Schistosomiasis afflicts >250 million people worldwide, leading to an annual loss of >3 million disability-adjusted life years. Schistosoma mansoni causes intestinal schistosomiasis with parasite eggs either transversing intestinal tissue or lodging within the liver and other organs, causing intestinal hemorrhage and liver pathology. Large (∼1 cm) adult worms survive for years within blood vessels, but we lack a clear understanding of their impact on hemostasis.
View Article and Find Full Text PDFHeterogeneity of bone marrow mesenchymal stromal cells (MSCs, frequently referred to as "mesenchymal stem cells") clouds biological understanding and hampers their clinical development. In MSC cultures most commonly used in research and therapy, we have identified an MSC subtype characterized by CD317 expression (CD317 (29.77 ± 3.
View Article and Find Full Text PDFImmune thrombocytopenia (ITP) is an acquired autoimmune condition characterized by both reduced platelet production and the destruction of functionally normal platelets by sustained attack from the immune system. However, the effect of prolonged ITP on the more immature hematopoietic progenitors remains an open area of investigation. By using a murine in vivo model of extended ITP, we revealed that ITP progression drives considerable progenitor expansion and bone marrow (BM) remodeling.
View Article and Find Full Text PDFDespite extensive mapping of long noncoding RNAs in immune cells, their function in vivo remains poorly understood. In this study, we identify over 100 long noncoding RNAs that are differentially expressed within 24 h of Th1 cell activation. Among those, we show that suppression of is a hallmark of CD4 T cell activation, but its complete deletion results in more potent immune responses to infection.
View Article and Find Full Text PDFImmunity to intestinal helminths is known to require both innate and adaptive components of the immune system activated along the Type 2 IL-4R/STAT6-dependent pathway. We have found that macrophage migration inhibitory factor (MIF) is essential for the development of effective immunity to the intestinal helminth , even following vaccination which induces sterile immunity in wild-type mice. A chemical inhibitor of MIF, 4-IPP, was similarly found to compromise anti-parasite immunity.
View Article and Find Full Text PDFDetermining the mechanisms that distinguish protective immunity from pathological chronic inflammation remains a fundamental challenge. miR-132 has been shown to play largely immunoregulatory roles in immunity; however, its role in CD4 T cell function is poorly understood. Here, we show that CD4 T cells express high levels of miR-132 and that T cell activation leads to miR-132 up-regulation.
View Article and Find Full Text PDFWe recently reported the discovery of a new parasite-derived protein that functionally mimics the immunosuppressive cytokine transforming growth factor (TGF)-β. The Heligmosomoides polygyrus TGF-β Mimic (Hp-TGM) shares no homology to any TGF-β family member, however it binds the mammalian TGF-β receptor and induces expression of Foxp3, the canonical transcription factor of both mouse and human regulatory T cells. Hp-TGM consists of five atypical Complement Control Protein (CCP, Pfam 00084) domains, each lacking certain conserved residues and 12-15 amino acids longer than the 60-70 amino acids consensus domain, but with a recognizable 3-cysteine, tryptophan, cysteine motif.
View Article and Find Full Text PDFHelminth parasites defy immune exclusion through sophisticated evasion mechanisms, including activation of host immunosuppressive regulatory T (Treg) cells. The mouse parasite Heligmosomoides polygyrus can expand the host Treg population by secreting products that activate TGF-β signalling, but the identity of the active molecule is unknown. Here we identify an H.
View Article and Find Full Text PDFInfection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H.
View Article and Find Full Text PDFRapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear.
View Article and Find Full Text PDFMicrobiol Spectr
December 2016
Many major tropical diseases are caused by long-lived helminth parasites that are able to survive by modulation of the host immune system, including the innate compartment of myeloid cells. In particular, dendritic cells and macrophages show markedly altered phenotypes during parasite infections. In addition, many specialized subsets such as eosinophils and basophils expand dramatically in response to these pathogens.
View Article and Find Full Text PDFMicroRNAs (miRNAs) are short non-coding RNAs that silence mRNAs. They are generated following transcription and cleavage by the DROSHA/DGCR8 and DICER/TRBP/PACT complexes. Although it is known that components of the miRNA biogenesis machinery can be phosphorylated, it remains poorly understood how these events become engaged during physiological cellular activation.
View Article and Find Full Text PDFHelminth infections have been suggested to impair the development and outcome of Th1 responses to vaccines and intracellular microorganisms. However, there are limited data regarding the ability of intestinal nematodes to modulate Th1 responses at sites distal to the gut. In this study, we have investigated the effect of the intestinal nematode Heligmosomoides polygyrus bakeri on Th1 responses to Mycobacterium bovis bacillus Calmette-Guérin (BCG).
View Article and Find Full Text PDFGlycan molecules from helminth parasites have been associated with diverse biological functions ranging from interactions with neighbouring host cell populations to down-modulation of specific host immunity. Glycoproteins secreted by the intestinal nematode Heligmosomoides polygyrus are of particular interest as the excretory-secretory products (termed HES) of this parasite contain both heat-labile and heat-stable components with immunomodulatory effects. We used MALDI-TOF-MS and LC-MS/MS to analyse the repertoire of N- and O-linked glycans released from Heligmosomoides polygyrus excretory-secretory products by PNGase A and F, β-elimination and hydrazinolysis revealing a broad range of structures including novel methylhexose- and methylfucose-containing glycans.
View Article and Find Full Text PDFOver 25% of the world's population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity.
View Article and Find Full Text PDFImmunobiology
July 2015
Tissue resident macrophages have vital homeostatic roles in many tissues but their roles are less well defined in the heart. The present study aimed to identify the density, polarisation status and distribution of macrophages in the healthy murine heart and to investigate their ability to respond to immune challenge. Histological analysis of hearts from CSF-1 receptor (csf1-GFP; MacGreen) and CX3CR1 (Cx3cr1(GFP/+)) reporter mice revealed a sparse population of GFP positive macrophages that were evenly distributed throughout the left and right ventricular free walls and septum.
View Article and Find Full Text PDFThe intestinal microbiota are pivotal in determining the developmental, metabolic and immunological status of the mammalian host. However, the intestinal tract may also accommodate pathogenic organisms, including helminth parasites which are highly prevalent in most tropical countries. Both microbes and helminths must evade or manipulate the host immune system to reside in the intestinal environment, yet whether they influence each other's persistence in the host remains unknown.
View Article and Find Full Text PDFHelminth parasites remain one of the most common causes of infections worldwide, yet little is still known about the immune signaling pathways that control their expulsion. C57BL/6 mice are chronically susceptible to infection with the gastrointestinal helminth parasite Heligmosomoides polygyrus. In this article, we report that C57BL/6 mice lacking the adapter protein MyD88, which mediates signaling by TLRs and IL-1 family members, showed enhanced immunity to H.
View Article and Find Full Text PDFHelminth parasites infect over one fourth of the human population and are highly prevalent in livestock worldwide. In model systems, parasites are strongly immunomodulatory, but the immune system can be driven to expel them by prior vaccination. However, no vaccines are currently available for human use.
View Article and Find Full Text PDFHuman lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol.
View Article and Find Full Text PDFThe nematode Heligmosomoides polygyrus is an excellent model for intestinal helminth parasitism. Infection in mice persists for varying lengths of time in different inbred strains, with CBA and C57BL/6 mice being fully susceptible, BALB/c partially so and SJL able to expel worms within 2-3 weeks of infection. We find that resistance correlates not only with the adaptive Th2 response, including IL-10 but with activation of innate lymphoid cell and macrophage populations.
View Article and Find Full Text PDFMacrophages (MΦs) colonize tissues during inflammation in two distinct ways: recruitment of monocyte precursors and proliferation of resident cells. We recently revealed a major role for IL-4 in the proliferative expansion of resident MΦs during a Th2-biased tissue nematode infection. We now show that proliferation of MΦs during intestinal as well as tissue nematode infection is restricted to sites of IL-4 production and requires MΦ-intrinsic IL-4R signaling.
View Article and Find Full Text PDFGastrointestinal nematode parasites infect over 1 billion humans, with little evidence for generation of sterilising immunity. These helminths are highly adapted to their mammalian host, following a developmental program through successive niches, while effectively down-modulating host immune responsiveness. Larvae of Heligmosomoides polygyrus, for example, encyst in the intestinal submucosa, before emerging as adult worms into the duodenal lumen.
View Article and Find Full Text PDFEpidemiological and interventional human studies, as well as experiments in animal models, strongly indicate that helminth parasitic infections can confer protection from immune dysregulatory diseases such as allergy, autoimmunity and colitis. Here, we review the immunological pathways that helminths exploit to downregulate immune responses, both against bystander specificities such as allergens and against antigens from the parasites themselves. In particular, we focus on a highly informative laboratory system, the mouse intestinal nematode, Heligmosomoides polygyrus, as a tractable model of host-parasite interaction at the cellular and molecular levels.
View Article and Find Full Text PDF