Extra-intestinal coccidians Apicomplexa Coccidia Gregarinea Piroplasmida Eimeriida Haemosporida -Theileriidae - Babesiidae - Eimeriidae - Cryptosporidiidae - Sarcocystidae (Sarcocystis) (Toxoplasma) -Haemosporiidae (Plasmodium) Similarities Global distribution of these parasites Indirect life cycles - intermediate hosts heteroxenous Life cycle has both intestinal and tissue stages Infective stage Oocyst Tissue cyst Sacrocystis cruzi Definitive host Carnivorous - canine Intermediate host Obligatory herbivorous bovine Toxoplasma Definitive host Feline Intermediate host Non-obligatory Wild animals Domestic animals humans 1
Sarcocystosis (many species) Cosmopolitan distribution Prevalence - near 100% in cattle Meat at slaughter houses is condemned for human consumption if heavily infected Infective: Oocysts Tissue cysts Intermediate hosts suffer symptoms Definitive host does not suffer pathology Sexual reproduction Merozoites invade the epithelium of small intestine and immediately form gamonts Why Study Toxoplasma? Signficant cause of congenital birth defects Important opportunistic pathogen in AIDS patients Serious livestock pathogen Good apicomplexan model system 2
Toxoplasmosis Cosmopolitan distribution Seropositive prevalence 15-75% (US is ~22%) Generally quite benign disease in healthy people Headache, fever, sore throat Ocular involvement in rare occasions Zoonosis Two situations can produce sever disease Impaired immune system Primary infection during pregnancy Toxoplasmic encephalitis Congenital toxoplasmosis Acquired Toxoplasmosis 1-4 week incubation period acute parasitemia persists for several weeks until development of tissue cysts often asymptomatic (>80%) a common symptom is lymphadenopathy without fever occasionally mononucleosis-like symptoms (fever, headache, fatigue, myalgia) likely persists for life of patient immunosuppression can lead to reactivation (eg., organ transplants) 3
Toxoplasma is an opportunistic pathogen 15-70% of the adult population is chronically infected (current rate in the US is 21.5%) Most people show no or only benign symptoms (head ache, sore throat, lymphadenitis, fever) In rare case ocular involvement Two situations can lead to severe disease: loss of a functional immune system and primordial infection during pregnancy Congenital Toxoplasmosis Incidence is ~ 1/1000 births Primary infection must occur during or shortly before pregnancy Probability and severity of disease depends on when infection occurs Can only occur once Early: low transmission - high severity Late: high transmission - low severity Children can be asymptomatic at birth but develop symptoms later Can result in spontaneous abortion, splenomegaly, fever, anemia, intracebral calcification, mental retardation 4
Congenital Toxoplasmosis Treatment against parasites as well as symptoms can be successful Despite calcification throughout the brain the 10 month old child underwent normal development Prevalences of Outcomes 5-10% death 8-10% severe brain and eye damage 10-13% moderate-severe visual impairment 58-72% asymptomatic at birth, many developing retino-choroiditis or mental impairment Toxoplasmic encephalitis (TE) 25% of all seropositive AIDS patients develop severe Toxoplasmic encephalitis. TE can be treated with pyrimethamine and sulfadrugs but not all patients tolerate side effects. In the majority of cases this is due to reactivation of the chronic infection rather than a new infection. Symptoms include lethargy, apathy, incoordination, dementia. Tissue cyst from rat brain 5
Toxoplasmosis treatment Antifolates Pyrimethamine pyrimidine starvation DHFR inhibitor Sulfonamides Sulfadiazine Inhibits folic acid biosynthesis Other drugs Clindamycin Translation inhibitor (prokaryotic) Ciprofloxacin (not approved) DNA gyrase inhibitor (topoisomerase) Typical treatment involves using both antifolates to act synergistically. Sulfa drugs are excreted rapidly (within hrs) so that repeated doses daily are required Drugs tolerated well! Toxoplasma Life Cycle Definitive Host Unsporulated oocyst Infective Cysts containing bradyzoites Tachyzoites transmitted through placenta Intermediate Host Sporulated oocyst Infective 6
Toxoplasma Life cycle Definitive Host Intestinal phase in the cat Important: most healthy cats shed oocysts during an acute infection, but will not shed them later. Tissue cyst Bradyzoite Cat ingests tissue cysts containing bradyzoites Number of merogonous cycles is variable Gametocytes develop in the small intestine but are more common in the ileum 2-4% of gametocytes are male, each produces around 12 microgametes Oocysts appear in the cat s feces 3-5 days after infection with peak production around 5 and 8 Cats can shed oocysts for up to two weeks Oocysts require oxygen and they sporulate in 1-5 days Oocyst 7
Does the cat have to go if you are pregnant? Avoid raw or undercooked meat. (Cooking kills Toxoplasma) Wash raw fruits and vegetables well before eating. Remove feces from the litter box every day, to eliminate any parasites before oocysts sporulate Keep cats indoors to prevent hunting. Cats can become infected by eating infected rodents or birds. Feed cats only commercial food or well-cooked meat. Do not feed cats raw or undercooked meat. Do not adopt cats who have lived outdoors. Do not handle stray cats. Wash hands well with soap and warm water after: Gardening Yard Work Any Other Outdoor Activity Involving Contact With Soil that could be contaminated with cat feces There is no treatment available to prevent Toxoplasma in cats, or to prevent an infected cat from shedding the parasite in its stool. Oocysts can survive in the environment for many months (moisture, shade, in soil or sand). Bradyzoite stage Dormant, persistent state Months or even years Tissue cysts primarily in brain and muscle Chronic or latent infections Slowly dividing stage Cysts are highly infective Bradyzoites are resistant to low ph and digestive enzymes Only stage that will initiate sexual reproduction Bradyzoites are resistant to all current drugs 8
Tachyzoite stage Crescent shaped - 2 x 6 µm Rapidly dividing merozoites Acute infections Asexual replication Repeated rounds of merogony Not resistant to low ph Stage that is involved in vertical transmission to fetus Fatal Feline Attraction Mice infected w/ Toxoplasma wonder around and bring attention to themselves!! Possible changes is sensory attraction to cats - attracted!! Humans with schizophrenia are correlated with a higher incedence of Toxoplasma infections Drug Haloperidol can reverse the fatal feline atrraction in mice infected with Toxoplasma contains 2 genes for dopamine biosynthesis 9