Protozoan DiseasesProtozoan Diseases

• Protozoans are unicellular eukaryotic organismsProtozoans are unicellular eukaryotic organisms

• Responsible for several serious human diseases: Responsible for several serious human diseases: ameobiasis, Chaga’s disease, ameobiasis, Chaga’s disease, malaria,malaria, African African sleeping sickness, leishmaniasissleeping sickness, leishmaniasis, and , and taxoplasmosis.taxoplasmosis.

• Type of immune response that develops depends Type of immune response that develops depends (in part) on the location of the parasite in the host.(in part) on the location of the parasite in the host.

•Bloodstream: humoral antibody most effectiveBloodstream: humoral antibody most effective• Intracellular: cell-mediated immune reactionsIntracellular: cell-mediated immune reactions

Got Malaria? Got Malaria?

PlasmodiumPlasmodium• Carried by the Carried by the

Anopheles Anopheles mosquito mosquito • P. falciparum–P. falciparum– most most

virulent and prevalentvirulent and prevalent

• Rate of multi-drug Rate of multi-drug resistance in resistance in PlasmodiumPlasmodium as well as as well as resistance to DDT by resistance to DDT by the mosquito increase the mosquito increase the spread of malaria the spread of malaria and call for new and call for new strategies.strategies.•http://

www.rph.wa.gov.au/labs/haem/malaria/history.html•http://www.cdc.gov/travel/malinfo.htm

Malaria. . . Malaria. . .

Plasmodium life Plasmodium life cyclecycle

• ♀ ♀ Anopheles Anopheles mosquito feeds on mosquito feeds on blood & serves as the vector.blood & serves as the vector.

• Sporozites enter blood stream Sporozites enter blood stream and proceed to the liver within and proceed to the liver within 30 min to infect hepatocytes30 min to infect hepatocytes

• Circumsporozite (CS), 45-Circumsporozite (CS), 45-kDa protein helps with kDa protein helps with adhesion to liver cells. adhesion to liver cells. The binding site, a The binding site, a conserved region on the conserved region on the carboxyl terminal end carboxyl terminal end (reg II) has a high degree (reg II) has a high degree of sequence homology of sequence homology with known cell adhesion with known cell adhesion molecules.molecules.

http://www.who.int/inf-fs/en/1InformationSheet03.pdf

Malaria. . .Malaria. . .• 1 week = Multiplication & transformation 1 week = Multiplication & transformation

in the liver leads to the release of about in the liver leads to the release of about 5,000-10,000 5,000-10,000 merozites merozites PER PER HEPATOCYTE infected with only one HEPATOCYTE infected with only one sporozite!sporozite!

• Merozites infect red blood cells, initiating Merozites infect red blood cells, initiating the symptoms and pathology of malaria.the symptoms and pathology of malaria.

• Merozites replicate and differentiate Merozites replicate and differentiate againagain

• Cell ruptures to release new merozites Cell ruptures to release new merozites (which will infect more red blood cells)(which will infect more red blood cells)

• Some merozites differentiate into Some merozites differentiate into ♂♂ and and ♀♀ gametocytes. gametocytes.

• Gametocytes ingested by Female Gametocytes ingested by Female Anopheles differentiate into male and Anopheles differentiate into male and female gametes which fuse to form a female gametes which fuse to form a zygote and become sporozites in the zygote and become sporozites in the salivary gland….salivary gland….

• Wash, Rinse, Repeat…Wash, Rinse, Repeat…

Malaria. . .Malaria. . .

• Chills, fever, sweating—Chills, fever, sweating—peak every 48hrspeak every 48hrs

• Weak, anemic, Weak, anemic, splenomegalysplenomegaly

• Blocked capillaries = Blocked capillaries = intense headaches, renal intense headaches, renal failure, heart failure, or failure, heart failure, or cerebral damagecerebral damage

• Some symptoms may not Some symptoms may not be caused by be caused by PlasmodiumPlasmodium but by excessive production but by excessive production of cytokinesof cytokines– Cancer patients treated Cancer patients treated

with recombinant TNF with recombinant TNF show similar symptomsshow similar symptoms

Immune Immune ResponseResponse to Malaria to Malaria• Where malaria is endemic, IR Where malaria is endemic, IR

is poor. Children is poor. Children < 14yrs < 14yrs have lowest IR and are most have lowest IR and are most likely to develop malaria. likely to develop malaria. Mortality rate 50% in some Mortality rate 50% in some regions; about 1million regions; about 1million children a year die of malaria.children a year die of malaria.

• Only 22% of children in Only 22% of children in endemic regions have endemic regions have detectable antibodies to the detectable antibodies to the sporozite stage, 84% of sporozite stage, 84% of adults have such antibodies.adults have such antibodies.

• Most people in endemic Most people in endemic regions have life long low-regions have life long low-level level PlamsmodiumPlamsmodium infections.infections.

Malaria in the placenta

Low-Level Immune Response. . Low-Level Immune Response. . ..• Changes from sporozite to merozoite to Changes from sporozite to merozoite to

gametocyte allow for changing of surface gametocyte allow for changing of surface molecules. So, antigens seen by immune molecules. So, antigens seen by immune system are continually different.system are continually different.

• Intracellular phases (hepatocytes & Intracellular phases (hepatocytes & erythrocytes) reduce the degree of immune erythrocytes) reduce the degree of immune activation. activation. PlasmodiumPlasmodium is allowed to is allowed to multiply while shielded from attack.multiply while shielded from attack.

• Sporozite stage, most susceptible to IR Sporozite stage, most susceptible to IR circulates for only 30 min.circulates for only 30 min.

• Plasmodium can slough off surface CS Ag Plasmodium can slough off surface CS Ag coat, rendering Ab ineffective.coat, rendering Ab ineffective.

Malaria Vaccine?Malaria Vaccine?

• Current approaches focus on sporozite Current approaches focus on sporozite stage. (Eg: Sporozites attenuated by stage. (Eg: Sporozites attenuated by x-rays used for vaccine)x-rays used for vaccine)

• Impractical. Sporozites do not breed Impractical. Sporozites do not breed well in culture, so mosquito well in culture, so mosquito populations need to be bred.populations need to be bred.

Yeah, lets breed mosquitoes. Great idea…Yeah, lets breed mosquitoes. Great idea…

African sleeping sickness…African sleeping sickness…ZZZZZZZZzzzzzzzz

TrypanosomaTrypanosoma• Flagellated protozoansFlagellated protozoans

—2 species—2 species• TseTse fly carriesTseTse fly carries• Stages:Stages:

– Systemic: multiplies in Systemic: multiplies in bloodblood

– Progresses to neurological Progresses to neurological stage, infects central stage, infects central nervous system nervous system

→ → meningoencephalitis meningoencephalitis (big (big word, must be bad…)word, must be bad…)

– Loss of consciousness. Loss of consciousness. Hence, the SLEEP part.Hence, the SLEEP part.

http://www.biosci.ohio-state.edu/~parasite/lifecycles/trypanosoma_lifecycle.html

AFS Immune ResponseAFS Immune Response• Humoral response to Humoral response to

glycoprotein coat (variant glycoprotein coat (variant surface glycoprotein VSG)surface glycoprotein VSG)

• MostMost of the parasite is of the parasite is eliminated from the blood…eliminated from the blood…

• BUT, 1% escape (because BUT, 1% escape (because they’re wearing a different they’re wearing a different coat)…all hell breaks loose!coat)…all hell breaks loose!

• Survivors proliferate and a Survivors proliferate and a new wave of parasitemia is new wave of parasitemia is observed.observed.

• Antigenic shift allows Antigenic shift allows trypanosomestrypanosomes to evade to evade immune systemimmune system

• Each new variant can Each new variant can escape humoral Ab escape humoral Ab generated for the generated for the preceeding variant.preceeding variant.

Sneaky sneaky. . .Sneaky sneaky. . .Variation in VSGVariation in VSG• Trypanosomes Trypanosomes carry a carry a

HUUUGE number of VSG genesHUUUGE number of VSG genes• Activation of VSG gene= Activation of VSG gene=

duplication & transposition to duplication & transposition to expression site at the expression site at the telomeric end of a specific telomeric end of a specific chromosomechromosome

• Activation of new gene Activation of new gene displaces previous genedisplaces previous gene

• Each new variant arises from Each new variant arises from the growth of multiple cells the growth of multiple cells that have activated the same that have activated the same VSG gene in the current wave.VSG gene in the current wave.

• Continual shifts in the epitope Continual shifts in the epitope displayed by the VSG make displayed by the VSG make vaccine development difficult.vaccine development difficult.

LeishmaniasisLeishmaniasisLeishmania majorLeishmania major• Lives in the phagosomes of Lives in the phagosomes of

macrophagesmacrophages• Resistence correlates with Resistence correlates with

IFN-IFN-γγ and development of and development of TTH H 1 response.1 response.

• Loss of Loss of IFN-IFN-γγ or or IFN-IFN-γγ receptor = fatalityreceptor = fatality

• BALB/c mice mount TBALB/c mice mount TH H 2 2 response = high IL-4 but response = high IL-4 but no no IFN-IFN-γγ

• BALB/c CD4+ Tcells can BALB/c CD4+ Tcells can see a particular epitope on see a particular epitope on L.majorL.major and produce high and produce high IL-4 early in the response. IL-4 early in the response. This skews the response to This skews the response to

TTH H 2 and the mice die……2 and the mice die……

SAY CHEESE!!!SAY CHEESE!!!

Leishmania Ulcer

Parasitic Worms… Parasitic Worms… mmm mmm mmm mmm goodgood

HelminthsHelminths

• Large, multicellular organismsLarge, multicellular organisms

• Reside in humans, but do not usually Reside in humans, but do not usually replicate therereplicate there

• NOT intracellularNOT intracellular

• Most infected individuals carry few, Most infected individuals carry few, immune system not heavily engaged, immune system not heavily engaged, level of immunity generated is often poorlevel of immunity generated is often poor

A Plethora of Disease…A Plethora of Disease…

• >1 billion have >1 billion have AscarisAscaris, a roundworm in , a roundworm in the small intestinethe small intestine

• >300 million infected with >300 million infected with SchistosomaSchistosoma, , trematode worm causing debilitating trematode worm causing debilitating infectioninfection

• TaeniaTaenia—tapeworm of cattle and pigs—tapeworm of cattle and pigs

• TrichinellaTrichinella—roundworm of pigs causing —roundworm of pigs causing Trichinosis Trichinosis

……just to name a fewjust to name a few

Ascaris

Taenia

SchistosomiasisSchistosomiasis

3 major species: 3 major species: – S. mansoni S. mansoni (intestinal (intestinal

mesenteric veins)mesenteric veins)– S. japonicum S. japonicum (intestinal (intestinal

mesenteric veins)mesenteric veins)– S. haematobium S. haematobium (urinary (urinary

bladder veins)bladder veins)

Africa, Middle East, S. Africa, Middle East, S. America, Caribbean,America, Caribbean,

China, S.E. AsiaChina, S.E. Asia

**Increase in irrigation has Increase in irrigation has expanded the habitat of the expanded the habitat of the fresh water snail, the fresh water snail, the intermediate host.intermediate host.

Attack of the Killer Snails!!!Attack of the Killer Snails!!!

• Snails release 300-3000 Snails release 300-3000 cercariae (free cercariae (free swimming larvae)swimming larvae)

• Cercariae secrete Cercariae secrete digestive enzymes and digestive enzymes and bore into skinbore into skin– Lose tail Lose tail → schistosomules→ schistosomules– Enter cappillaries → lungs Enter cappillaries → lungs

→ liver →main infection → liver →main infection site (depending on site (depending on species)species)

– Mature into ♀and ♂ Mature into ♀and ♂ worms → mateworms → mate

– ♀♀produces 300 spiny produces 300 spiny eggs/dayeggs/day

Attack of the Killer Snails!!!Attack of the Killer Snails!!!

• Eggs do not mature—some get into Eggs do not mature—some get into feces & urine where, upon excretion, feces & urine where, upon excretion, they infect more snailsthey infect more snails

• # of worms in the individual # of worms in the individual increases only with repeated increases only with repeated exposureexposure

• Most symptoms initiated by the Most symptoms initiated by the eggs…eggs…

SYPMTOMSSYPMTOMS

• ½ ½ the eggs can remain: invade the eggs can remain: invade intestinal wall, liver, or bladder intestinal wall, liver, or bladder → → hemorrhagehemorrhage

• Unexcreted eggs induce cell-mediated Unexcreted eggs induce cell-mediated delayed type hypersensitvity. Large delayed type hypersensitvity. Large granulomas are formed and walled off by granulomas are formed and walled off by fibrous tissuefibrous tissue

• Granulomas often obstruct venous blood Granulomas often obstruct venous blood flow to the liver or bladder.flow to the liver or bladder.

Immune ResponseImmune Response

• No IR to Schistomosomes; survive for up No IR to Schistomosomes; survive for up to 20 years evading attack of localized to 20 years evading attack of localized cellular buildup of immune and cellular buildup of immune and inflammatory cellsinflammatory cells

• Several mechanisms of defense: Several mechanisms of defense: decrease Ag expression, Cover in decrease Ag expression, Cover in glycolipid/protein coat from the host glycolipid/protein coat from the host → → host’s own ABO blood group antigens are host’s own ABO blood group antigens are on the worm’s body along with on the worm’s body along with histocompatibility antigenshistocompatibility antigens

For All You HypochondriacsFor All You Hypochondriacs

Possible signs and symptoms of internal parasites:Possible signs and symptoms of internal parasites:• Feel tired most of the time (Chronic Fatigue)? Feel tired most of the time (Chronic Fatigue)? • Have digestive problems? (gas, bloating, constipation or diarrhea that come and go but never Have digestive problems? (gas, bloating, constipation or diarrhea that come and go but never

really clear up) really clear up) • Have gastrointestinal symptoms and bulky stools with excess fat in feces? Have gastrointestinal symptoms and bulky stools with excess fat in feces? • Suffer with food sensitivities and environmental intolerance? Suffer with food sensitivities and environmental intolerance? • Developed allergic-like reactions and can’t understand why? Developed allergic-like reactions and can’t understand why? • Have joint and muscle pains and inflammation often assumed to be arthritis? Have joint and muscle pains and inflammation often assumed to be arthritis? • Suffer with anemia or iron deficiency (pernicious anemia)? Suffer with anemia or iron deficiency (pernicious anemia)? • Have hives, rashes, weeping eczema, cutaneous ulcers, swelling, sores, papular lesions, itchy Have hives, rashes, weeping eczema, cutaneous ulcers, swelling, sores, papular lesions, itchy

dermatitis? dermatitis? • Suffer with restlessness and anxiety? Suffer with restlessness and anxiety? • Experience multiple awakenings during the night particularly between 2 and 3 am? Experience multiple awakenings during the night particularly between 2 and 3 am? • Grind your teeth? Grind your teeth? • Have an excessive amount of bacterial or viral infections? Have an excessive amount of bacterial or viral infections? • Depressed? Depressed? • Difficulty gaining or losing weight no matter what you do? Difficulty gaining or losing weight no matter what you do? • Did a Candida program which either didn’t help at all or helped somewhat but you still can’t Did a Candida program which either didn’t help at all or helped somewhat but you still can’t

stay away from bread, alcohol, fruit, or fruit juices? stay away from bread, alcohol, fruit, or fruit juices? • Just can’t figure out why you don’t feel really great and neither can your doctor? Just can’t figure out why you don’t feel really great and neither can your doctor? • itchy ears, nose, anus itchy ears, nose, anus • forgetfulness, slow reflexes, gas and bloating, unclear thinking; forgetfulness, slow reflexes, gas and bloating, unclear thinking; • loss of appetite, yellowish face loss of appetite, yellowish face • fast heartbeat, heart pain, pain in the navel; fast heartbeat, heart pain, pain in the navel; • eating more than normal but still feeling hungry; eating more than normal but still feeling hungry; • pain in the back, thighs, shoulders; pain in the back, thighs, shoulders; • lethargy; lethargy; • numb hands; numb hands; • burning sensation in the stomach; burning sensation in the stomach; • drooling while sleeping; drooling while sleeping; • damp lips at night, dry lips during the day, grinding teeth while asleep; damp lips at night, dry lips during the day, grinding teeth while asleep; • bed wetting; bed wetting; • women: problems with the menstrual cycle; women: problems with the menstrual cycle; • men: sexual dysfunction; men: sexual dysfunction;

These are only possible symptoms, and please keep in mind that not everyone that has a few of these symptoms should automatically make the assumption that they are infected; however, if you suspect infection or have been unsuccessfully treated for a problem, it is worth doing some specific parasite cleansing.

For your enjoyment. . .For your enjoyment. . .And because I’m supposed to And because I’m supposed to be writing a term paperbe writing a term paper

• http://www.curezone.com/diseases/parasites/default.asphttp://www.curezone.com/diseases/parasites/default.asp

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