Protozoan Diseases

1. Protozoan Diseases • Protozoans are unicellular eukaryotic organisms • Responsible for several serious human diseases: ameobiasis, Chaga’s disease, malaria,African sleeping sickness, leishmaniasis, and taxoplasmosis. • Type of immune response that develops depends (in part) on the location of the parasite in the host. • Bloodstream: humoral antibody most effective • Intracellular: cell-mediated immune reactions

2. Got Malaria? Plasmodium • Carried by the Anopheles mosquito • P. falciparum– most virulent and prevalent • Rate of multi-drug resistance in Plasmodium as well as resistance to DDT by the mosquito increase the spread of malaria and call for new strategies. • http://www.rph.wa.gov.au/labs/haem/malaria/history.html • http://www.cdc.gov/travel/malinfo.htm

3. Malaria. . . Plasmodium life cycle • ♀ Anopheles mosquito feeds on blood & serves as the vector. • Sporozites enter blood stream and proceed to the liver within 30 min to infect hepatocytes • Circumsporozite (CS), 45-kDa protein helps with adhesion to liver cells. The binding site, a conserved region on the carboxyl terminal end (reg II) has a high degree of sequence homology with known cell adhesion molecules. http://www.who.int/inf-fs/en/1InformationSheet03.pdf

4. Malaria. . . • 1 week = Multiplication & transformation in the liver leads to the release of about 5,000-10,000 merozites PER HEPATOCYTE infected with only one sporozite! • Merozites infect red blood cells, initiating the symptoms and pathology of malaria. • Merozites replicate and differentiate again • Cell ruptures to release new merozites (which will infect more red blood cells) • Some merozites differentiate into ♂ and ♀ gametocytes. • Gametocytes ingested by Female Anopheles differentiate into male and female gametes which fuse to form a zygote and become sporozites in the salivary gland…. • Wash, Rinse, Repeat…

5. Malaria. . . • Chills, fever, sweating—peak every 48hrs • Weak, anemic, splenomegaly • Blocked capillaries = intense headaches, renal failure, heart failure, or cerebral damage • Some symptoms may not be caused by Plasmodium but by excessive production of cytokines • Cancer patients treated with recombinant TNF show similar symptoms

6. Immune Response to Malaria • Where malaria is endemic, IR is poor. Children < 14yrs have lowest IR and are most likely to develop malaria. Mortality rate 50% in some regions; about 1million children a year die of malaria. • Only 22% of children in endemic regions have detectable antibodies to the sporozite stage, 84% of adults have such antibodies. • Most people in endemic regions have life long low-level Plamsmodium infections. Malaria in the placenta

7. Low-Level Immune Response. . . • Changes from sporozite to merozoite to gametocyte allow for changing of surface molecules. So, antigens seen by immune system are continually different. • Intracellular phases (hepatocytes & erythrocytes) reduce the degree of immune activation. Plasmodium is allowed to multiply while shielded from attack. • Sporozite stage, most susceptible to IR circulates for only 30 min. • Plasmodium can slough off surface CS Ag coat, rendering Ab ineffective.

8. Malaria Vaccine? • Current approaches focus on sporozite stage. (Eg: Sporozites attenuated by x-rays used for vaccine) • Impractical. Sporozites do not breed well in culture, so mosquito populations need to be bred. Yeah, lets breed mosquitoes. Great idea…

9. African sleeping sickness…ZZZZzzzz Trypanosoma • Flagellated protozoans—2 species • TseTse fly carries • Stages: • Systemic: multiplies in blood • Progresses to neurological stage, infects central nervous system → meningoencephalitis (big word, must be bad…) • Loss of consciousness. Hence, the SLEEP part. http://www.biosci.ohio-state.edu/~parasite/lifecycles/trypanosoma_lifecycle.html

11. AFS Immune Response • Humoral response to glycoprotein coat (variant surface glycoprotein VSG) • Most of the parasite is eliminated from the blood… • BUT, 1% escape (because they’re wearing a different coat)…all hell breaks loose! • Survivors proliferate and a new wave of parasitemia is observed. • Antigenic shift allows trypanosomes to evade immune system • Each new variant can escape humoral Ab generated for the preceeding variant.

12. Sneaky sneaky. . . Variation in VSG • Trypanosomes carry a HUUUGE number of VSG genes • Activation of VSG gene= duplication & transposition to expression site at the telomeric end of a specific chromosome • Activation of new gene displaces previous gene • Each new variant arises from the growth of multiple cells that have activated the same VSG gene in the current wave. • Continual shifts in the epitope displayed by the VSG make vaccine development difficult.

13. Leishmaniasis Leishmania major • Lives in the phagosomes of macrophages • Resistence correlates with IFN-γ and development of TH 1 response. • Loss of IFN-γ or IFN-γ receptor = fatality • BALB/c mice mount TH 2 response = high IL-4 but no IFN-γ • BALB/c CD4+ Tcells can see a particular epitope on L.major and produce high IL-4 early in the response. This skews the response to TH 2 and the mice die……

14. SAY CHEESE!!! Leishmania Ulcer

15. Parasitic Worms… mmm mmm good Helminths • Large, multicellular organisms • Reside in humans, but do not usually replicate there • NOT intracellular • Most infected individuals carry few, immune system not heavily engaged, level of immunity generated is often poor

16. A Plethora of Disease… • >1 billion have Ascaris, a roundworm in the small intestine • >300 million infected with Schistosoma, trematode worm causing debilitating infection • Taenia—tapeworm of cattle and pigs • Trichinella—roundworm of pigs causing Trichinosis …just to name a few

17. Ascaris Taenia

18. Schistosomiasis 3 major species: • S. mansoni (intestinal mesenteric veins) • S. japonicum (intestinal mesenteric veins) • S. haematobium (urinary bladder veins) Africa, Middle East, S. America, Caribbean, China, S.E. Asia *Increase in irrigation has expanded the habitat of the fresh water snail, the intermediate host.

19. Attack of the Killer Snails!!! • Snails release 300-3000 cercariae (free swimming larvae) • Cercariae secrete digestive enzymes and bore into skin • Lose tail → schistosomules • Enter cappillaries → lungs → liver →main infection site (depending on species) • Mature into ♀and ♂ worms → mate • ♀produces 300 spiny eggs/day

20. Attack of the Killer Snails!!! • Eggs do not mature—some get into feces & urine where, upon excretion, they infect more snails • # of worms in the individual increases only with repeated exposure • Most symptoms initiated by the eggs…

21. SYPMTOMS • ½ the eggs can remain: invade intestinal wall, liver, or bladder → hemorrhage • Unexcreted eggs induce cell-mediated delayed type hypersensitvity. Large granulomas are formed and walled off by fibrous tissue • Granulomas often obstruct venous blood flow to the liver or bladder.

22. Immune Response • No IR to Schistomosomes; survive for up to 20 years evading attack of localized cellular buildup of immune and inflammatory cells • Several mechanisms of defense: decrease Ag expression, Cover in glycolipid/protein coat from the host → host’s own ABO blood group antigens are on the worm’s body along with histocompatibility antigens

23. For All You Hypochondriacs Possible signs and symptoms of internal parasites: Feel tired most of the time (Chronic Fatigue)? Have digestive problems? (gas, bloating, constipation or diarrhea that come and go but never really clear up) Have gastrointestinal symptoms and bulky stools with excess fat in feces? Suffer with food sensitivities and environmental intolerance? Developed allergic-like reactions and can’t understand why? Have joint and muscle pains and inflammation often assumed to be arthritis? Suffer with anemia or iron deficiency (pernicious anemia)? Have hives, rashes, weeping eczema, cutaneous ulcers, swelling, sores, papular lesions, itchy dermatitis? Suffer with restlessness and anxiety? Experience multiple awakenings during the night particularly between 2 and 3 am? Grind your teeth? Have an excessive amount of bacterial or viral infections? Depressed? 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 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? itchy ears, nose, anus forgetfulness, slow reflexes, gas and bloating, unclear thinking; loss of appetite, yellowish face fast heartbeat, heart pain, pain in the navel; eating more than normal but still feeling hungry; pain in the back, thighs, shoulders; lethargy; numb hands; burning sensation in the stomach; drooling while sleeping; damp lips at night, dry lips during the day, grinding teeth while asleep; bed wetting; women: problems with the menstrual cycle; 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.

24. For your enjoyment. . .And because I’m supposed to be writing a term paper • http://www.curezone.com/diseases/parasites/default.asp

25. WARNING: The following images are graphic and offensive in nature. They are unnecessary but really cool. Please take care and remove children from the room.