Lecture 10 - Parasite Immunity

Explain, using examples, how parasites are a huge burden on global health.

-          Human immunodeficiency viruses – 40 million cases worldwide, 690,000 yearly deaths.

-          Mtb – 10 million cases worldwide, 1.5 million yearly deaths.

-          Intestinal parasites – 3.5 billion cases worldwide, 450 million critical illnesses.

Give examples of eukaryotic parasites, proliferating and non-proliferating.

-          Proliferating unicellular: Malaria, Trypanosomes, Leishmania, Toxoplasma

-          Non-Proliferating multicellular helminths: Pinworm, Ascaris, Hookworm, Schistosomiasis and Filariasis

-          Parasites are a complex, therefore complex immune response.

Explain the complex of interaction of helminths with the immune response.

-          Complicating factors: Numerous development stages, numerous hosts (vertebrate and Invertebrate), many environments (Inside and outside host).

-          Long term chronic infections: Immune evasion, immune modulation, immune pathology they generate varies depending on infection dose.

-          Absence of sterilising immunity – can still be infected again after clearing the infection.

What are helminths? Give examples.

-          Multicellular parasitic worms –lifecycle within (mature, mate, produce eggs) and outside (eggs develop into infectious larvae) the mammalian host

-          Flatworms - Trematodes (Flukes) e.g., Schistosomes and Cestodes (Tapeworms) e.g., Taenia sp.

-          Nematodes e.g., Humans - Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm), Necator americanus and Ancylostoma duodenale (hookworms), Filarial nematodes

Why are helminth infections important?

-          VERY COMMON: low- and middle-income countries, tropical and sub-tropical regions. ~2 billion infections worldwide

-          Intestinal obstruction, malabsorption-malnutrition, anaemia, stunted growth, cognitive defects in children

-          Importantly, helminth infections can have bystander effects on unrelated conditions (e.g., allergy), infections and medical interventions (vaccinations)

Give an overview of helminth induced immunity.

-          Primary infection, helminth-induced tissue damage – immune-mediated tissue repair

-          Secondary infections - immune control

-          Helminth-induced immune regulation/modulation of the host

-          Bystander and systemic effects during co-infections 

Explain the primary helminth infection cycle.

-          Once host becomes infected, larvae colonise mucosal sites (e.g., nematodes, tapeworms)

-          Lung, Gastrointestinal (GI) tract

-          Where the anti-helminth immune response is initiated 

-          Adults à live in the intestine and produce eggs that are passed faecally into the environment

eggs are sticky and produced in vast quantities

eggs stick to fingers or food à swallow the eggs

eggs hatch in small intestine

burrow out of the small intestine and move into the liver and lungs causing pathology

crawl up the windpipe à swallow them

process repeats.

Explain how helminths infect host tissue.

-          Large size – helminths can cause significant tissue damage when migrating through and residing in mucosal tissues

-          Lung: significant inflammation, reduced airway spaces, focal lesions and damage to important pulmonary vasculature – lung disease in severe infections

-          Gut: severe infections can result in significant intestinal inflammation and pathology

Explain the immune response to helminth infection.

-          Mucosal epithelium (lung/intestinal) important cell type to trigger type 2 immunity

-          Nematode migration damages mucosal epithelium

-          Release DAMPS (Danger associated molecular patterns) and cytokine alarmins (e.g., IL-25, IL-33 and thymic stromal lymphopoietin (TSLP))

-          Raised IL33 can cause an allergic response.

What are type 2 cytokine producers?

-          Alarmins activate innate lymphoid type 2 cells (ILC2s), which produce ‘type 2’ cytokines e.g., IL-5 and IL-13

-          ILC2s are important local orchestrators of type 2 immunity

-          Only small amounts of them.

-          During infection, there is an expansion of tissue-resident ILC2s as well as recruitment e.g., from the intestine to the lung

Explain the Th2 cell response.

-          Polarisation of naïve CD4⁺ T cells to TH2 – hallmark of helminth immunity

-          Mediated by IL-4-IL-4 receptor (IL-4R), transcription factors STAT6 and GATA3

-          Th2 cells produce ‘type 2’ cytokines IL-4, IL-5 and IL-13

-          IL-4, IL-5 and IL-13 activate effector cells

Explain the role of IL-5 mediated eosinophils in the immune response to helminths.

-          IL-5-mediated eosinophilia is a key feature of helminth infection

-          Eosinophils – granulocytes, degranulate and release eosinophil secondary granule proteins e.g., eosinophil peroxidase (EPO)

-          Do this in concert with the parasite being coated by IgE of IgG4

-          Role not fully understood during primary infection – disruption does not alter susceptibility

-          Produce ‘type 2’ cytokines IL-4 and IL-13, aids in type 2 responses but not essential

-          Eosinophils may aid in clearing cellular debris and tissue repair after helminth tissue invasion

-          Reside in tissue – play a role during secondary resistance

-          Allow the lungs to produce collagen and heal holes produced by the parasite.

Explain the weep and sweep response.

-          IL-4- and IL-13-, IL-4Rα-mediated ‘weep and sweep’ response

-          Reduces worm fecundity and increases expulsion

-          Intestinal smooth muscle contraction

-          Goblet cell hyperplasia and mucous secretion

-          Changes to gut epithelial permeability

-          Various cells in the epithelium are hit and release molecules that make the gut lumen a less desriable place for the parasite to be.

-          Acetylcholine induces contraction in the intestine to try and flick the worm out.

-          This response can be replicated in the lung and cause allergic-like pathology

Explain the memory Th2 response.

-          Tissue-resident effector CD4+ TH2 cells rapidly accumulate around helminth during recall infection

-          Tissue resident T-cells see the antigen and expand, and continue expanding each time they see it, B-cell expand.

-          Central memory CD4+ TH2 cells (e.g., in draining lymph nodes) rapidly migrate to tissue

-          Earlier and elevated release of ‘type 2’ cytokines e.g., IL-4, IL-5, IL-13 – signal effector cells/functions

-          Larvae can’t progress to adulthood.

Explain the other roles of B-cells in the immune response to helminths.

-          B cells contribute to protective ‘type 2’ immune response

-          B cells can present antigen to mediate TH2 activation, responsive to IL-4/IL-13 via IL-4Rα, and produce ‘type 2’ cytokines such as IL-13

-          ‘Type 2’ cytokine production by IL-4Rα-responsive B cells are required for effective immunity during secondary hookworm infection

What are bystander and systemic effects of helminths?

-          Have  a large effect on other infections.

-          Causes responses to viral infections and cancer biology, effects efficacy of vaccines.

Explain how helminths modulate the immune system through excretory-secretory (ES) products.

-          Helminths release ES products which modulate host immunity – promote parasite survival

-          Antigen and ES stimulate dendritic cells (DCs) to release TGF-β, IL-10 – activate naïve CD4+ T cells to regulatory T cells (T_regs)

-          Regulation of inflammation by Tregs is important – prevent exacerbation of responses and reduce tissue damage

-          Allows helminths to launch chronic infections with low immunopathology.

Explain the hygiene hypothesis.

-          Autoimmune disorders are more prevalent in areas where hygiene is better.

-          In areas of high helminth infection, the incidence of allergy and autoimmune disease is lower.

Explain how helminths immunoregulate allergy.

-          H. polygyrus produces and releases a TGF-β ortholog (structure different but functions the same – protected against excessive inflammation) and an IL-33 inhibitor

-          These ES products dampen abnormal Th2 responses to an allergen

-          People with a history of helminth infections have a better history with organ transplants.

-          ES products being explored as therapeutic products.

What are the pro-allergenic effects of helminths.

-        Helminth exposure can also increase risk of allergy and asthma

-          E.g., Ascaris lumbricoides exposure has been associated with lowered lung function and increased risk of asthma (Jogi et al., 2021 JACI)

-          Zoonotic helminth exposure can also increase risk of allergies (Jogi et al., 2018 Clin Exp Allergy)

-          Reduced lung function. Anti-allergenic infections are from parasites that are better adapted to us.

Explain the balance of pro-allergenic and anti allergenic responses in helminth infection.

What is genital schistomiasis and its effects.

-          Geographical overlap between helminth infections and STIs makes coinfection highly likely

-          Little is known about how helminth infections systemically alter immunity and susceptibility to STIs

-          Genital Schistosomiasis

-          Eggs lodged in cervix – granulomas and inflammation

-          Tissue damage, scarring

-          Increased HIV risk – impaired barrier function and increased target cells

-          Devasting impact of the direct pathology caused by this parasite

-          Systemic effects are less understood

-          Helminth induce Th2/T_reg responses and impaired Th1/Th17 – needed for STI control

-          Studies have reported increased HPV prevalence in soil-transmitted helminth (STH) infected women

Explain the immune response to schistomiasis.

-          Increased ‘type 2’ cytokines in vaginal fluids

-          Mechanisms underlying this association are not well established

-          Helminth infection can systemically induce type 2 cellular immunity in vagina

-          Helminth-induced eosinophil accumulation in the vagina has shown to be detrimental for subsequent viral STI infection

-          Increased immunopathology