Nature

Ascaris spp. are parasitic intestinal nematodes that have been associated with humans for thousands of years. A. lumbricoides is the largest intestinal roundworm and typically infects humans (occasionally A. suum), while A. suum typically infects pigs (1). However, cross-species transmission and hybridization is possible between the two species (2).

Adult worms have a life expectancy of approximately 1‒2 years and live in the small intestine, where they can achieve lengths of 15‒25 cm (male) and 20‒35 cm (female); they produce tens of thousands of un-embryonated eggs daily that are shed in the feces (1, 3, 4).

Outside the human body, Ascaris eggs develop to infectivity under appropriate conditions of temperature and moisture (1). Eggs are very sticky and attach easily to objects such as soil and dust particles, children’s toys, food items, currency notes, and insects such as flies and cockroaches (4). The life cycle in humans starts with oral ingestion of embryonated eggs that hatch in the large intestine, releasing larvae that undergo a hepato-tracheal migration via the liver, advance to the lungs, penetrate the alveolar spaces, move to the pharynx from where they are coughed up and swallowed, and then develop to adulthood in the small intestine (1, 3-5). From ingestion of eggs to their detection in feces ranges from 10‒11 weeks (4).

Taxonomy 

Allergenic molecules

The following allergens and their molecular epitopes have been characterized from Ascaris lumbricoides (Asc l) (14):

There is some evidence that antigen production by Ascaris spp. larvae is heterogeneous depending on the life cycle stage of development (19). Collectively termed excretory/secretory products, these antigens can elicit significant antibody responses in humans and animal models (18, 19). Four allergens have been characterized in the published literature to date (Asc l 1, Asc l 3, Asc l 5, and Asc l 13), however, the whole extract of Ascaris has at least nine additional IgE binding components which could be potential allergens (20).

Asc l 13 is a glutathione-S-transferase (GST), a multifunctional enzyme that functions in worms as part of a type II detoxification system essential for parasite survival, neutralization of oxygen reactive species, and metabolism of environmental substances (8, 16). Purified GST from A. lumbricoides binds specific human IgE antibodies and also induces type I hypersensitivity skin reactions in sensitized subjects (18). Specific IgE to GST was detected in 19.9% (42/215) of patients with asthma, versus 13.2% (12/91) in non-asthmatic control subjects (18).

Biomarkers of severity

As antibody isotype responses correlate with infection intensity, the well characterized allergen ABA-1 can be used as a coproantigen marker for infection with A. lumbricoides (8, 21). Of note, evaluations of total anti-Ascaris antibodies could overestimate the active infection rates, as these antibodies can remain elevated for several months following treatment of ascariasis, especially in geographical areas with frequent re-infection (3).

Cross-reactivity

A high prevalence of Ascaris IgE seropositivity has been observed in populations from developed countries where ascariasis is not expected to be endemic, and cross-reactivity should be considered as a potential confounding factor when assessing the effect of ascariasis as a risk factor for asthma and allergy (8, 11).

Humans with ascariasis have shown variable IgG antibody responsiveness to ABA-1 (Asc l 1), one of the most abundant proteins synthesized by Ascaris; the genetic basis for this variability is unknown (15). A molecular cloning study showed significant similarity between ABA-1 from Ascaris and a soluble protein produced by adult Brugia, a nematode that causes lymphatic filariasis (22).

Asc l 3 is a tropomyosin, an invertebrate pan allergen that is phylogenetically conserved and widely recognized as a major allergen with extensive cross-reactivity (8). Approximately 50% of the total IgE response to Ascaris extract could be due to specific IgE to tropomyosin (16). Asc l 3 is expected to show variable cross-reactivity with other tropomyosins such as Group 10 allergens in mites (e.g., Der p 10, Der f 10, Blo t 10, Lep d 10, Tyr p 10), Group 1 allergens in crustaceans and molluscs (e.g., Pen a 1, Met e 1, Pen i 1, Hom a 1, Pan s 1, Cha f 1, Cra g 1, Tur c 1, Tod p 1), Group 7 allergens in cockroach (e.g., Bla g 7, Per a 7, Per f 7), and Group 3 allergens in nematodes (e.g. Ani s 3 from Anisakis spp.) (8).

Asc l 5 belongs to the SXP/RAL-2 protein family, which is exclusive to nematodes and contains a number of allergens with similar sequencing including As16 and As14 (Ascaris suum), Ag2 (Bayliascaris schroederi), and nematode infection markers such as SPX antigens from Brugia malayi and Wuchereria bancrofti (20, 23). Of note, three allergens from the parasitic nematode that causes anisakiasis (Anisakis simplex: Ani s 5, Ani s 8, and Ani s 9) also belong to the SXP/RAL-2 protein family (20).

Co-exposure to A. lumbricoides and house dust mites induces a strong Th2 and immunomodulatory response with complex interactions that can either potentiate or suppress cross-reactivity between their respective allergens by several mechanisms (8). As exposure to mite allergens is perennial, cross-reacting allergens from mites could stimulate and sustain high levels of total IgE and specific IgE responses to some Ascaris allergens (8). In one study, 70% of 100 subjects allergic to house dust mite allergens (14–240 kDa; Blomia tropicalis, Dermatophagoides pteronyssinus, and D. farinae) exhibited positive IgE-reactivity to A. lumbricoides allergens (15–250 kDa), while conversely, 20–28% of 60 ascariasis subjects demonstrated positive IgE-reactivity to the house dust mite allergens, suggesting multi-allergen sensitization (24). Another study reported a strong correlation between IgE levels to GST from A. lumbricoides and GST from other invertebrates such as cockroach and house dust mite (18). However, the authors noted that the study population (asthmatic patients) was co-exposed to the allergenic sources so it was not possible to know if the correlations resulted from co-sensitization or cross-reactivity (16).

Pre-sensitization with antigens from Ascaris spp. has been shown to accelerate the mite-specific IgE response upon mite antigen inhalation, supporting a potential cross-reactivity between Ascaris and arthropod antigens (1). Additionally, pre-existing allergic sensitization to house dust mite may drive a CD4+ Th2-mediated eosinophil-dependent immune response that mimics a primary Ascaris infection, and protects against early larval helminths prior to their establishing long-lasting infections in the host (25).