Lecture 3: Parasites and Childhood Growth Retardation PDF

Parasites and childhood growth retardation: Biochemical Evidence Course outline Some importance definitions Childhood growth retardation Global prevalence of stunting, wasting, underweight Potential key pathways linking parasitic infection to childhood growth retardation Par...

Parasites and childhood growth retardation: Biochemical Evidence Course outline Some importance definitions Childhood growth retardation Global prevalence of stunting, wasting, underweight Potential key pathways linking parasitic infection to childhood growth retardation Parasites reduce host nutrient intake Parasites causing diarrhoea Parasitic cause of environmental enteric dysfunction (EED) Progression of EED and microbiome changes in response to parasitic infection Parasitic cause of systemic inflammation which contributes to growth retardation Parasitic causes of anaemia Parasitic alteration of epigenetic regulation  Important definitions Crypt hypertrophy: Crypt hyperplasia is Environmental enteric dysfunction: when the grooves are elongated compared Environmental enteric dysfunction to a normal intestinal lining which has short (EED) refers to an incompletely defined crypts syndrome of inflammation, reduced The intestinal crypt is a sterile invagination absorptive capacity, and reduced composed of goblet, stem, and Paneth cells, barrier function in the small intestine which can secrete mucus and antimicrobial peptides such as cryptdins DNA methylation: DNA methylation is a Immune activation: appropriate biological process by which methyl groups response to invading pathogens are added to the DNA molecule. Methylation can change the activity of a Growth retardation: stunting, wasting, DNA segment without changing the underweight sequence. Childhood growth retardation Human height reflects a combination of an individual’s genotype and environmental factors which influence phenotypic expression of that genotype. An estimated 149.2 million children under the age of 5 had growth retardation 2020 Growth retardation is a visible indicator of a deficient environment, the consequences of which include child morbidity, including an increased risk of long-term chronic diseases, and in severe cases even mortality. Global prevalence of stunting, wasting, underweight Potential key pathways linking parasitic infection to childhood growth retardation Parasites reduce host nutrient intake It is well recognized that a chronic and/or reoccurring lack of sufficient, nutritious foods for mother and child in pre- and postnatal periods contributes to growth retardation. Like many illnesses, parasitic infections may result in withdrawal of food from individuals who are overtly ill, or reduce appetite as a result of active abdominal pain and discomfort, the latter being common symptoms of parasitic gastrointestinal infection. Parasites may also influence neuroendocrine control of appetite, for example, there is evidence that enteroendocrine cells ‘sense’ the presence of gastrointestinal parasites or their products in the gut and induce cytokine expansion. Parasites reduce host nutrient intake This subsequently alters taste receptor expression and release of satiety hormones. Leptin is a well-known satiety hormone. Leptin is a major appetite suppressant hormones, found to be elevated in children infected with Entamoeba histolytica, Strongyloides spp., and Giardia lamblia Similarly, childhood Trichuris trichiura infection has been associated with below the recommended intake of protein, energy, iron, and riboflavin Parasites causing diarrhoea Protozoan and helminthic parasites are major causative agents of diarrhoeal illness (including bloody diarrhoea) in children. Diarrhoea, particularly when recurrent and/or severe, can impair absorption and digestion of macronutrients and micronutrients and increase catabolism of nutrient reserves, change intestinal enzyme activity, and damage the intestinal lining. Diarrhoea has also been causally linked to growth retardation by directly reducing levels of the growth hormone insulin-like growth factor (IGF-1). Parasitic cause of environmental enteric dysfunction (EED) Parasitic infection has been implicated in the aetiology of EED, which is an acquired, subclinical enteropathy of the small intestine and may contribute to growth retardation. Villous atrophy reduces the surface area of the small intestine, with fewer mature absorptive intestinal epithelial cells available for nutrient absorption and digestion. Therefore, EED likely contributes to exacerbation of undernutrition and/or micronutrient deficiencies. Parasites cause environmental enteric dysfunction (EED) Although direct evidence in humans is limited, associations between villous atrophy, G. lamblia infection and growth retardation have been made in murine models. EED leads to depletion of catalytically active brush-border enzymes and nutrient transporters, providing a realistic route for parasites to limit absorption and digestion. Parasites cause environmental enteric dysfunction (EED) Parasites may increase gut permeability; for example, E. histolytica can loosen tight junctions between intestinal epithelial cells by producing proteases. Parasitic protozoa cause damage via attachment to, and invasion of the epithelium (e.g., E. histolytica), and increasing enterocyte apoptosis (e.g., G. lamblia). Further, undernourished, parasitized children may have insufficient of essential nutrients to repair mucosal damage, thus exacerbating the effects of EED. Parasites cause environmental enteric dysfunction (EED) As a result of increased mucosal permeability, microbes and microbial-associated macromolecules may translocate into the lamina propria, causing: i. an influx of inflammatory cells ii. activation of local intestinal inflammation and iii. a perpetual cycle of deteriorating barrier function, nutritional status, and chronic inflammation Progression of EED and microbiome changes in response to parasitic infection Progression of EED and microbiome changes in response to parasitic infection The feeding behaviour of helminthic parasites in the gastrointestinal tract and invasion of the gut by protozoal parasites leads to damage of the intestinal epithelium. Chronic exposure to parasitic disease may result in inflammation, crypt hypertrophy, and increased intestinal permeability. Further, this ensuing damage may allow for bacteria to cross the intestinal epithelium, into the lamina propria, causing further infiltration of immune cells and subsequent inflammation. Progression of EED and microbiome changes in response to parasitic infection The resulting damage, characteristic of EED, may lead to reduced micronutrient and macronutrient absorption across the damaged and inflamed gut epithelium, exacerbating malnutrition. Furthermore, in the healthy gut, the microbiota provides colonization resistance against invading pathogens. In a state of inflammation and EED in children, the composition of the microbiota is underdeveloped and less able to provide beneficial nutritional and immune support. All of this may impact gut epithelial and systemic changes in epigenetic regulation, affecting host gene expression and overall health. Parasitic cause of systemic inflammation which contributes to growth retardation Parasitic infection may directly – and via local gut inflammation as a result of EED, induce systemic inflammation and immune activation, potentially leading to growth retardation. Immune activation is both energetically and metabolically costly and this may directly divert calories and nutrients away from other physiological processes such as linear growth, in an energetic trade-off. In children, an increased antiparasite adaptive immune response (total IgE level) has been associated with growth reductions Parasites cause systemic inflammation which contributes to growth retardation Parasites may deplete amino acids by using them up, or via increased requirement by the immune system during infection. Essential amino acids are critical for nucleic acid and hormone (e.g., IGF-1) biosynthesis and cellular replication, and in turn, child growth. Parasites may utilize host amino acids; for example, Giardia intestinalis directly consumes arginine as an energy source. Furthermore, amino acids are also important for intestinal barrier function, with scarcity potentially exacerbating the EED cycle by reducing intestinal injury repair. Low serum glutamine and arginine concentrations are associated with impaired barrier function and reduced linear growth in children Parasites cause systemic inflammation which contributes to growth retardation Parasitic infection can cause dysregulation of growth factors which are important for prenatal and postnatal growth. Immune activation upregulates acute-phase proteins, which inhibit IGF-1 in the liver, leading to growth hormone (GH) resistance and inhibition of longitudinal bone growth via effects on the growth plate, potentially reducing linear growth. Cryptosporidium spp. infection is indirectly associated with lower length-for-age through increased systemic inflammation and reduced plasma IGF-1 concentrations in infants. Parasitic causes of anaemia Parasites can cause anaemia, which contributes to growth retardation Anaemia and growth retardation often coexist, although it is difficult to distinguish cause and coexistence between these two conditions since they hold similar underlying determinants (e.g., malnutrition) indicative of a deficient environment. Anaemia may directly limit child growth via reduced oxygen-dependent cellular energy metabolism, imposing hypoxic conditions on cells. Hypoxia contributes to embryonic growth retardation via interference with the IGF-1 system There is also ample evidence for helminths and parasitic protozoa, including parasitic protozoa residing in the blood (such as those causing malaria, leishmaniasis, and babesiosis), as risk factors for anaemia. Parasites can cause anaemia, which contributes to growth retardation Certain parasite species may contribute to anaemia of the host via several mechanisms. Firstly, parasites may contribute to anaemia via consumption of host blood and/or extracorporeal blood loss Helminths inhabit blood vessels and/or feed directly on red blood cells (RBCs) within host vessels. This causes loss of blood directly to the parasite, and extracorporeal blood loss at the feeding site due to epithelial damage, and secretion of anticoagulases allowing for continued bleeding at the site Parasites can cause anaemia, which contributes to growth retardation Further, spined Schistosoma eggs penetrate host tissues, through the intestinal walls into the faeces (Schistosoma mansoni and Schistosoma japonicum) or bladder into the urine (Schistosoma haematobium), rupturing blood vessels and causing extracorporeal blood loss. Additionally, certain parasites are known to cause blood loss as a result of bloody diarrhoea, proposed to be a consequence of mucosal damage and inflammation. Parasites can cause anaemia, which contributes to growth retardation Secondly, certain parasites may infect RBCs, causing destruction via autoimmune haemolysis (haemolytic anaemia), and reductions in RBC lifespan Thirdly, parasitic disease may induce a proinflammatory response. This is characterised by proinflammatory cytokine (particularly tumour necrosis factor-alpha and interleukin-6) production and upregulation of the protein hepcidin. Hepcidin causes erythrophagocytosis of RBCs, decreased RBC production in bone marrow, and sequestration of bioavailable iron (Fe) to storage forms (trapping the iron) in the spleen, liver, and in macrophages, causing a decrease in intestinal absorption of iron. Parasites can cause anaemia, which contributes to growth retardation Finally, hypersplenism, or an overactive spleen resulting from parasitic infection, may remove RBCs too quickly and/or early, leading to anaemia. Parasitic alteration of epigenetic regulation Evidence has accumulated for a role of DNA methylation in regulating childhood growth For example, epigenetic signatures are associated with birth weight across studies. In fact, evidence supports a role for DNA methylation in mediating the effects of exposure to malnutrition during gestation on growth and life-long metabolic health. Parasites can alter epigenetic regulation Studies demonstrating the influence of parasitic infections on host epigenetic regulation relating to inflammation and the immune response are, however, accumulating. Epigenetic states may confer susceptibility or resistance to parasite infection, while manipulation of host epigenetic regulation of gene expression by parasites may be an important pathway for host immune system evasion. Active Schistosoma haematobium and Ascaris lumbricoides infection induces a specific DNA methylation signature in human primary immune cells.