Toxoplasma gondii

HAL Dopamine D2 Antagonist

- HALs superior therapeutic impact may be through a combination of both its ability to directly inhibit T.gondii replication and to reduce dopamine levels - Identified an enzyme (tyrosine hydroxylase) encoded In T.gondii genome that synthesises L-DOPA

Prey reaction to predators

- T. gondii infected rats more active - T. gondii infected rats are less neophobic (fear of smell) - infected rats have shown no avoidance to cat areas - infected rats = the preference for cat-scented areas increase with rat activity

Hypothesis

- T.gondii can alter host behaviour - some cases of human affective disorders may be caused by T.gondii - anti-psychotic medication work, at least in some part, in inhibit T.gondii

Neurological T. gondii schizophrenia link

- T.gondii persistent in CNS infection and behavioural alterations - neurological and psychiatric symptoms in some T.gondii infected individuals - T.gondii +ve schizophrenia patients express more severe psychosis than T.gondii -ve patients - similar glial cells, especially astrocytes are selectively affected - similar neurotransmitters/neuromodulator changes

Treatment of congenital toxoplasmosis

- all newborns infected with T.gondii should be treated even if they do not have any clinical manifestations of the infection because treatment may be effective in preventing acute disease that damage vital organs - infants should be treated with pyrimethamine, sulfadiazine, leukovorin for 1 year

Haloperidol

- anti-psychotic drug - with in vitro anti-T.gondii tachyzoite properties and a dopamine D2 antagonist - effective as anti-T.gondii drugs and prevention of parasite - modified behaviour traits

Epidemiological T. gondii schizophrenia link

- cat exposure - countries with high levels of T.gondii also have high levels of schizophrenia - T.gondii increases risk of schizophrenia

Treatment for Animals

- cats and other animals after often never treated - sheep have a live vaccine sold as toxovax - no approved vaccine for humans or other animals - genetically engineered vaccine under development for use in cats

The Manipulation Hypothesis

- certain parasites can alter host behaviour to their own selective benefit, usually to enhance transmission - many examples from invertebrate host-parasite systems - few examples from vertebrate host-parasite systems

Immunological T. gondii schizophrenia link

- first-incidence schizophrenia associated with significantly increased T.gondii Ab titres and post-mortem CSF T.gondii titres than controls - T.gondii Abs reduced with anti-schizophrenia treatment - Anti-psychotic drugs inhibit T.gondii replication in vitro (Haloperidol)

Evidence from other intermediate/secondary hosts

- highly prevalent across all mammals - unlikely that the parasite would have evolved mechanism to limit behaviour manipulation only to (currently) suitable intermediate hosts - thus: predict parasite-altered behaviour in latently-infected mammals independent of 'current' intermediate host status e.g. sea-otter and sharks, wildebeest and lion

Evidence from humans

- hyperactivity - altered anxiety/personally profiles - decreased psychomotor performance - increased propensity to be involved in traffic accidents - "fatal feline attraction"

Acute-Postnatally Acquired Toxoplasmosis

- in immuncompromised humans, either initial acquisition or recrudescence of latent organism can cause signs and symptoms related to the CNS - disseminated infection, including myocarditis, pneumonia and CNS toxoplasmosis - in immunocompetent people, acute acquired infection may be asymptomatic, cause lymphadenopathy or affect almost any organ - symptomatic infection is characterised as a heterophil-negative mononucleosis syndrome that includes lymphadenopathy, fever and heptatosplenomegaly - rare psychosis

Sexual transmission

- in some animals, they can pass tachyzoites in semen

Toxoplasmosis

- intracellular apicomplexan protozoan - worldwide distribution - all endothermic vertebrates - humans - 22-92% - cats 40-50% - rodents 20-60%

Congenital Toxoplasmosis: Severe Signs

- intracerebral calcification - ocular toxoplasmosis - hydrocephaly - microcephaly - convulsions - mental retardation - cardiomegaly - increased subsequent risk of schizophrenia

Congenital Transmission

- passing to unborn body (tachyzoites)

Congenital Toxoplasmosis: Mild Symptoms

- premature birth - small size for gestational age - retinal scars - persistent jaundice - mild thrombocytopenia

Treatment of acute adult acquired toxoplasmosis

- pyrimethamine with sulfadiazine

Tachyzoite stage

- rapidly growing stage observed in early stage of infection - acute phase - habits in bodily fluids - infect phagocytic and non-phagocytic cells

Evidence from human models

- renewed interest in pathogens as causes of chronic human disease - T.gondii associated ocular abnormalities, brain tumours - increased first incidence schizophrenia and affective disorders

Oocyst stage

- sexual cycle produces the oocyst which is excreted in the faeces - oocysts appear in the cat faeces 3-5 days of infection - oocysts require oxygen and sporulate within 1-5 days - very resistant in the environment

Bradyzoite stage

- slow growing stage inside tissue cysts - mark the chronic phase of infection - bradyzoites are resistant to low pH and digestive enzymes - protective cyst wall finally dissolves and bradyzoite infect tissue and transform into tachyzoites

Latent Toxoplasmosis

- tissue cysts contain thousands of parasites and persist in tissues, especially in the CNS, skeletal and heart muscle for lifetime of a host

Horizontal transmission

- touching or coming into contact with infected cat faeces (oocyst) - by eating contaminated unwashed fruit or vegetables - by eating infected raw or undercooked meat (bradyzoites/tachyzoites) or contaminated raw or undercooked meat (oocyst)

Neuromodulator change

- toxoplasma and schizophrenia characterised by significant differences in levels of norepinephrine and altered dopamine - substances which mediates locomotor activity, mood, learning, memory, and cerebral blood flow

Food Chain

- via intermediate to definitive host - parasite juvenile stage in intermediate host - parasite lifecycle completed in definitive host

Congenital Toxoplasmosis: Humans

- when a pregnant women gets the infection during pregnancy and passed it on to the foetus - babies that get infected during the first trimester show to have the most serve symptoms

Diagnosis

1. demonstration of the T.gondii organism in the blood, bodily fluids or tissues 2. ELISA - antigen 3. Sabin-Fieldman dye test = standard reference test for toxoplasmosis 4. serologically 5. PCR on bodily fluids 6. Skin - tests show delayed skin hypersensitivity to T.gondii antigens 7. Animal inoculation - infected tissue into experimental animals 8. tissue culture

T. gondii lifecycle

1. unsporulated oocysts are shed in cat faeces. Oocycts take 1-5 days to sporulate in the environment and become infective. Intermediate hosts become infected after ingesting soil, water,or plant material contaminated with oocysts 2. after ingestion, oocysts transform into tachzyoites which localise in muscle and neural tissue and develop into tissue cyst bradyzoites. 3. cats become infected after consuming intermediate host harbouring tissue cysts or can become infected directly in ingesting sporulated oocysts

Implications for other affective and neurological disorders

Correlations also found with T.gondii for: - OCD - Bipolar - Depression - Parkinsons - Alzheimers - Anxiety and panic disorders

What triggers severe pathological effects in some host species and then subtle effects in others?

Host factors? - genetic dispositions and/or state of the immune system - timing of exposure - 1st trimester - duration of infection - humans live longer than rodents

Summary

T. gondii manipulates intermediate host behaviour in a manner likely to enhance predation rate by definitive host - can override, even reverse, innate behaviour - modification of behaviour rather than elimination