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The worm turns Malcolm McDonald MBBS PhD FRACP FRCPA Apunipima Cape York Health Council and James Cook University The JCU Cairns Institute Mandingalbay Yidindji people Opening philosophical statements “To do is to be.” Réne Descartes [1596-1660] French philosopher “To be is to do.” GWF Hagel [1770-1831] German philosopher “Do–be-do-be-do” Frank Sinatra [1915-1998] American crooner The wormier world of the 1950s • worms: ‘love dirt’ • dirt: on the way out • flush toilets: on the way in • kids: got ‘wormed’ [nv] • worms: in decline • nowadays: few personal worm stories in this room Gut helminths: a spectrum Disease [due to infection] α dose X virulence host resistance Weak immune response heavy worm burden illness Strong immune response low worm burden tolerance or even immune-driven pathology Strongyloides stercoralis Greek: ‘strongylos’ = round ‘eidos’ = form Latin: ‘stercora’ = dung, pus, general icky stuff Percutiat te Dominus ulcere Aegypti et parte corporis per quam stercora digeruntur scabie quoque et prurigine ita ut curari nequea. Deuteronomy 28.27 The LORD will smite thee with the boils of Egypt, with the festering sores, the scabs and the itch, whereof thou canst not be healed. Deuteronomy 28.27 Strongyloides stercoralis life cycle Autoinfection Strongyloidiasis: clinical • Infection/autoinfection persistence, often for decades. Mostly asymptomatic. Eosinophilia common, but not universal • Skin: ground itch, later purpura • Lung: cough, wheeze, pneumonitis • GIT: abdominal pain, nausea, vomiting, diarrhoea, malabsorption [rare] • Buttocks: larva currens Hyperinfection Syndrome [<10 cases/year] • Autoinfection: rhabditiform larvae transform to filariform larvae and penetrate the gut wall massive dissemination and sepsis • Fever, cough, haemoptysis, wheeze, GI symptoms, septic shock [enteric Gm – ve] • Eosinophilia typically absent • Usually precipitated by impairment of cell-mediated immunity: c’steroids [>65%], chemotherapy, transplantation, severe malnutrition, HTLV-1, etc Letter: MJA 6th July 2015 – routine serology in pregnancy? Helminth immunomodulation Worms need to live in our gut. Routinely killing the host is not a cool strategy Regulating the host’s immune response helps worms to flourish and survive T helper cell subsets: Th1, Th2, Th9, Th17 and Th22 each has an accompanying response • Th1: pro-inflammatory with TNF-α, IFN-γ, IL-12 and high levels of IgG2/3 Th1 anti-microbial response; autoimmune diseases • Th2: anti-inflammatory with IL-4, IL-5, IL-10, IL13 and higher levels of IgG4 • Th17: pro-inflammatory IL-17 and IL-22 [dual roles] Let’s dance Helminths • Switch the Th1 to Th2-type responses [complex: partly through TLRs] and they down-regulate Th17 • Have modulatory effects on both regulatory T and B cells; and DCs • Produce eosinophilia [through IL-5] and a Th2 responses in adipose tissue AAM accompanied by insulin sensitivity • Also have a variable effect on the gut microbiome greater bacterial diversity and reduced gut permeability reduced circulating pro-inflammatory markers Th1 response Th2 response Lean Adipocytes Obese IL-33 M2 M1 Insulin sensitivity Insulin resistance Th1 inflammation and type II diabetes mellitus Raised inflammatory cytokines precede development of clinical manifestations, often for decades Genetic & epigenetic factors Dietary fat Th1 inflammatory cytokines Activation of serine kinases Phosphorylate insulin receptor substrate proteins insulin resistance Hyper-insulinaemia Adiponectin Liver: gluconeogenesis & fat deposition Th1 inflamed adipose tissue Islet cell ‘burnout’ IL-1β IL-6 IFNα Reduced pro-insulin conversion Loss of glucose sensitivity Th1 inflamed pancreatic islets Increased amyloid polypeptide Grossman V, et al. Diab Care 2015 [Apr]: ePub Vaarala O, et al. Nature Rev 2012;8:323-5 Donath MY, et al. Nature Rev 2011:11:98-107 • Cross-sectional survey of 259 Aboriginal adults in a remote WA community • Prior S stercoralis infection determined by ELISA • Ninety two (36%) had prior infection and 131 (51%) had T2DM • Those with prior S stercoralis infection were 60% less likely to have T2DM than those uninfected [adjusted for age, triglycerides, blood pressure and BMI using propensity score: OR=0.39, 0.230.67, P=0.001] • Strong ‘protective’ association but not causation – certainly worth exploring with longitudinal studies in populations at high risk of both conditions Indonesian-Dutch study published June 2015 The homeostatic model assessment for insulin resistance (HOMAIR) JCU study in a nearby community • Cross sectional study using de-identified data from the community’s annual Young Persons Check [15-24yrs] • Serology [ELISA test] to determine past/current S stercoralis infection • Identify who has the ‘metabolic syndrome’ [WHO criteria: based on glucose indicators, obesity, lipid profile, BP and albuminuria] • Aim: to determine if a positive ELISA is a predictor of the metabolic syndrome, whilst controlling for confounders [especially BMI] • Study proposal has received JCU ethics approval and is about to go ahead this month Does exposure to ‘Old Friend’ organisms influence the risk/progression of autoimmune diseases? • There are many published mouse studies • Some have impressive results • About 25 human trials completed/in progress/registered • Numbers are small; all phase I/II • Inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, allergic rhinitis • Mixed results: as expected Local champion Hookworm vaccine candidates Relationship between hookworm infection, IBD and coeliac disease Use of microarray technology to explore the activities of identified helminth immunemodulating determinants [ES proteins – AIP1 & AIP2] Effect of helminth infection on the gut microbiome ‘Autoimmune conditions’: Aboriginal Australians, Torres Strait and Pacific Islanders multiple factors [microbiome/worms?] MM PM DB Relatively common Rare [a brave diagnosis] • Systemic lupus erythematosus • Crohn’s disease and ulcerative colitis • Psoriasis • Reactive arthritis • Myositis [also asymptomatic raised CK with statins] • Raised inflammatory markers: ESR, CRP, ferritin [with ‘low’ Vit D] • Raised gammaglobulins [polyclonal] +ve RhF & ANA • [Rheumatoid arthritis] • Sarcoidosis • Systemic sclerosis • Ankylosing spondylitis [K] • Type 1 diabetes mellitus • Coeliac disease • Pernicious anaemia • Multiple sclerosis • Eczema [scabies?] What of the future? Therapeutic possibilities The immune modulatory potential of gut helminths varies greatly. • Potential benefits of helminth infection in autoimmune and metabolic disease It depends on: • the worm species • the worm burden • the gut microbiome • the individual’s host response • many other ‘knowns and unknowns’ • Further therapeutic trials of live eggs/worms. Many ethical issues. • Identification of immune modulating determinants clinical trials • Prospect of vaccines protection against helminth-related disease……..and maybe even autoimmune and metabolic diseases The future "I would not say that the future is necessarily less predictable than the past. I think the past was not predictable when it started." Donald Rumsfeld Former US Secretary of Defence “Today I saw a little worm wriggling on its belly [rhabditiform?] perhaps he’d like to come inside and see what’s on the telly?” “To whom do lions cast their gentle looks? Not to the beast that would usurp their den. The smallest worm will turn, being trodden on, And doves will peck in safeguard of their brood.” William Shakespeare: Henry VI, Part 3 Spike Milligan The worm turns Thanks for your attention