Helminths
3 major classes cause disease in humans: Protozoa, Ectoparasites and Helminths
2 classes of helminths: Roundworms and Flatworms
- Live in and feed on host.
- Cannot reproduce entirely in the host.
- Produce eggs that can survive in the environment.
- Rely on specific environmental conditions for the life stages outside of the host hence tropical environments
are often suitable – warm, moist, shaded soil.
Main examples:
- Ascaris – soil-transmitted, lives in intestine. Disease = Ascariasis.
- Schistosoma – Fresh-water snail intermediate host, blood fluke. Disease = Schistosomiasis.
- Filaria – mosquitos and blackfly transmitted. Disease = Lymphatic filariasis and river blindness.
- Whipworm – soil-transmitted, lives in intestine. Disease = Trichuriasis.
- Hookworm – soil-transmitted, lives in intestine. Disease = hookworm disease.
Lots of mouse models for these diseases.
Schistosomiasis (bilharzia)
Stats: >200,000 deaths a year. >20 million suffer severe morbidity.
Lifecycle: Infected Cercariae are released into water from snail. Mature into adults in blood vessels.
Location in body: Live in blood vessels at different locations throughout the body.
Damage: Crossing over of eggs from mesentery to luminal site causes damage – chronic inflammation, tissue fibrosis
and cancer. Kidney failure. Hepatosplenomegaly. Genitourinary, which increases HIV transmission.
- Liver inflammation caused from lodged eggs results in granuloma formed around the egg when the immune
system tries to respond. Fibrotic tissue formed that can cause liver fibrosis and liver failure as well as cancer.
Lymphatic Filariasis
Stats: >120 million infected (2000). >40 million disfigured and incapacitated. 90% of disease caused by Wuchereria
bancrofti.
Lifecycle: Infected L3 larvae enter skin through a mosquito (intermediate host).
Location in body: Lymphatics
Damage: Accumulation of lymph. Swelling and elephantiasis.
Soil-transmitted helminths (STH): Ascaris, Hookworm, Whipworm.
Stats: ~1.5 billion people (>20%) of the world is infected with a STH (2020). Cause 5.2 million disability adjusted life
years (DALYs). 300 million people (20%) suffer from severe morbidity. 150,000 deaths annually (from heavy
infections or if you are immunocompromised). 80% of patients are asymptomatic.
Damage: Ascaris and whipworm infect children and can cause cognitive issues. Diarrhoea, abdominal pain. Acsaris
can cause inflammatory lung disease “Loeffler’s syndrome”. Whipworm can cause anaemia, colitis and Trichuris
dysentery syndrome.
Current treatment: Mass Anthelmintic administration
- Benzimidazoles (Albendazole & Mebendazole)
o Bind β- tubulin of parasite, disrupting microtubule uptake of glucose, leading to death.
- Ivermectin
o Binds glutamate-gated chlorine channels, causing increased permeability to chlorine ions, paralysis, and death of the parasite.
- Praziquantal
o Alters schistosome membrane permeability, inducing parasite contraction and paralysis.
Drugs are usually used in combination to help prevent drug resistance.
Humans do not develop resistance to a second infection, so soil needs to be treated as well to prevent re-infection.
Clinical trials for anthelmintics are limited: Oxfendazole, Doxycycline, Emodepside, Mirazid, Mefloquine, Artesunate..
Effect on the host: “Weep and sweep” response
Physiological changes: dramatic alterations to gut tissue e.g. goblet cell hyperplasia (increase in size and number),
increased mucus production, muscle contraction (attempt to sweep helminths out), epithelial cell permeability
Immune response: Type 2 immune response
, Specific dendritic cells drain lymph nodes and drives T-helper 2 (Th2) cell activation and the production of the
canonical type-2 cytokines: IL-4, IL-5 and IL-13.
Adaptive type 2 responses:
- Th2 cells (CD4+) producing IL-4, IL-13, IL-5.
- Amplification of helminth-specific B cells (IgE)
Innate type 2 responses
- Eosinophilia
- Mast cell activation, basophilia
- Activation of ILCs (innate lymphoid cells) producing typical type 2 cytokines IL-4, IL-13, and IL-5.
- “Alternatively-activated” macrophages (M2)
- Alarmin production IL-33, IL-25, TSLP (Thymic stromal lymphopoietin).
Can cause allergic eosinophilic airway inflammation – allergic asthma.
IL-4Rα: Interlueukin-4 receptor alpha subunit - Drives both responses.
- Needs to bind to a receptor to signal.
- Can form a type 1 IL-receptor that binds with high affinity to IL-4 (with gamma common chain).
- Can form a type 2 IL-receptor that binds with IL-4 or IL-13 (with IL-13Rα chain).
- IL-4Rα expressed everywhere (ubiquitously) on hematopoietic (immune) and non-hematopoietic (epithelial) cells.
- IL-13Rα is absent on T cells but expressed on B cells, epithelial cells and monocytes.
Evidence of the importance of IL-4Rα/IL-13Rα signalling in human-parasite endemic populations and asthma.
Mouse models to study IL-4Rα
1. Cre recombinase-loxP recombination system
- Gene of interest surrounded by loxP sites which can be cut by a cre-recombinase enzyme.
- Results in global knockout of IL-4Rα, or cell specific IL-4Rα deletion.
2. Genetically engineering stem cells
- Use of CRISPR/Cas9 to genetically engineer cells, inject into mice to create knockout mice.
Study hypothesis: Mice deficient for IL-4Rα do not develop allergic airway disease. (not true)
- LckcreIL-4ra-/lox mice showed asthma could still develop in absence of IL4Ra on T cells.
- Airway inflammation could develop in ovalbumin (Ova)-sensitised IL-4Ra-deficient mice.
- IL-13 is more important in development of allergic airway disease.
Study hypothesis: IL-4Rα is more important in helminth expulsion. (true)
- IL-4Rα-deficient mice were not able to expel the worm and had higher egg and worm burdens – did
not form granulomas in the intestine which normally help to resist infection.
- IL-4Rα signalling controls ability to generate sterile immunity following helminth infection – mice can
resist a secondary challenge of helminth infection.
- An adaptive immune system is required for optimal helminth expulsion.
- Mice lacking an adaptive immune response can be supplemented with rIL-4 and anti-IL-4 (IL-4) which
allows them to partially expel the worm. Adding in rIL-25 also helps.
IL-25: Alarmin produced by ‘Tuft cells’ in the intestine. Detect succinate production by commensal flora. IL-25
binds IL-25R on ILCs present in tissue. Activates ILCs to produce IL-13, which acts on epithelial crypt progenitors to
promote differentiation of tuft and goblet cells. ILC-derived IL-13 and IL-5 are important in driving eosinophilia,
alternative activation of macrophages, as well as the activation of CD4+ T cells.
Combining IL-25 and IL-4Rα maximises macrophage alternate activation. ILC depletion does not impair IL-15/IL-4C.
Alternatively activated macrophages: Good at immobilising helminth larvae and killing
them. Mice with good clearance had high levels of granulomas.
Key questions
Describe some of the current treatments strategies for parasitic helminth.
What governs parasite expulsion?
3 major classes cause disease in humans: Protozoa, Ectoparasites and Helminths
2 classes of helminths: Roundworms and Flatworms
- Live in and feed on host.
- Cannot reproduce entirely in the host.
- Produce eggs that can survive in the environment.
- Rely on specific environmental conditions for the life stages outside of the host hence tropical environments
are often suitable – warm, moist, shaded soil.
Main examples:
- Ascaris – soil-transmitted, lives in intestine. Disease = Ascariasis.
- Schistosoma – Fresh-water snail intermediate host, blood fluke. Disease = Schistosomiasis.
- Filaria – mosquitos and blackfly transmitted. Disease = Lymphatic filariasis and river blindness.
- Whipworm – soil-transmitted, lives in intestine. Disease = Trichuriasis.
- Hookworm – soil-transmitted, lives in intestine. Disease = hookworm disease.
Lots of mouse models for these diseases.
Schistosomiasis (bilharzia)
Stats: >200,000 deaths a year. >20 million suffer severe morbidity.
Lifecycle: Infected Cercariae are released into water from snail. Mature into adults in blood vessels.
Location in body: Live in blood vessels at different locations throughout the body.
Damage: Crossing over of eggs from mesentery to luminal site causes damage – chronic inflammation, tissue fibrosis
and cancer. Kidney failure. Hepatosplenomegaly. Genitourinary, which increases HIV transmission.
- Liver inflammation caused from lodged eggs results in granuloma formed around the egg when the immune
system tries to respond. Fibrotic tissue formed that can cause liver fibrosis and liver failure as well as cancer.
Lymphatic Filariasis
Stats: >120 million infected (2000). >40 million disfigured and incapacitated. 90% of disease caused by Wuchereria
bancrofti.
Lifecycle: Infected L3 larvae enter skin through a mosquito (intermediate host).
Location in body: Lymphatics
Damage: Accumulation of lymph. Swelling and elephantiasis.
Soil-transmitted helminths (STH): Ascaris, Hookworm, Whipworm.
Stats: ~1.5 billion people (>20%) of the world is infected with a STH (2020). Cause 5.2 million disability adjusted life
years (DALYs). 300 million people (20%) suffer from severe morbidity. 150,000 deaths annually (from heavy
infections or if you are immunocompromised). 80% of patients are asymptomatic.
Damage: Ascaris and whipworm infect children and can cause cognitive issues. Diarrhoea, abdominal pain. Acsaris
can cause inflammatory lung disease “Loeffler’s syndrome”. Whipworm can cause anaemia, colitis and Trichuris
dysentery syndrome.
Current treatment: Mass Anthelmintic administration
- Benzimidazoles (Albendazole & Mebendazole)
o Bind β- tubulin of parasite, disrupting microtubule uptake of glucose, leading to death.
- Ivermectin
o Binds glutamate-gated chlorine channels, causing increased permeability to chlorine ions, paralysis, and death of the parasite.
- Praziquantal
o Alters schistosome membrane permeability, inducing parasite contraction and paralysis.
Drugs are usually used in combination to help prevent drug resistance.
Humans do not develop resistance to a second infection, so soil needs to be treated as well to prevent re-infection.
Clinical trials for anthelmintics are limited: Oxfendazole, Doxycycline, Emodepside, Mirazid, Mefloquine, Artesunate..
Effect on the host: “Weep and sweep” response
Physiological changes: dramatic alterations to gut tissue e.g. goblet cell hyperplasia (increase in size and number),
increased mucus production, muscle contraction (attempt to sweep helminths out), epithelial cell permeability
Immune response: Type 2 immune response
, Specific dendritic cells drain lymph nodes and drives T-helper 2 (Th2) cell activation and the production of the
canonical type-2 cytokines: IL-4, IL-5 and IL-13.
Adaptive type 2 responses:
- Th2 cells (CD4+) producing IL-4, IL-13, IL-5.
- Amplification of helminth-specific B cells (IgE)
Innate type 2 responses
- Eosinophilia
- Mast cell activation, basophilia
- Activation of ILCs (innate lymphoid cells) producing typical type 2 cytokines IL-4, IL-13, and IL-5.
- “Alternatively-activated” macrophages (M2)
- Alarmin production IL-33, IL-25, TSLP (Thymic stromal lymphopoietin).
Can cause allergic eosinophilic airway inflammation – allergic asthma.
IL-4Rα: Interlueukin-4 receptor alpha subunit - Drives both responses.
- Needs to bind to a receptor to signal.
- Can form a type 1 IL-receptor that binds with high affinity to IL-4 (with gamma common chain).
- Can form a type 2 IL-receptor that binds with IL-4 or IL-13 (with IL-13Rα chain).
- IL-4Rα expressed everywhere (ubiquitously) on hematopoietic (immune) and non-hematopoietic (epithelial) cells.
- IL-13Rα is absent on T cells but expressed on B cells, epithelial cells and monocytes.
Evidence of the importance of IL-4Rα/IL-13Rα signalling in human-parasite endemic populations and asthma.
Mouse models to study IL-4Rα
1. Cre recombinase-loxP recombination system
- Gene of interest surrounded by loxP sites which can be cut by a cre-recombinase enzyme.
- Results in global knockout of IL-4Rα, or cell specific IL-4Rα deletion.
2. Genetically engineering stem cells
- Use of CRISPR/Cas9 to genetically engineer cells, inject into mice to create knockout mice.
Study hypothesis: Mice deficient for IL-4Rα do not develop allergic airway disease. (not true)
- LckcreIL-4ra-/lox mice showed asthma could still develop in absence of IL4Ra on T cells.
- Airway inflammation could develop in ovalbumin (Ova)-sensitised IL-4Ra-deficient mice.
- IL-13 is more important in development of allergic airway disease.
Study hypothesis: IL-4Rα is more important in helminth expulsion. (true)
- IL-4Rα-deficient mice were not able to expel the worm and had higher egg and worm burdens – did
not form granulomas in the intestine which normally help to resist infection.
- IL-4Rα signalling controls ability to generate sterile immunity following helminth infection – mice can
resist a secondary challenge of helminth infection.
- An adaptive immune system is required for optimal helminth expulsion.
- Mice lacking an adaptive immune response can be supplemented with rIL-4 and anti-IL-4 (IL-4) which
allows them to partially expel the worm. Adding in rIL-25 also helps.
IL-25: Alarmin produced by ‘Tuft cells’ in the intestine. Detect succinate production by commensal flora. IL-25
binds IL-25R on ILCs present in tissue. Activates ILCs to produce IL-13, which acts on epithelial crypt progenitors to
promote differentiation of tuft and goblet cells. ILC-derived IL-13 and IL-5 are important in driving eosinophilia,
alternative activation of macrophages, as well as the activation of CD4+ T cells.
Combining IL-25 and IL-4Rα maximises macrophage alternate activation. ILC depletion does not impair IL-15/IL-4C.
Alternatively activated macrophages: Good at immobilising helminth larvae and killing
them. Mice with good clearance had high levels of granulomas.
Key questions
Describe some of the current treatments strategies for parasitic helminth.
What governs parasite expulsion?
