(L14) IMED2001 - Parasitic Infections 1 (Protozoa)

Need to know examples of protozoan and helminth parasites for each mode of transmission, and also need to knwo an example of each group of parasites (next lecture)

- also need to know some examples of anti-protozoan and anti-helminth drugs

LEARNING OUTCOMES

Vaccines for parasitic diseases

- July 2015 RTS,S/AS01 (Mosquirix) against malaria - 29%effective (57% against severe disease)

- December 2023 R21 vaccine - improved adjuvant, 70-80% efficacy

- Protection can wane quickly

Parasite Incidence

DIAGRAM ON SLIDE 3

Example of Outbreak of Parasitic Disease

DIAGRAM ON SLIDE 4 (whole slide)

Which country has the highest incidence of the roundworm Strongyloides

Australia

Except - Leishmanisation

- Variolation and First vaccine Edward Jenner 1796 for smallpox is not the first vaccine

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- Leishmanisation predates the 1700s and probably dates back over 1000 years. Inoculation of live parasites into the buttock

- Good news is that it works

- Bad news is that it only works as the parasites remain with you for life

When was the last new anti-helminth drug licensed for humans

DIAGRAM ON SLIDE 8

What is a parasite

PARASITES:

- are much smaller than their hosts

- Are all eukaryotes (like you and me)

- in many cases, it's difficult to demonstrate that the host is harmed, but most

- reduce host fitness: exploit hosts for food, habitat, dispersal.

- show a high degree of specialization

- reproduce more quickly in greater numbers than hosts - faster to adapt

Why do you need to know about parasites?

BECAUSE SOME ARE MAJOR CAUSES OF HUMAN AND ANIMAL DISEASE

- there are many major human pathogens

- Often, but no means exclusively in tropical or less- developed countries

- And others are very dangerous to immunocompromised people

- Because they are eukaryotic and are related (very distantly) to you, they are often very difficult to treat!

True impact of parasitic diseases

DIAGRAM ON SLIDE 11

Are parasites a serious problem

DIAGRAM ON SLIDE 12

Opportunistic Parasites

- Eukaryotic organisms that are generally not pathogenic or that can reoccur from a quiescent stage, harmless to the immunocompetent, lethal to the immunocompromised

- the AIDs epidemic has reminded us that pathogenicity depends on the host as well as the organism

- should we call these organisms human pathogens?

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Immunosupression can be due to:

- other infections (AIDS)

- cancer

- Drug or radiotherapy (in organ transplant or cancer traetment)

- More subtle, due to age or even pregnancy

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- many are quiescent, re-emerge many years later

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- quiescent means dormant

Parasite Life Cycles

ALL PARASITES PASS THROUGH A SERIES OF DEVELOPMENTAL STAGES TO COMPLETE THEIR LIFE CYCLES

- Direct = only one host in life cycle (basically means one person gives parasitic infection to another)

- Indirect = Two or more host required

- Definitive or primary host - where parasite reaches maturity and undergoes sexual reproduction

- Reservoir host - can harbour pathogen often with minimal effect

- Secondary or intermediate host - where the parasite usually undergoes asexual reproduction

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- have both asexual and sexual reproduction(which normally occurs in definitive host).

Direct Transmission

- Passed directly from one infected host to another by some physical means or by direct invasion by the parasite

Food or Waterborne Transmission

- just an example of transmission

Intermediate Host or Vector (Transmission)

- Very common amongst parasites

- The stage where the sexual stages of the life cycle take place is the definitive host - may or may not be the human

- Sometimes just mechanical but usually one or more essential life-cycle stages take place here

- The distinction between intermediate host and vector is fairly arbitrary and depends on size, speed of movement and active involvement - e.g. a pig versus a mosquito!

Protozoan Parasites

- single celled

- Intracellular - difficult to treat (they have capacity to enter host cell, which is why its difficult to treat)

- Extracellular - poor immune response (a lot of parasites live in the gut, and elicit poor immune response)

- Co-evolution (co-evolved with humans)

Protozoan parasites of humans

- you can get a parasitic infection anywhere in the body

Protozoan parasites direct transmission

Very few protozoal pathogens in humans are spread by direct contact, most are by either a vector or by consuming contaminated food or water.

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Trichomonas vaginalis - very common ~200 million cases per year, commonest sexually transmitted disease

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Acanthamoeba spp. - uncommon condition - can cause encephalitis and keratitis (more common since the 1980s due to the use of contact lenses

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Primary amoebic encephalitis Naegleria fowleri - very uncommon (could also be described as water borne) - 99% fatal even with aggressive treatment. Very few protozoal pathogens in humans are spread by direct contact, most are by either a vector or by consuming contaminated food or water.

Food and water borne parasites

GIARDIASIS - Giardia intestinalis

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Amoebiasis - Entamoeba histolytica (amoebic dysentry - common in low income countries)

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Cryptosporidiosis - Cryptosporidium

- Parvum + hominis - common globally, outbreaks occur frequently in Australia associated with swimming pools. Causes deadly infections in immunocompromised people

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Toxoplasmosis - Toxoplasma gondii

- Most successful parasite ever, 30% of world population is infected, no country is free of the diseases. Infects every mammal and every nucleated cell type - infection for life

Vector Borne Protozoan Parasites

MALARIA

- plasmodium spp - biggest killer

BABESIOSIS

- Zoonosis, mild infections, tick borne

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LEISHMANIASIS

- Leishmania spp - most pleitropic disease

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CHAGAS DISEASE

- Trypanosoma cruzi - silent killer

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SLEEPING SICKNESS

- trypanosoma brucei gambiensie/rhodesiense

- Fatal without treatment, tertiary stage uses the only arsenical drug licensed

Anti-protozoan drugs

THE ONES YOU SHOULD REMEMBER:

- Paromomycin 1960: Good general anti protozoal drug for amoebiasis, giardiasis, leishmaniasis. Protein synthesis inhibitor

- Metronidazole/ Tinidazole 1960/1972: Antibiotic used to treat enteric protozoan pathogens, inhibit nucleic acid synthesis

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THE OTHERS YOU DONT REALLY HAVE TO RMBR

- Pentavalent antimony - 1929 - meglutamine antimonial. Sodium stibogluconate - Frontline drug for leishmaniasis, mode of action unclear

- Nitazoxanide - 1980s - Alina - Broad spectrum anti parasitic, only drug for cryptosporidiosis, interferes with pyruvate and ferredoxin oxidoreductase

- Nifurtimox - 1965 - Lampit - One of only two drugs active against Chagas disease

- Eflornithine - 1990 - Used to treat African trypanosomiasis (T gambiensie only), blocks ornithine interactions

- Melarsoprol - 1949 - - Only arsenical licensed for human use, for African trypanosomiasis. Will directly kill 2-8% of patients

Helminth parasites

- Complex, multicellular, much larger

- Extracellular (except for one - Trichinella spp)

- Large genomes, very immunogenic

- Can survive for decades

- Drugs are toxic

Helminth Parasites IMAGE

- can infect almost everywhere in body

Helminths - more common then you think

- present in every environment on earth

- 342 infect humans (Crompton 1999)

- Global problem, higher incidence in tropics

- Over half the worlds population infected

Parasites and Health - Helminth infections and atopy/asthma

The association of helminth infections with protection against asthmaand atopy.

- 1913 Herrick " Common to both bronchial asthma and roundworm infestation is anincrease of the eosinophils of the blood, one day we will ask the significance ofthis" - not until 1986 was this revisited with publication of hygiene hypothesis byGodfrey in the Lancet.

- Asthma and other allergies high in developed nations, low in developing countries,Helminth infections low in developed countries, high in developing countries.

- Successful use of helminth therapy for asthma

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- basically shows that parasites can benefit humans

Parasites and Health - Helminth infctions and IBD (Crohn's and UC)

- Lack of exposure to helminths in developed world has led to increased incidence of IBD, Crohn's and ulcertaive colitis and other autoimmune like disorders.

- IBD more common in people with high socioeconomic status

- Use of Trichuris suis and Necator americanus improve IBD

- Search for non-live worm antigens to treat these diseases

- Review - Shi W et al 2022 in Journal of Inflammation Research. Helminth infections and IBD (Crohn's and UC)

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- not super important

Studies published on therapeutic use of helminths

DIAGRAM ON SLIDE 26

Which worm has contributed more to medical science then any other? Which worm has contributed to 3 Nobel Prizes (2002, 2006, 2008)? Which worm has been to space twice (and back) and survived the Columbia space shuttle disaster/

Caenorhabditis elegans

Caenorhabditis elegans

NEMATODES (NEMATODA)

- Possibly one of the most important nematodes for medicine

- Nematode used in research

- Transparent, emit blue/green fluorescence when they die

- Subject of three Nobel Prizes

- Only worm in space

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- the reason its so good for research is becasuse they are super similar to humans

Nematodes - Round worms

NEMATODES (NEMATODA)

Second largest phylum in animal kingdom~25,000 described (1 million species predicted)~ half are parasitic (humans, animals, plants, insects)<1mm to > 1 meter in length

Cylindrical, are dioecious (male& female), have 'teeth'

Have an open intestine and nervous system and body cavity

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GASTROINTESTINAL

- Ascaris lumbricoides

- Trichuris trichura

- Hookworms

- Strongyloides stercoralis

- Enterobius vermicularis

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TISSUE OR BLOOD:

- Toxocara canis

- Trichinella spiralis

- Filarial worms

- Guinea worm

Gastrointestinal Nematodes

- Commonest worm infections

- 3.5 Billion people infected (50% of worlds pop)

- 450 million seriously ill (mainly children)

- 125,000 deaths per year, 39 million DALYs (basically total number of years of life lost)

- Situation unchanged for 50 years

- No intermediate host, not zoonotic

- Eggs or larvae infect humans

- Ingested or larvae burrow into skin

Gastrointestinal Nematodes EXAMPLES

- Ascaris lumbricoides - 1 billion infected, ~ 3,000 deaths/yr - Hookworms- Ancyclostoma duadenale and Necator americanus. ~700 million infected, 22 million DALYs lost

- Trichuris trichura - whipworm, 600 million infected

- Strongyloides stercolis- Only free living helminth

- Enterobius vermicularis - Pinworm, global occurrence, common infection in children (pruritus - itchy bum)

Tissue Nematodes

- Filarial worms (filiraisis) - Lymphatic filiariasis - Wuchereria bancrofti, Brugia malayi, Brugia timori - Elephantiasis - 120 million infected - Subcutaneous filiariasis - Onchocerca volvulus (river blindness) 37 million infected, Loa Loa

- Trichinella spiralis - Only intracellular helminth

- Guinea Worm - Dracunculus medinesis - next disease to be eradicated - 1986 3.5 million, 2015 = 22 cases, 2024 = 13 cases

- Toxocara canis - worm often targets the eye, from dogs

Cestodes - tapeworms

- Haemaphrodite - worm has male + female reproductive organs

- Body composed of segments or proglottids, no body cavity

- Adults attach to gut by scolex, have a closed intestine

- Live for decades

- Intestinal worms asymptomatic, tissue stages cause pathology

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INTESTINAL TAPEWORMS

- Taenia solium (pork TW)*

- Taenia saginata (beef TW)

- Diphyllobothrium latum (fish TW)• Hymenolepis nana (dwarf TW)

- Hymenolepis diminuta (Rat TW)

- Exists as worms in intestine

- *can also form cysts in tissues

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TISSUE TAPEWORMS:

- Echinococcus granulosis (Dog TW)

- Echinococcus multilocularis

- Spargenosis (Spirometra spp)

- Form cysts in the tissues

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- example of tissue tapeworms is the ones in raw pork

Trematodes - flukes

- Tissue flukes - Simultanoeus Haemaphrodite - have male and female reproductive organs, closed intestine

- Schistosomes are dioecious (separate sexes)

- Complex life cycles (primary vertebrate host, intermediate invertebrate host

- Obligate parasites

- Live for decades

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BLOOD FLUKES (SCHISTOSOMES)

- Schistosoma mansoni (gut)

- Schistosoma haematobium (bladder)

- Schistosoma japonica (gut)

- Pathology caused by eggs

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TISSUE (LIVER) FLUKES

- Fasciola hepatica (Liver fluke)

- Clonorchis (Opisthorchis) sinensis

- Opisthorcus viverrini

- Paragonimus westermani

- Live in organs - liver, lung, carcinogenic!

Anti Helminthic drugs

- Benzimidazole family- 1962- triclabendazole, albendazole, mebendazole, thiabendazole, flubendazole ( Treats enteric nematode infections and some systemic tape worm infections)

- Praziquantal - 1970 (not licensed for humans in UK) - Treat Schistosomiasis and fluke infections, paralyses worms

- Macrocyclic lactones - (1978) Avermectin, Ivermectin ( Onchocerciasis, Strongyloides, Filariasis (scabies)

- Diethylcarbamazine - 1947 - Treat filarial worms, may not cure infection

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- should remember albendazole, praziquantal and ivermectin

- ivermectin is used to treat the things listed next to it, but it cannot treat covid

Treatments for helminths - bad news

Why are there so few drugs and why no recent drug development?

1. Helminths are eukaryotes - similar metabolic pathways to humans - drugs are toxic

2. More prevalent in the tropics, countries that have limited resources - drug companies cannot make a profit - No drug development (there is more money in veterinary use - e.g. 2009, Novartis new class of drugs for use in sheep No Vaccines, no prophylaxis

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- basically there are no vaccines for helminths, and no prophylaxis for any helminth infection

Treatments for

1. The drugs are cheap, readily available*:

- Praziquantel - $0.20, Albendazol $0.20, Benzimidazole $0.10 --- Cup of coffee $4.00

2. Most of the drugs can target several helminths• = Cost to health agencies treating people in highly endemic areas, much more expensive in wealthy countries. All these drugs are on the WHO list of essential medicines

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- Suggested global drug regime of simultaneous administration of praziquantel and benzimidazole would treat the main intestinal nematodes and schistosomiasis! Patients get re-infected!

Neglected diseases

MOST PARASITIC INFECTIONS COME UNDER THE CATEGORY OF NEGLECTED DISEASES

- Most people with the diseases are poor

- Drugs are often toxic, require monitoring

- Little incentive for drug companies to devleop drugs

Neglected diseases - a question of profits

DIAGRAM ON SLIDE 39 (whole slide)

Summary of parasites

- ones in bold are the ones that will be covered in nxet lecture

Example MCQ questions

- Answers:

Trichomonas

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Leishmanisation

Exampke Short Answer Questions

- we only have 2 and they are for the same disease

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- no answer for the second one

• Cestodes (tapeworms) and nematodes (roundworms) are both parasitic worms, but differ significantly in structure: cestodes are flat, segmented, and lack a digestive system (absorbing nutrients directly), while nematodes are round, unsegmented, and possess a complete digestive tract