulus of type 1 responses. Trickle infections resulted in no clear polarisation of the immune response. It was possible to build up the level of infection to a threshold level beyond which type 2 responses and expulsion were initiated. This threshold level was dependent upon host genetic background. Our results reveal a complex spectrum of responses and demonstrate that resistance and type 2 responses can be built up with increasing parasite exposure. The data provide compelling evidence to support a role for acquisition of acquired immunity to gastro-intestinal nematodes under complex infection patterns such as those found in the field.     

Echinococcus granulosus: different cytokine profiles are induced by single versus multiple experimental infections in dogs

Modulation of host responses is an important strategy by which parasites ensure successful establishment and persistence. Host counteraction against this modulation may be required for the host to develop resistance to infection. In this pilot study, experimental infection of dogs with Echinococcus granulosus induced a strong polarization of the cytokine response towards a Th2 phenotype. Consecutive rounds of infection and cure induced resistance to infection resulting in a dramatically lower parasite burden. Repeatedly-infected resistant dogs also lost immune polarization and developed a balanced Th1/Th2 response. No major differences were observed in the production of regulatory cytokines (IL-10, TGF-β) between dogs with high parasite load and dogs with only few intestinal parasites. These results suggest that E. granulosus-driven immunomodulation contributes to successful infection in the definitive host. This information might be relevant for the development of more effective vaccines against this stage of the parasite.     

THE CELLULAR IMMUNE RESPONSE OF DAPHNIA MAGNA UNDER HOST–PARASITE GENETIC VARIATION AND VARIATION IN INITIAL DOSE

In invertebrate–parasite systems, the likelihood of infection following parasite exposure is often dependent on the specific combination of host and parasite genotypes (termed genetic specificity). Genetic specificity can maintain diversity in host and parasite populations and is a major component of the Red Queen hypothesis. However, invertebrate immune systems are thought to only distinguish between broad classes of parasite. Using a natural host–parasite system with a well‐established pattern of genetic specificity, the crustacean Daphnia magna and its bacterial parasite Pasteuria ramosa, we found that only hosts from susceptible host–parasite genetic combinations mounted a cellular response following exposure to the parasite. These data are compatible with the hypothesis that genetic specificity is attributable to barrier defenses at the site of infection (the gut), and that the systemic immune response is general, reporting the number of parasite spores entering the hemocoel. Further supporting this, we found that larger cellular responses occurred at higher initial parasite doses. By studying the natural infection route, where parasites must pass barrier defenses before interacting with systemic immune responses, these data shed light on which components of invertebrate defense underlie genetic specificity.     

Recent advances in cryptosporidiosis: the immune response

An increased understanding of host immune responses to Cryptosporidium parvum which are responsible for clearance of primary infection and resistance to reinfection, and characterization of the parasite molecules to which they are directed, are essential for discovery of effective active and passive immunization strategies against cryptosporidiosis. In this article, recent advances in knowledge of humoral and cellular immune responses to C. parvum, their antigen specificities, and mechanisms of protection are briefly reviewed.     

Modulation of Innate Antigen-Presenting Cell Function by Pre-patent Schistosome Infection

Schistosomes are intravascular helminths that infect over 200 million people worldwide. Deposition of eggs by adult schistosomes stimulates Th2 responses to egg antigens and induces granulomatous pathology that is a hallmark of schistosome infection. Paradoxically, schistosomes require host immune function for their development and reproduction and for egress of parasite eggs from the host. To identify potential mechanisms by which immune cells might influence parasite development prior to the onset of egg production, we assessed immune function in mice infected with developing schistosomes. We found that pre-patent schistosome infection is associated with a loss of T cell responsiveness to other antigens and is due to a diminution in the ability of innate antigen-presenting cells to stimulate T cells. Diminution of stimulatory capacity by schistosome worms specifically affected CD11b⁺ cells and did not require concomitant adaptive responses. We could not find evidence for production of a diffusible inhibitor of T cells by innate cells from infected mice. Rather, inhibition of T cell responsiveness by accessory cells required cell contact and only occurred when cells from infected mice outnumbered competent APCs by more than 3∶1. Finally, we show that loss of T cell stimulatory capacity may in part be due to suppression of IL-12 expression during pre-patent schistosome infection. Modulation of CD4⁺ T cell and APC function may be an aspect of host immune exploitation by schistosomes, as both cell types influence parasite development during pre-patent schistosome infection.     

Parasite polyclonal activators: new targets for vaccination approaches?

Taking into consideration that the immune response following infection promotes the expansion of lymphocyte clones that are essentially non-specific, ensuring both parasite evasion and persistence inside the host, what would be the major consequences of this polyclonal response to the development of immunopathology? We favor the hypothesis that the polyclonal B cell responses triggered by the infection is responsible of the host susceptibility and is a major contributor to the maintenance of a progressive disease. In particular, the activation of B cells by parasite mitogens would contribute to the class determination of T cell responses and to the inhibition of macrophages - target cells for parasite multiplication and also responsible for parasite clearance. We also envisage that the activation of T cells by parasite 'superantigens', and the ensuing energy and deletion of these cells, processes that are frequently observed, would contribute for the immunosuppression as well as to parasite escape and persistence in the host. We had concentrated our efforts on the study of the non-specific aspects of the immune response following Trypanosoma cruzi infection. We aimed at finding new strategies to modulate and control the mechanisms leading to both the immunosuppression and the development of chronic auto-immunity leading to rational vaccine approaches against parasite infection and immunopathology.     

Relative importance of chemical attractiveness to parasites for susceptibility to trematode infection

While the host immune system is often considered the most important physiological mechanism against parasites, precontact mechanisms determining exposure to parasites may also affect infection dynamics. For instance, chemical cues released by hosts can attract parasite transmission stages. We used the freshwater snail Lymnaea stagnalis and its trematode parasite Echinoparyphium aconiatum to examine the role of host chemical attractiveness, physiological condition, and immune function in determining its susceptibility to infection. We assessed host attractiveness through parasite chemo‐orientation behavior; physiological condition through host body size, food consumption, and respiration rate; and immune function through two immune parameters (phenoloxidase‐like and antibacterial activity of hemolymph) at an individual level. We found that, although snails showed high variation in chemical attractiveness to E. aconiatum cercariae, this did not determine their overall susceptibility to infection. This was because large body size increased attractiveness, but also increased metabolic activity that reduced overall susceptibility. High metabolic rate indicates fast physiological processes, including immune activity. The examined immune traits, however, showed no association with susceptibility to infection. Our results indicate that postcontact mechanisms were more likely to determine snail susceptibility to infection than variation in attractiveness to parasites. These may include localized immune responses in the target tissue of the parasite. The lack of a relationship between food consumption and attractiveness to parasites contradicts earlier findings that show food deprivation reducing snail attractiveness. This suggests that, although variation in resource level over space and time can alter infection dynamics, variation in chemical attractiveness may not contribute to parasite‐induced fitness variation within populations when individuals experience similar environmental conditions.     

Heterogeneous interspecific interactions in a host-parasite system

Macroparasites of vertebrates usually occur in multi-species communities, producing infections whose outcome in individual hosts or host populations may depend on the dynamics of interactions amongst the different component species. Within a single co-infection, competition can occur between conspecific and heterospecific parasite individuals, either directly or via the host's physiological and immune responses. We studied a natural single-host, multi-parasite model infection system (polystomes in the anuran Xenopus laevis victorianus) in which the parasite species show total interspecific competitive exclusion as adults in host individuals. Multi-species infection experiments indicated that competitive outcomes were dependent on infection species composition and strongly influenced by the intraspecific genetic identity of the interacting organisms. Our results also demonstrate the special importance of temporal heterogeneity (the sequence of infection by different species) in competition and co-existence between parasite species and predict that developmental plasticity in inferior competitors, and the induction of species-specific host resistance, will partition the within-host-individual habitat over time. We emphasise that such local (within-host) context-dependent processes are likely to be a fundamental determinant of population dynamics in multi-species parasite assemblages.     

Protective immune mechanisms in helminth infection

Important insights have recently been gained in our understanding of how host immune responses mediate resistance to parasitic helminths and control associated pathological responses. Although similar cells and cytokines are evoked in response to infection by helminths as diverse as nematodes and schistosomes, the components of the response that mediate protection are dependent on the particular parasite. In this Review, we examine recent findings regarding the mechanisms of protection in helminth infections that have been elucidated in murine models and discuss the implications of these findings in terms of future therapies.     

Balancing immunity and pathology in visceral leishmaniasis

Experimental visceral leishmaniasis (VL) caused by infection with Leishmania donovani results in the development of organ-specific immunity in the two main target tissues of infection, the spleen and the liver. The liver is the site of an acute resolving infection associated with the development of inflammatory granulomas around infected Kupffer cells, and resistance to reinfection. Paradoxically, the spleen is an initial site for the generation of cell-mediated immune responses, but ultimately becomes a site of parasite persistence with associated immunopathological changes. These include splenomegaly and a breakdown in tissue architecture that is postulated to contribute to the immunocompromized status of the host. The progressive development of splenic pathology is largely associated with high levels of TNF and interleukin (IL)-10. Follicular dendritic cell (DC) networks are lost, whereas TNF mediates the destruction of marginal zone macrophages and gp38(+) stromal cells, and IL-10 promotes impaired DC migration into T-cell areas with consequent ineffective T-cell priming. Splenic stromal cell function is also altered, promoting the selective development of IL-10-producing DC with immunoregulatory properties. Ultimately, a fine immunological balance determines responses that effectively promote parasite clearance in the liver and those that promote pathology in the spleen, and future investigation aims to separate these responses to offer further means of parasite control in chronically infected VL patients.     

Innate responses to Toxoplasma gondii in mice and humans

Primary infection with Toxoplasma gondii stimulates production of high levels of interleukin 12 (IL-12) and interferon γ (IFN-γ) by cells of the innate immune system. These two cytokines are central to resistance to T. gondii. Signaling through the Toll-like receptor (TLR) adaptor protein MyD88 is indispensible for activating early innate immune responses. Recent studies have established that TLR11 plays a dominant role in sensing T. gondii. At the same time, TLR11 is represented in humans only by a pseudogene, and the major question of how innate and adaptive immune responses occur in the absence of TLR11 remains unanswered. In this article, similarities and differences in sensors and effector molecules that determine host resistance to the parasite in humans and mice are discussed.     

The ecology of host immune responses to chronic avian haemosporidian infection

Host responses to parasitism in the wild are often studied in the context of single host–parasite systems, which provide little insight into the ecological dynamics of host–parasite interactions within a community. Here we characterized immune system responses to mostly low-intensity, chronic infection by haemosporidian parasites in a sample of 424 individuals of 22 avian host species from the same local assemblage in the Missouri Ozarks. Two types of white blood cells (heterophils and lymphocytes) were elevated in infected individuals across species, as was the acute-phase protein haptoglobin, which is associated with inflammatory immune responses. Linear discriminant analysis indicated that individuals infected by haemosporidians occupied a subset of the overall white blood cell multivariate space that was also occupied by uninfected individuals, suggesting that these latter individuals might have harbored other pathogens or that parasites more readily infect individuals with a specific white blood cell profile. DNA sequence-defined lineages of haemosporidian parasites were sparsely distributed across the assemblage of hosts. In one well-sampled host species, the red-eyed vireo (Vireo olivaceus), heterophils were significantly elevated in individuals infected with one but not another of two common parasite lineages. Another well-sampled host, the yellow-breasted chat (Icteria virens), exhibited no differences in immune response to different haemosporidian lineages. Our results indicate that while immune responses to infection may be generalized across host species, parasite-specific immune responses may also occur.     

Towards a new conceptual approach to "parasitoproteomics"

Many parasitologists are betting heavily on proteomic studies to explain biochemical host-parasite interactions and, thus, to contribute to disease control. However, many "parasitoproteomic" studies are performed with powerful techniques but without a conceptual approach to determine whether the host genomic responses during a parasite infection represent a nonspecific response that might be induced by any parasite or any other stress. In this article, a new conceptual approach, based on evolutionary concepts of immune responses of a host to a parasite, is suggested for parasitologists to study the host proteome reaction after parasite invasion. Also, this new conceptual approach can be used to study other host-parasite interactions such as behavioral manipulation.     

IL-4 is required to prevent filarial nematode development in resistant but not susceptible strains of mice

The murine Litomosoides sigmodontis model of filarial infection provides the opportunity to elucidate the immunological mechanisms that determine whether these nematode parasites can establish a successful infection or are rejected by the mammalian host. BALB/c mice are fully susceptible to L. sigmodontis infection and can develop patent infection, with the microfilarial stage circulating in the bloodstream. In contrast, mice on the C57BL background are largely resistant to the infection and never produce a patent infection. In this study, we used IL-4 deficient mice on the C57BL/6 background to address the role of IL-4 in the development of L. sigmodontis parasites in a resistant host. Two months after infection, adult worm recovery and the percentage of microfilaraemic mice in infected IL-4 deficient mice were comparable with those of the susceptible BALB/c mice while, as expected, healthy adults were not recovered from wild type C57BL/6 mice. The cytokine and antibody responses reveal that despite similar parasitology the two susceptible strains (BALB/c and IL-4 deficient C57BL/6) have markedly different immune responses: wild type BALB/c mice exhibit a strong Th2 immune response and the IL-4 deficient C57BL/6 mice exhibit a Th1 response. We also excluded a role for antibodies in resistance through infection of B-cell deficient C57BL/6 mice. Our data suggest that the mechanisms that determine parasite clearance in a resistant/non-permissive host are Th2 dependent but that in a susceptible/permissive host, the parasite can develop in the face of a Th2 dominated response.     

Contrasting consequences of different defence strategies in a natural multihost–parasite system

Hosts counteract infections using two distinct defence strategies, resistance (reduction in pathogen fitness) and tolerance (limitation of infection damage). These strategies have been minimally investigated in multi-host systems, where they may vary across host species, entailing consequences both for hosts (virulence) and parasites (transmission). Comprehending the interplay among resistance, tolerance, virulence and parasite success is highly relevant for our understanding of the ecology and evolution of infectious and parasitic diseases. Our work investigated the interaction between an insect parasite and its most common bird host species, focusing on two relevant questions: (i) are defence strategies different between main and alternative hosts and, (ii) what are the consequences (virulence and parasite success) of different defence strategies? We conducted a matched field experiment and longitudinal studies at the host and the parasite levels under natural conditions, using a system comprising Philornis torquans flies and three bird hosts – the main host and two of the most frequently used alternative hosts. We found that main and alternative hosts have contrasting defence strategies, which gave rise in turn to contrasting virulence and parasite success. In the main bird host, minor loss of fitness, no detectable immune response, and high parasite success suggest a strategy of high tolerance and negligible resistance. Alternative hosts, on the contrary, resisted by mounting inflammatory responses, although with very different efficiency, which resulted in highly dissimilar parasite success and virulence. These results show clearly distinct defence strategies between main and alternative hosts in a natural multi-host system. They also highlight the importance of defence strategies in determining virulence and infection dynamics, and hint that defence efficiency is a crucial intervening element in these processes.     

Modulation of innate immunity by African trypanosomes

The experimental studies of Brucei group trypanosomes presented here demonstrate that the balance of host and parasite factors, especially IFN-γ GPI-sVSG respectively, and the timing of cellular exposure to them, dictate the predominant MP and DC activation profiles present at any given time during infection and within specific tissues. The timing of changes in innate immune cell functions following infection consistently support the conclusion that the key events controlling host resistance occur within a short time following initial exposure to the parasite GPI substituents. Once the changes in MP and DC activities are initiated, there appears little that the host can do to reverse these changes and alter the final outcome of these regulatory events. Instead, despite the availability of multiple innate and adaptive immune mechanisms that can control parasites, there is an inability to control trypanosome numbers sufficiently to prevent the emergence and establishment of virulent trypanosomes that eventually kill the host. Overall it appears that trypanosomes have carefully orchestrated the host innate and adaptive immune response so that parasite survival and transmission, and alterations of host immunity, are to its ultimate benefit.     

Alternative measures of response to Pseudomonas aeruginosa infection in Drosophila melanogaster

Studies of invertebrate immune defence often measure genetic variation either for the fitness cost of infection or for the ability of the host to clear the parasite. These studies assume that variation in measures of resistance is related to variation in fitness costs of infection. To test this assumption, we infected strains of the fruit fly, Drosophila melanogaster, with a pathogenic bacterium. We then measured the correlation between host bacterial load and the ability to survive infection. Despite the presence of genotypic variation for both traits, bacterial load and survival post-infection were not correlated. Our results support previous arguments that individual measures of immune function and the host's ability to survive infection may be decoupled. In light of these results, we suggest that the difference between tolerance and resistance to infection, a distinction commonly found in the plant literature, may also be of value in studies of invertebrate immunity.