Heligmosomoides polygyrus | |
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Female H. polygyrus from the digestive tract of a woodmouse | |
Scientific classification | |
Domain: | Eukaryota |
Kingdom: | Animalia |
Phylum: | Nematoda |
Class: | Chromadorea |
Order: | Rhabditida |
Family: | Heligosomidae |
Genus: | Heligmosomoides |
Species: | H. polygyrus |
Binomial name | |
Heligmosomoides polygyrus | |
Heligmosomoides polygyrus, previously named Nematospiroides dubius, is a naturally occurring intestinal roundworm of rodents. [1] It belongs to the family Trychostrongylidae, and male and female worms are morphologically distinguishable. [2] The parasite has a direct lifecycle, with its larval form being the infective stage. H. polygyrus has the ability to establish chronic infections in rodents and alter host immune responses. This nematode is widely used as a gastrointestinal parasitic model in immunological, pharmacological, and toxicological studies. [3]
This parasite has a direct lifecycle with no intermediate hosts. The lifecycle takes about 13–15 days to complete. [1] [4] Infected mice pass faeces containing eggs, and egg sizes vary between 70 and 84 micrometres (µm) in length and 37 and 53 µm in width. [5] Eggs are shed from the host at the 8– to 16-cell stage and hatch in the environment, roughly 24 hours after passing through the host. [6] L1 larvae emerge from the egg and measure from 300–600 µm in length. Three lip-like structures can be seen around a rudimentary mouth. L1 larvae moult to L2 larvae after 2–3 days; they then begin feeding on bacteria in the environment. The L1-stage cuticle loosens from either end of the larvae, but remain loosely associated with the L2 larvae, becoming an outer sheath up until infection. After 3 days, the L2 partially moults into ensheathed L3, the infective nonfeeding stage. Infective larval stages measure 480–563 µm long.
Mice ingest the L3 stage of the parasite and after 18 hours, exsheathed L3 appears in the intestinal lumen. The L1 sheath is shed following ingestion, at which point the larvae shorten slightly and measure 376–540 µm in length. After 24 hours after ingestion, larvae invade the mucosal layer of the intestine. Around 4 days after ingestion, L3 moult into L4 in the submucosa of the intestine. At 6 days after ingestion, they encyst in the muscle layer of the intestine and start maturing in to adult parasites. By day 14, adult male and female worms contact in the lumen of the intestine, mate, and produce eggs that are passed in the faeces, thus continuing the lifecycle. Adult males are tightly coiled and usually measure 8–10 mm in length. The females are also tightly coiled, but larger, measuring 18–21mm in length. Adults are characterized by a dark red pigmentation, whereas the free-living larval forms are mostly translucent.
In natural infections, H. polygyrus is found almost ubiquitously within populations of wild wood mice ( Apodemus sylvaticus ). In one study of wood mouse populations in Oxfordshire, England, 70% of all mice sampled carried an infection with H. polygyrus, with an average infection burden of about 12 worms per mouse. [7] Natural infection intensity displays high variability in wood mice, ranging from none to 244 adult worms per mouse. Male and female mice show equal parasitic burdens. Parasite occurrence appears to positively correlate with weight and age of the mouse, showing an increase in prevalence in older, heavier mice. Infection was also seasonally regulated in the wood mouse population, with highest prevalence of infection/worm burden intensity occurring in early spring and reaching their lowest values in late summer/early autumn. This is inversely correlated with typical breeding behaviors of the wood mouse, where the population peaks in late summer or early autumn, and is at its lowest in the early spring. [7] The bulk of research on H. polygyrus has been conducted on the laboratory mouse, Mus musculus, as it is used as a model of human helminth infection to which a spectrum of natural resistance to parasite infection exists. [4]
Upon infection with H. polygyrus, innate and adaptive host immune responses are generated to prevent the establishment of the parasite in the gut. A strong wound-healing immune response (Th2-type) associated with intestinal pathology is mounted. Similar to other roundworm infections, Th2 immunity focuses on eliminating the parasite or confining it to minimize host damage.
Mucus secreted by goblet cells of the intestine acts as the first line of defense, hence increases in goblet cell number are a major observable change during H. polygyrus infection. [8] Macrophages are activated through Th2 cytokines and they are important in parasite clearance by increase intestinal motility and to induce fibrosis and healing. [9] These immune cells are also important in granuloma formation. This is a defensive response by the host to trap the parasite and minimize its damage to the gut. In addition, these cells are important in increasing contractions of the gut wall, which facilitates worm expulsion. [4] The spleen, mesenteric lymph nodes, Peyer’s patches, and lamina propria lymphocytes induce a strong Th2 immune response by producing different cytokines (Interleukin 3, IL4, IL5, IL9, IL10, and IL13), which are important in controlling and expelling worms. These cytokines aid in generating CD4 T helper 2 effector cells necessary for adaptive immune responses against the parasite. In addition, costimulatory signals via CD80 and CD86 have also be shown important in mounting a Th2 immune response and producing immunoglobulin E (IgE). [5] In the humoral arm of immunity, parasite-specific IgG1 plays a greater role in protection during infection, and IgA has been shown to have a minor effect. IgM and IgE have not been shown to be important in H. polygyrus protection.
However, despite this impressive immune response, H. polygyrus is able to hijack the host immune response, dampening the Th2 response generated against itself, resulting in chronic infection. This immune regulation occurs through a strong regulatory T cell response elicited in the spleen and the mesenteric lymph nodes of the host, mainly involving CD25+ CD103+ regulatory T cells. [10] Another factor might be the production of H. polygyrus alarmin release inhibitor ( A0A3P7XL18 ), an IL-33-suppressive 26-kDa Sushi domain protein, inhibiting processing of IL33 into its active form. [11] H. polygyrus also secretes a molecule that is a mimic of TGF-β, termed Hp-TGM (H. polygyrus TGF-β mimic). [12] [13] Although Hp-TGM has no structural homology to mammalian TGF-β it is similarly able to bind to the TGF-β receptor complex and stimulate downstream signalling processes. These include driving the expression of FOXP3, the master transcription factor of regulatory T cells. Hp-TGM has been shown to induce populations of regulatory T cells in mice that had increased stability in the presence of inflammation in vivo. [14] Hp-TGM can also induce populations of human regulatory T cells from both naive and memory CD4+ T cells that were stable in the presence of inflammation. [15] As such Hp-TGM shows potential for development as a novel therapeutic to re-establish immune tolerance in inflammatory disease.
No formal prevention strategies exist for control of H. polygyrus, although the parasite is susceptible to a number of drug treatments. Treatment of an infected mouse with pyrantel pamoate, ivermectin, or other anthelmintic drugs help clear infection and provide immunity to reinfection. [4] Furthermore, a cocktail of H. polygyrus excretory-secretory antigens can be collected, and administered to mice in the presence of alum to induce sterilizing immunity before infection. [4] [16]
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.
In medicine, the hygiene hypothesis states that early childhood exposure to particular microorganisms protects against allergies by strengthening the immune system. In particular, a lack of such exposure is thought to lead to poor immune tolerance. The time period for exposure begins before birth and ends at school age.
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.
Trichuris muris is a nematode parasite of mice. It is very similar to the human roundworm parasite Trichuris trichiura due to its immunological reactivity when crossed, and so is often used in related studies.
Parasitic worms, also known as helminths, are large macroparasites; adults can generally be seen with the naked eye. Many are intestinal worms that are soil-transmitted and infect the gastrointestinal tract. Other parasitic worms such as schistosomes reside in blood vessels.
Helminthic therapy, an experimental type of immunotherapy, is the treatment of autoimmune diseases and immune disorders by means of deliberate infestation with a helminth or with the eggs of a helminth. Helminths are parasitic worms such as hookworms, whipworms, and threadworms that have evolved to live within a host organism on which they rely for nutrients. These worms are members of two phyla: nematodes, which are primarily used in human helminthic therapy, and flat worms (trematodes).
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.
Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.
Interleukin-25 (IL-25) – also known as interleukin-17E (IL-17E) – is a protein that in humans is encoded by the IL25 gene on chromosome 14. IL-25 was discovered in 2001 and is made up of 177 amino acids.
Intraepithelial lymphocytes (IEL) are lymphocytes found in the epithelial layer of mammalian mucosal linings, such as the gastrointestinal (GI) tract and reproductive tract. However, unlike other T cells, IELs do not need priming. Upon encountering antigens, they immediately release cytokines and cause killing of infected target cells. In the GI tract, they are components of gut-associated lymphoid tissue (GALT).
A helminth protein, or helminthic antigen, is a protein derived from a parasitic worm that causes an immune reaction. When secreted, these proteins may modify the host's immune response in order to promote longevity of the parasite. Helminth proteins can result in a deregulated response to infection, and are implicated in reduced reactivity to other antigens. Other helminth proteins promote parasite survival in other ways, particularly since parasites must depend on hosts for the supply of essential nutrients. Despite their pathogenic properties, helminth proteins have potential to be co-opted to treat a number of other human diseases.
T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.
T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.
Nippostrongylus brasiliensis is a gastrointestinal roundworm that infects rodents, primarily rats. This worm is a widely studied parasite due to its simple lifecycle and its ability to be used in animal models. Its lifecycle similar to the human hookworms Necator americanus and Ancylostoma duodenale which includes five molting stages to become sexually mature.
The effects of parasitic worms, or helminths, on the immune system is a recently emerging topic of study among immunologists and other biologists. Experiments have involved a wide range of parasites, diseases, and hosts. The effects on humans have been of special interest. The tendency of many parasitic worms to pacify the host's immune response allows them to mollify some diseases, while worsening others.
Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.
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De’Broski. R. Herbert is an immunologist, parasitologist, academic, and biomedical researcher. He is currently Full Professor of Immunology, and Penn Presidential Professor at the University of Pennsylvania School of Veterinary Medicine. He is also the Associate Director for Institute of Infectious and Zoonotic Disease (PennVet), and an affiliated Scientist at the Monell Chemical Senses Center.