Salivarian trypanosomes are single cell extracellular parasites that cause infections in a wide range of hosts. Most pathogenic infections worldwide are caused by one of four major species of trypanosomes including (i) Trypanosoma brucei and the human infective subspecies T. b. gambiense and T. b. rhodesiense, (ii) Trypanosoma evansi and T. equiperdum, (iii) Trypanosoma congolense and (iv) Trypanosoma vivax. Infections with these parasites are marked by excessive immune dysfunction and immunopathology, both related to prolonged inflammatory host immune responses. Here we review the classification and global distribution of these parasites, highlight the adaptation of human infective trypanosomes that allow them to survive innate defense molecules unique to man, gorilla, and baboon serum and refer to the discovery of sexual reproduction of trypanosomes in the tsetse vector. With respect to the immunology of mammalian host-parasite interactions, the review highlights recent findings with respect to the B cell destruction capacity of trypanosomes and the role of T cells in the governance of infection control. Understanding infection-associated dysfunction and regulation of both these immune compartments is crucial to explain the continued failures of anti-trypanosome vaccine developments as well as the lack of any field-applicable vaccine based anti-trypanosomosis intervention strategy. Finally, the link between infection-associated inflammation and trypanosomosis induced anemia is covered in the context of both livestock and human infections.

https://biblio.ugent.be/publication/8614888/file/8614889.pdf

Salivarian Trypanosomosis: A Review of Parasites Involved, Their Global Distribution and Their Interaction With the Innate and Adaptive Mammalian Host Immune System.

African trypanosomosis (AT) is a chronically debilitating parasitic disease of medical and economic importance for the development of sub-Saharan Africa. The trypanosomes that cause this disease are extracellular protozoan parasites that have developed efficient immune escape mechanisms to manipulate the entire host immune response to allow parasite survival and transmission. During the early stage of infection, a profound pro-inflammatory type 1 activation of the mononuclear phagocyte system (MPS), involving classically activated macrophages (i.e., M1), is required for initial parasite control. Yet, the persistence of this M1-type MPS activation in trypanosusceptible animals causes immunopathology with anemia as the most prominent pathological feature. By contrast, in trypanotolerant animals, there is an induction of IL-10 that promotes the induction of alternatively activated macrophages (M2) and collectively dampens tissue damage. A comparative gene expression analysis between M1 and M2 cells identified galectin-3 (Gal-3) and macrophage migration inhibitory factor (MIF) as novel M1-promoting factors, possibly acting synergistically and in concert with TNF-α during anemia development. While Gal-3 enhances erythrophagocytosis, MIF promotes both myeloid cell recruitment and iron retention within the MPS, thereby depriving iron for erythropoiesis. Hence, the enhanced erythrophagocytosis and suppressed erythropoiesis lead to anemia. Moreover, a thorough investigation using MIF-deficient mice revealed that the underlying mechanisms in AT-associated anemia development in trypanosusceptible and tolerant animals are quite distinct. In trypanosusceptible animals, anemia resembles anemia of inflammation, while in trypanotolerant animals' hemodilution, mainly caused by hepatosplenomegaly, is an additional factor contributing to anemia. In this review, we give an overview of how trypanosome- and host-derived factors can contribute to trypanosomosis-associated anemia development with a focus on the MPS system. Finally, we will discuss potential intervention strategies to alleviate AT-associated anemia that might also have therapeutic potential.

https://biblio.ugent.be/publication/8572172/file/8576507.pdf

African Trypanosomiasis-Associated Anemia: The Contribution of the Interplay between Parasites and the Mononuclear Phagocyte System.

Early pregnancy loss (EPL), also termed early miscarriage, is determined as the unintentional expulsion of an embryo or fetus prior to the 12th week of gestation. EPL frequency is ~15% in pregnancies. Fetal development and growth is associate with placental function and vessel development; therefore, the placental genome would represent a useful miscarriage model for (epi)genetic and genomic studies. An important factor of placental development and function is epigenetic regulation of gene expression. microRNAs (miRNAs) are the primary epigenetic regulators which have an important role in placental development and function. In the present study, maternal plasma and villous tissue were collected from 16 EPL cases in 6th‑8th gestational weeks (GWs) and 8 abortions (control group) in 6th‑8th GWs. Detection of the differences in miRNA expression was performed using microarrays and dysregulated miRNAs were validated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). miRNA microarray findings revealed that four miRNAs, including hsa‑miRNA (miR)‑125a‑3p, hsa‑miR‑3663‑3p, hsa‑miR‑423‑5p and hsa‑miR‑575 were upregulated in tissue samples. In maternal plasma, two miRNAs (hsa‑let‑7c, hsa‑miR‑122) were upregulated and one miRNA (hsa‑miR‑135a) was downregulated. A total of 6 out of 7 dysregulated miRNAs were validated using RT‑qPCR. The target genes of these dysregulated miRNAs were detected using the GeneSpring database. The aim of the present study was to detect dysregulated miRNAs in maternal plasma and villous cells and identify the target genes of dysregulated miRNAs and their associated pathways. The target gene analyses have revealed that the affected genes are primarily associated with cell migration, proliferation, implantation, adhesion, angiogenesis and differentiation and all are involved with EPL pathogenesis. Therefore, the present study may contribute to the understanding of the molecular mechanisms which lead to EPL.

/pdf/microrna-expression-profiling-in-placenta-and-maternal-307ynlcivh.pdf

MicroRNA expression profiling in placenta and maternal plasma in early pregnancy loss

The non-mammalian MIF superfamily.

African trypanosomosis is a debilitating disease of great medical and socioeconomical importance It is caused by strictly extracellular protozoan parasites capable of infecting all vertebrate classes including human, livestock, and game animals To survive within their mammalian host, trypanosomes have evolved efficient immune escape mechanisms and manipulate the entire host immune response, including the humoral response This report provides an overview of how trypanosomes initially trigger and subsequently undermine the development of an effective host antibody response Indeed, results available to date obtained in both natural and experimental infection models show that trypanosomes impair homeostatic B-cell lymphopoiesis, B-cell maturation and survival and B-cell memory development Data on B-cell dysfunctioning in correlation with parasite virulence and trypanosome-mediated inflammation will be discussed, as well as the impact of trypanosomosis on heterologous vaccine efficacy and diagnosis Therefore, new strategies aiming at enhancing vaccination efficacy could benefit from a combination of (i) early parasite diagnosis, (ii) anti-trypanosome (drugs) treatment, and (iii) anti-inflammatory treatment that collectively might allow B-cell recovery and improve vaccination

https://biblio.ugent.be/publication/8528054/file/8542781.pdf

African Trypanosomes Undermine Humoral Responses and Vaccine Development: Link with Inflammatory Responses?

Animal African trypanosomosis is a major threat to the economic development and human health in sub-Saharan Africa. Trypanosoma congolense infections represent the major constraint in livestock production, with anemia as the major pathogenic lethal feature. The mechanisms underlying anemia development are ill defined, which hampers the development of an effective therapy. Here, the contribution of the erythropoietic and erythrophagocytic potential as well as of hemodilution to the development of T. congolense-induced anemia were addressed in a mouse model of low virulence relevant for bovine trypanosomosis. We show that in infected mice, splenic extramedullary erythropoiesis could compensate for the chronic low-grade type I inflammation-induced phagocytosis of senescent red blood cells (RBCs) in spleen and liver myeloid cells, as well as for the impaired maturation of RBCs occurring in the bone marrow and spleen. Rather, anemia resulted from hemodilution. Our data also suggest that the heme catabolism subsequent to sustained erythrophagocytosis resulted in iron accumulation in tissue and hyperbilirubinemia. Moreover, hypoalbuminemia, potentially resulting from hemodilution and liver injury in infected mice, impaired the elimination of toxic circulating molecules like bilirubin. Hemodilutional thrombocytopenia also coincided with impaired coagulation. Combined, these effects could elicit multiple organ failure and uncontrolled bleeding thus reduce the survival of infected mice. MIF (macrophage migrating inhibitory factor), a potential pathogenic molecule in African trypanosomosis, was found herein to promote erythrophagocytosis, to block extramedullary erythropoiesis and RBC maturation, and to trigger hemodilution. Hence, these data prompt considering MIF as a potential target for treatment of natural bovine trypanosomosis.

https://pure.itg.be/ws/files/1777894/2016ppate1005862.pdf

MIF-mediated hemodilution promotes pathogenic anemia in experimental African trypanosomosis

Background: The central nervous system has a complex structural organization and consists of different subdomains along the antero-posterior axis However, questions remain about the molecular mechanisms leading to the regionalization of this organ We used a previously developed methodology to identify the novel patterning role of GDF11, a TGF-β signaling factor Findings: Using an assay based on neural differentiated mouse embryonic stem cells, GDF11 is shown to induce diencephalic (posterior forebrain), mesencephalic (midbrain) and metencephalic (anterior hindbrain) fates at the expense of telencephalic (anterior forebrain) specification GDF11 has not previously been implicated in the early patterning of the nervous system In addition, inhibition of the TGF-β type I receptors Alk4, Alk5 and Alk7 by the pharmacological inhibitor SB431542 caused a strong anteriorization of the cells Conclusions: Our findings suggest that GDF11 is involved in the earliest steps of the brain patterning during neurogenesis in the vertebrate embryo and is shown to be a regionalizing factor of the regional fate in the developing brain This regionalization is not a typical posteriorizing signal as seen with retinoic acid, FGF or BMP molecules To our knowledge, this is the first time that GDF11 is implicated in the earliest steps of the patterning of the neural plate

/pdf/growth-differentiation-factor-11-is-an-encephalic-r8hiqvbizm.pdf

Growth differentiation factor 11 is an encephalic regionalizing factor in neural differentiated mouse embryonic stem cells.

Whole-mount in situ hybridization (WISH) is a technique widely used in developmental biology to study the localization of RNA sequences in intact tissues or whole organisms. In this chapter we present a detailed protocol that was optimized for gene expression analysis in early stage mouse embryos (5.5-10.5 days post-coitum) and embryoid bodies formed by differentiating embryonic stem cells and can be used for the detection of up to two distinct RNA sequences simultaneously. The initial steps of the procedure are the generation of the labeled riboprobe(s) and the embryo or embryoid body preparation, which can be completed in less than 2 days. The actual WISH procedure, comprised of the hybridization, the post-hybridization washes, and the immunological staining, can be completed in 3 days.

Nele Vanbekbergen

Papers

MIF-mediated hemodilution promotes pathogenic anemia in experimental African trypanosomosis

Growth differentiation factor 11 is an encephalic regionalizing factor in neural differentiated mouse embryonic stem cells.

Whole-mount in situ hybridization (WISH) optimized for gene expression analysis in mouse embryos and embryoid bodies