Trematode Diplostomum pseudospathaceum inducing differential immune gene expression in sexual and gynogenetic gibel carp (Carassius gibelio): parasites facilitating the coexistence of two reproductive forms of the invasive species.

Introduction: Parasite-mediated selection is considered one of the potential mechanisms contributing to the coexistence of asexual-sexual complexes. Gibel carp (Carassius gibelio), an invasive fish species in Europe, often forms populations composed of gynogenetic and sexual specimens. Methods: The experimental infection was induced in gynogenetic and sexual gibel carp using eye-fluke Diplostomum pseudospathaceum (Trematoda), and the transcriptome profile of the spleen as a major immune organ in fish was analyzed to reveal the differentially expressed immunity-associated genes related to D. pseudospathaceum infection differing between gynogenetic and sexual gibel carp. Results: High parasite infection was found in gynogenetic fish when compared to genetically diverse sexuals. Although metacercariae of D. pseudospathaceum are situated in an immune-privileged organ, our results show that eye trematodes may induce a host immune response. We found differential gene expression induced by eye-fluke infection, with various impacts on gynogenetic and sexual hosts, documenting for the majority of DEGs upregulation in sexuals, and downregulation in asexuals. Differences in gene regulation between gynogenetic and sexual gibel carp were evidenced in many immunity-associated genes. GO analyses revealed the importance of genes assigned to the GO terms: immune function, the Notch signaling pathway, MAP kinase tyrosine/threonine/phosphatase activity, and chemokine receptor activity. KEGG analyses revealed the importance of the genes involved in 12 immunity-associated pathways - specifically, FoxO signaling, adipocytokine signaling, TGF-beta signaling, apoptosis, Notch signaling, C-type lectin receptor signaling, efferocytosis, intestinal immune network for IgA production, insulin signaling, virion - human immunodeficiency virus, Toll-like receptor signaling, and phosphatidylinositol signaling system. Discussion: Our study indicates the limited potential of asexual fish to cope with higher parasite infection (likely a loss of capacity to induce an effective immune response) and highlights the important role of molecular mechanisms associated with immunity for the coexistence of gynogenetic and sexual gibel carp, potentially contributing to its invasiveness.

Using our understanding of interactions between helminth metabolism and host immunity to target worm survival.

Helminths can adapt to environmental conditions in the host, utilising anaerobic processes like fermentation and malate dismutation to produce energy from carbohydrate. Although targeting carbohydrate metabolism is an established therapeutic strategy to combat helminth infection, questions remain over the metabolic pathways they employ as adults to survive and evade host immunity. Helminths also use amino acid, polyunsaturated fatty acid (PUFA), and cholesterol metabolism, a possible strategy favouring the production of immunomodulatory compounds that may influence survival in the host. Here, we discuss the significance of these differing metabolic pathways and whether targeting of helminth metabolic pathways may allow for the development of novel anthelmintics.

SOD3 suppresses early cellular immune responses to parasite infection.

Host immune responses are tightly controlled by various immune factors during infection, and protozoan parasites also manipulate the immune system to evade surveillance, leading to an evolutionary arms race in host‒pathogen interactions; however, the underlying mechanisms are not fully understood. We observed that the level of superoxide dismutase 3 (SOD3) was significantly elevated in both Plasmodium falciparum malaria patients and mice infected with four parasite species. SOD3-deficient mice had a substantially longer survival time and lower parasitemia than control mice after infection, whereas SOD3-overexpressing mice were much more vulnerable to parasite infection. We revealed that SOD3, secreted from activated neutrophils, bound to T cells, suppressed the interleukin-2 expression and concomitant interferon-gamma responses crucial for parasite clearance. Overall, our findings expose active fronts in the arms race between the parasites and host immune system and provide insights into the roles of SOD3 in shaping host innate immune responses to parasite infection.

How are Trypanosoma brucei receptors protected from host antibody-mediated attack?

Trypanosoma brucei is the causal agent of African Trypanosomiasis in humans and other animals. It maintains a long-term infection through an antigenic variation based population survival strategy. To proliferate in a mammal, T. brucei acquires iron and haem through the receptor mediated uptake of host transferrin and haptoglobin-hemoglobin respectively. The receptors are exposed to host antibodies but this does not lead to clearance of the infection. Here we discuss how the trypanosome avoids this fate in the context of recent findings on the structure and cell biology of the receptors.

Expression of IL-10 and TGF-ß1 in horses experimentally infected with T. equi merozoites is associated with antibody production but not modulation of pro-inflammatory responses.

Theileria equi (T. equi) is an apicomplexan parasite that causes severe hemolytic anemia in equids. Presently, there is inadequate knowledge of the immune responses induced by T. equi in equid hosts impeding understanding of the host parasite relationship and development of potent vaccines for control of T. equi infections. The objective of this study was to evaluate the host-parasite dynamics between T. equi merozoites and infected horses by assessing cytokine expression during primary and secondary parasite exposure, and to determine whether the pattern of expression correlated with clinical indicators of disease. Our findings showed that the expression of pro-inflammatory cytokines was very low and inconsistent during both primary and secondary infection. There was also no correlation between the symptoms observed during primary infection and expression of the cytokines. This suggests that the symptoms might have occurred primarily due to hemolysis and likely not the undesirable effects of pro-inflammatory responses. However, IL-10 and TGF-ß1 were highly expressed in both phases of infection, and their expression was linked to antibody production but not moderation of pro-inflammatory cytokine responses.

Leishmania major MAPK4 intercepts and redirects CD40 signaling promoting infection.

The parasite Leishmania resides as amastigotes within the macrophage parasitophorous vacuoles inflicting the disease Leishmaniasis. Leishmania selectively modulates mitogen-activated protein kinase (MAPK) phosphorylation subverting CD40-triggered anti-leishmanial functions of macrophages. The mechanism of any pathogen-derived molecule induced host MAPK modulation remains poorly understood. Herein, we show that of the fifteen MAPKs, LmjMAPK4 expression is higher in virulent L. major. LmjMAPK4- detected in parasitophorous vacuoles and cytoplasm- binds MEK-1/2, but not MKK-3/6. Lentivirally-overexpressed LmjMAPK4 augments CD40-activated MEK-1/2-ERK-1/2-MKP-1, but inhibits MKK3/6-p38MAPK-MKP-3, phosphorylation. A rationally-identified LmjMAPK4 inhibitor reinstates CD40-activated host-protective anti-leishmanial functions in L. major-infected susceptible BALB/c mice. These results identify LmjMAPK4 as a MAPK modulator at the host-pathogen interface and establish a pathogen-intercepted host receptor signaling as a scientific rationale for identifying drug targets.

The myxozoans Myxobolus cerebralis and Tetracapsuloides bryosalmonae modulate rainbow trout immune responses: quantitative shotgun proteomics at the portals of entry after single and co-infections.

Introduction: Little is known about the proteomic changes at the portals of entry in rainbow trout after infection with the myxozoan parasites, Myxobolus cerebralis, and Tetracapsuloides bryosalmonae. Whirling disease (WD) is a severe disease of salmonids, caused by the myxosporean M. cerebralis, while, proliferative kidney disease (PKD) is caused by T. bryosalmonae, which instead belongs to the class Malacosporea. Climate change is providing more suitable conditions for myxozoan parasites lifecycle, posing a high risk to salmonid aquaculture and contributing to the decline of wild trout populations in North America and Europe. Therefore, the aim of this study was to provide the first proteomic profiles of the host in the search for evasion strategies during single and coinfection with M. cerebralis and T. bryosalmonae. Methods: One group of fish was initially infected with M. cerebralis and another group with T. bryosalmonae. After 30 days, half of the fish in each group were co-infected with the other parasite. Using a quantitative proteomic approach, we investigated proteomic changes in the caudal fins and gills of rainbow trout before and after co-infection. Results: In the caudal fins, 16 proteins were differentially regulated post exposure to M. cerebralis, whereas 27 proteins were differentially modulated in the gills of the infected rainbow trout post exposure to T. bryosalmonae. After co-infection, 4 proteins involved in parasite recognition and the regulation of host immune responses were differentially modulated between the groups in the caudal fin. In the gills, 11 proteins involved in parasite recognition and host immunity, including 4 myxozoan proteins predicted to be virulence factors, were differentially modulated. Discussion: The results of this study increase our knowledge on rainbow trout co-infections by myxozoan parasites and rainbow trout immune responses against myxozoans at the portals of entry, supporting a better understanding of these host-parasite interactions.

Immunology and pathology of echinostomes and other intestinal trematodes.

Intestinal trematodes constitute a major group of helminths that parasitize humans and animals with relevant morbidity and mortality. Despite the importance of the intestinal trematodes in medical and veterinary sciences, immunology and pathology of these helminth infections have been neglected for years. Apart from the work focused on the members of the family Echnistomatidae, there are only very isolated and sporadic studies on the representatives of other families of digeneans, which makes a compilation of all these studies necessary. In the present review, the most salient literature on the immunology and pathology of intestinal trematodes in their definitive hosts in examined. Emphasis will be placed on members of the echinostomatidae family, since it is the group in which the most work has been carried out. However, we also review the information on selected species of the families Brachylaimidae, Diplostomidae, Gymnophallidae, and Heterophyidae. For most of these families, coverage is considered under the following headings: (i) Background; (ii) Pathology of the infection; (iii) Immunology of the infection; and (iv) Human infections.

Contribution of parasite and host genotype to immunopathology of schistosome infections.

BACKGROUND: The role of pathogen genotype in determining disease severity and immunopathology has been studied intensively in microbial pathogens including bacteria, fungi, protozoa and viruses but is poorly understood in parasitic helminths. The medically important blood fluke Schistosoma mansoni is an excellent model system to study the impact of helminth genetic variation on immunopathology. Our laboratory has demonstrated that laboratory schistosome populations differ in sporocyst growth and cercarial production in the intermediate snail host and worm establishment and fecundity in the vertebrate host. Here, we (i) investigate the hypothesis that schistosome genotype plays a significant role in immunopathology and related parasite life history traits in the vertebrate mouse host and (ii) quantify the relative impact of parasite and host genetics on infection outcomes. METHODS: We infected BALB/c and C57BL/6 mice with four different laboratory schistosome populations from Africa and the Americas. We quantified disease progression in the vertebrate host by measuring body weight and complete blood count (CBC) with differential over a 12-week infection period. On sacrifice, we assessed parasitological (egg and worm counts, fecundity), immunopathological (organ measurements and histopathology) and immunological (CBC with differential and cytokine profiles) characteristics to determine the impact of parasite and host genetics. RESULTS: We found significant variation between parasite populations in worm numbers, fecundity, liver and intestine egg counts, liver and spleen weight, and fibrotic area but not in granuloma size. Variation in organ weight was explained by egg burden and intrinsic parasite factors independent of egg burden. We found significant variation between infected mouse lines in cytokine levels (IFN-γ, TNF-α), eosinophils, lymphocytes and monocyte counts. CONCLUSIONS: This study showed that both parasite and host genotype impact the outcome of infection. While host genotype explains most of the variation in immunological traits, parasite genotype explains most of the variation in parasitological traits, and both host and parasite genotypes impact immunopathology outcomes.

Leeches Baicalobdella torquata feed on hemolymph but have a low effect on the cellular immune response of amphipod Eulimnogammarus verrucosus from Lake Baikal.

Lake Baikal is one of the largest and oldest freshwater reservoirs on the planet with a huge endemic diversity of amphipods (Amphipoda, Crustacea). These crustaceans have various symbiotic relationships, including the rarely described phenomenon of leech parasitism on amphipods. It is known that leeches feeding on hemolymph of crustacean hosts can influence their physiology, especially under stressful conditions. Here we show that leeches Baicalobdella torquata (Grube, 1871) found on gills of Eulimnogammarus verrucosus (Gerstfeldt, 1858), one of the most abundant amphipods in the Baikal littoral zone, indeed feed on the hemolymph of their host. However, the leech infection had no effect on immune parameters such as hemocyte concentration or phenoloxidase activity and also did not affect glycogen content. The intensity of hemocyte reaction to foreign bodies in a primary culture was identical between leech-free and leech-infected animals. Artificial infection with leeches also had only a subtle effect on the course of a model microbial infection in terms of hemocyte concentration and composition. Despite we cannot fully exclude deleterious effects of the parasites, our study indicates a low influence of a few leeches on E. verrucosus and shows that leech-infected amphipods can be used at least for some types of ecophysiological experiments.

Population-level immunologic variation in wild threespine stickleback (Gasterosteusaculeatus).

Wild organisms are regularly exposed to a wide range of parasites, requiring the management of an effective immune response while avoiding immunopathology. Currently, our knowledge of immunoparasitology primarily derives from controlled laboratory studies, neglecting the genetic and environmental diversity that contribute to immune phenotypes observed in wild populations. To gain insight into the immunologic variability in natural settings, we examined differences in immune gene expression of two Alaskan stickleback (Gasterosteus aculeatus) populations with varying susceptibility to infection by the cestode Schistocephalus solidus. Between these two populations, we found distinct immune gene expression patterns at the population level in response to infection with fish from the high-infection population displaying signs of parasite-driven immune manipulation. Further, we found significant differences in baseline immune gene profiles between the populations, with uninfected low-infection population fish showing signatures of inflammation compared to uninfected high-infection population fish. These results shed light on divergent responses of wild populations to the same parasite, providing valuable insights into host-parasite interactions in natural ecosystems.

Recognition of nonself is necessary to activate Drosophila's immune response against an insect parasite.

BACKGROUND: Innate immune responses can be activated by pathogen-associated molecular patterns (PAMPs), danger signals released by damaged tissues, or the absence of self-molecules that inhibit immunity. As PAMPs are typically conserved across broad groups of pathogens but absent from the host, it is unclear whether they allow hosts to recognize parasites that are phylogenetically similar to themselves, such as parasitoid wasps infecting insects. RESULTS: Parasitoids must penetrate the cuticle of Drosophila larvae to inject their eggs. In line with previous results, we found that the danger signal of wounding triggers the differentiation of specialized immune cells called lamellocytes. However, using oil droplets to mimic infection by a parasitoid wasp egg, we found that this does not activate the melanization response. This aspect of the immune response also requires exposure to parasite molecules. The unidentified factor enhances the transcriptional response in hemocytes and induces a specific response in the fat body. CONCLUSIONS: We conclude that a combination of danger signals and the recognition of nonself molecules is required to activate Drosophila's immune response against parasitic insects.

New insights into Trypanosoma cruzi genetic diversity, and its influence on parasite biology and clinical outcomes.

Chagas disease, caused by Trypanosoma cruzi, remains a serious public health problem worldwide. The parasite was subdivided into six distinct genetic groups, called "discrete typing units" (DTUs), from TcI to TcVI. Several studies have indicated that the heterogeneity of T. cruzi species directly affects the diversity of clinical manifestations of Chagas disease, control, diagnosis performance, and susceptibility to treatment. Thus, this review aims to describe how T. cruzi genetic diversity influences the biology of the parasite and/or clinical parameters in humans. Regarding the geographic dispersion of T. cruzi, evident differences were observed in the distribution of DTUs in distinct areas. For example, TcII is the main DTU detected in Brazilian patients from the central and southeastern regions, where there are also registers of TcVI as a secondary T. cruzi DTU. An important aspect observed in previous studies is that the genetic variability of T. cruzi can impact parasite infectivity, reproduction, and differentiation in the vectors. It has been proposed that T. cruzi DTU influences the host immune response and affects disease progression. Genetic aspects of the parasite play an important role in determining which host tissues will be infected, thus heavily influencing Chagas disease's pathogenesis. Several teams have investigated the correlation between T. cruzi DTU and the reactivation of Chagas disease. In agreement with these data, it is reasonable to suppose that the immunological condition of the patient, whether or not associated with the reactivation of the T. cruzi infection and the parasite strain, may have an important role in the pathogenesis of Chagas disease. In this context, understanding the genetics of T. cruzi and its biological and clinical implications will provide new knowledge that may contribute to additional strategies in the diagnosis and clinical outcome follow-up of patients with Chagas disease, in addition to the reactivation of immunocompromised patients infected with T. cruzi.

Coevolution of Age-Structured Tolerance and Virulence.

Hosts can evolve a variety of defences against parasitism, including resistance (which prevents or reduces the spread of infection) and tolerance (which protects against virulence). Some organisms have evolved different levels of tolerance at different life-stages, which is likely to be the result of coevolution with pathogens, and yet it is currently unclear how coevolution drives patterns of age-specific tolerance. Here, we use a model of tolerance-virulence coevolution to investigate how age structure influences coevolutionary dynamics. Specifically, we explore how coevolution unfolds when tolerance and virulence (disease-induced mortality) are age-specific compared to when these traits are uniform across the host lifespan. We find that coevolutionary cycling is relatively common when host tolerance is age-specific, but cycling does not occur when tolerance is the same across all ages. We also find that age-structured tolerance can lead to selection for higher virulence in shorter-lived than in longer-lived hosts, whereas non-age-structured tolerance always leads virulence to increase with host lifespan. Our findings therefore suggest that age structure can have substantial qualitative impacts on host-pathogen coevolution.

Regulation of host metabolic health by parasitic helminths.

Obesity is a worldwide pandemic and major risk factor for the development of metabolic syndrome (MetS) and type 2 diabetes (T2D). T2D requires lifelong medical support to limit complications and is defined by impaired glucose tolerance, insulin resistance (IR), and chronic low-level systemic inflammation initiating from adipose tissue. The current preventative strategies include a healthy diet, controlled physical activity, and medication targeting hyperglycemia, with underexplored underlying inflammation. Studies suggest a protective role for helminth infection in the prevention of T2D. The mechanisms may involve induction of modified type 2 and regulatory immune responses that suppress inflammation and promote insulin sensitivity. In this review, the roles of helminths in counteracting MetS, and prospects for harnessing these protective mechanisms for the development of novel anti-diabetes drugs are discussed.

Genetic factors underlying host resistance to Rhipicephalus microplus tick infestation in Braford cattle: a systems biology perspective.

Approximately 80% of the world's cattle are raised in regions with a high risk of tick-borne diseases, resulting in significant economic losses due to parasitism by Rhipicephalus (Boophilus) microplus. However, the lack of a systemic biology approach hampers a comprehensive understanding of tick-host interactions that mediate tick resistance phenotypes. Here, we conducted a genome-wide association study (GWAS) of 2933 Braford cattle and found 340 single-nucleotide polymorphisms (SNPs) associated with tick counts. Gene expression analyses were performed on skin samples obtained from previously tick-exposed heifers with extremely high or low estimated breeding values for R. microplus counts. Evaluations were performed both before and after artificial infestation with ticks. Differentially expressed genes were found within 1-Mb windows centered at significant SNPs from GWAS. A total of 330 genes were related to the breakdown of homeostasis that was induced by larval attachment to bovine skin. Enrichment analysis pointed to a key role of proteolysis and signal transduction via JAK/STAT, NFKB and WNT/beta catenin signaling pathways. Integrative analysis on matrixEQTL revealed two cis-eQTLs and four significant SNPs in the genes peptidyl arginine deiminase type IV (PADI4) and LOC11449251. The integration of genomic data from QTL maps and transcriptome analyses has identified a set of twelve key genes that show significant associations with tick loads. These genes could be key candidates to improve the accuracy of genomic predictions for tick resistance in Braford cattle.

Asymptomatic Low-Density Plasmodium falciparum Infections: Parasites Under the Host's Immune Radar?

A large body of evidence suggests that low parasite carriage in Plasmodium falciparum asymptomatic infection is required for the maintenance of malaria immunity. However, the fact that treating such infections has little to no impact on subsequent clinical malaria is rarely noted. In this paper, we review data and argue that low-density parasite carriage in asymptomatic infection may not support host immune processes and that parasites are virtually under the host's immunological radar. We also discuss factors that may be constraining parasitemia in asymptomatic infections from reaching the threshold required to cause clinical symptoms. A thorough understanding of this infectious reservoir is essential for malaria control and eradication because asymptomatic infections contribute significantly to Plasmodium transmission.

Persistent asymptomatic Plasmodium falciparum parasite carriage has been recognized as one of the major contributors to malaria transmission that impedes worldwide elimination efforts. Asymptomatic infection is required for maintaining clinical immunity, hence the controversy regarding its treatment. Evidence from transcriptional and cellular profiling indicates asymptomatic low parasite carriage may not support host immune processes. Interventions targeted at persistent asymptomatic infections may be crucial for malaria control.

Systemic Immune Modulation by Gastrointestinal Nematodes.

Gastrointestinal nematode (GIN) infection has applied significant evolutionary pressure to the mammalian immune system and remains a global economic and human health burden. Upon infection, type 2 immune sentinels activate a common antihelminth response that mobilizes and remodels the intestinal tissue for effector function; however, there is growing appreciation of the impact GIN infection also has on the distal tissue immune state. Indeed, this effect is observed even in tissues through which GINs never transit. This review highlights how GIN infection modulates systemic immunity through (a) induction of host resistance and tolerance responses, (b) secretion of immunomodulatory products, and (c) interaction with the intestinal microbiome. It also discusses the direct consequences that changes to distal tissue immunity can have for concurrent and subsequent infection, chronic noncommunicable diseases, and vaccination efficacy.

Leishmania genetic exchange is mediated by IgM natural antibodies.

Host factors that mediate Leishmania genetic exchange are not well defined. Here we demonstrate that natural IgM (IgMn)1-4 antibodies mediate parasite genetic exchange by inducing the transient formation of a spherical parasite clump that promotes parasite fusion and hybrid formation. We establish that IgMn from Leishmania-free animals binds to the surface of Leishmania parasites to induce significant changes in the expression of parasite transcripts and proteins. Leishmania binding to IgMn is partially lost after glycosidase treatment, although parasite surface phosphoglycans, including lipophosphoglycan, are not required for IgMn-induced parasite clumping. Notably, the transient formation of parasite clumps is essential for Leishmania hybridization in vitro. In vivo, we observed a 12-fold increase in hybrid formation in sand flies provided a second blood meal containing IgMn compared with controls. Furthermore, the generation of recombinant progeny from mating hybrids and parental lines were only observed in sand flies provided with IgMn. Both in vitro and in vivo IgM-induced Leishmania crosses resulted in full genome hybrids that show equal patterns of biparental contribution. Leishmania co-option of a host natural antibody to facilitate mating in the insect vector establishes a new paradigm of parasite-host-vector interdependence that contributes to parasite diversity and fitness by promoting genetic exchange.