Toxoplasma gondii

Toxoplasma Gondii.

Toxoplasmosis - Congenital Toxoplasmosis

The transition between tachyzoites and bradyzoites.

T.gondii as an Epigenator.

Immune Response Pathway.

Behavior Changer by T.gondii infection.

1. Toxoplasma Gondii and Human Response Presented By: Hadiah Bassam Al Mahdi PhD. Student in Genetics Faculty of Science , King Adulaziz University Developmental Genetics Course Bio707

2. Outline Toxoplasma Gondii . Toxoplasmosis - Congenital Toxoplasmosis The transition between tachyzoites and bradyzoites . T.gondii as an Epigenator . Immune Response Pathway. Behavior Changer by T.gondii infection. Conclusion.

3. Toxoplasma Gondii Toxoplasma gondii is a coccidian parasite which is unicellular eukaryote is a member of the phylum Apicomplexa . The Apicomplexa , typically live as obligate intracellular parasites within host cells.  This The prevalence of T. gondii infection varies by country, 30–50 % of the world’s human population. These organisms are characterized by Apical secretory organelles- -- rhoptries , micronemes Dense granules — that secrete parasite products essential for host cell invasion, defense against the host, and coopting of host metabolism . ( Corvi et al., 2011)

4. Life Cycle It has a complex life cycle Sexual phases are limited to the definitive host. Asexual phases can occur in both the definitive and intermediate hosts. Cat as its definitive host but any warm-blooded animal, including humans, may act as intermediate hosts. ( Freppel et al., 2019)

5. Toxoplasmosis Infection with Toxoplasma gondii . It was initially described in 1908 in Tunis by Nicolle and Manceaux (1908) and in Brazil by Splendore (1908). It has three infectious forms: Sporozoites (in oocysts ) Tachyzoites (rapidly multiplying form) Bradyzoites (tissue cyst form) ( Cerutti et al., 2020)

6. Risk Factors of Transmission infection Toxoplasma gondii  consists of three main clonal lineages (types I, II, and III) type II is the major strain that causes human infections. Acquired : Cat feces contaminated with oocysts Raw/undercooked meat containing tissue cysts of the parasite.  Organ transplantation blood transfusion Congenital: Transplacental transmission ( Mother Pregnancy) Reactivation Infection : Immunocompromised or Immunosuppression

7. Common mode of infection of  Toxoplasma gondii . (Khan and Khan, 2018)

8. Congenital Toxoplasmosis It is a very complex phenomenon; the outcome depends of the genetics of three beings: the mother, the conceptus and the parasite ( teratogenic effects ). The rate with risk for severe fetal varies from 15 to 68%, depending on gestational age and the transmission rate is highest in the later stages of pregnancy. H ost innate and adaptative immune response genes are induced during infection in adults, which control the rapidly replicating tachyzoite . Tachyzoite infects nucleated host cells and utilizes the macrophages, dendritic cells and monocytes to evade the host immune defense and bypass blood to infect all tissues primarily the CNS, eyes, muscles and placenta.

9. Congenital Toxoplasmosis T here are two different phenomena remarkably dependent on the time of gestation at challenge: 1. the probability of vertical transmission at the moment of maternal infection and the pathological effect on the embryo/fetus. 2. Genetic polymorphisms related to an early Th1 response (for example,  CCR2, CCR5, IL-12 or IFN -γ ) followed by proper regulation products (for example, IL-10 or TGF -β) are very important. Early Th1 microenvironment is important for control of infectious diseases and successful implantation, although it has to be regulated to support trophoblast survival. (Ortiz- Alegría et al., 2010)

10. Many non-immune genes of the host may influence tissue pathology during embryogenesis. Two molecules were specifically studied, the IIB isoform of collagen 2A1 , involved in optic nerve conduction during early development the ABCA4 form of the retina-specific ATP-binding cassette transporter protein, present in the choroid plexus and at the rim of the photoreceptor outer membrane Congenital Toxoplasmosis

11. Manifestation of Infection Intracranial calcifications   refer to calcifications within the brain parenchyma or vasculature. Hydrocephalus  is a condition in which an accumulation of cerebrospinal fluid (CSF) occurs within the brain . Retinochoroiditis i.e Ocular Toxoplasmosis (in Congenital and Acquired) Infection with T. gondii results in amplified expression of hypoxia-inducible factor 1-α (HIF1-α), as a result of which there is an increase in the levels of vascular endothelial growth factor ( VEGF ) transcription which in turn aids the growth of new blood vessels

12. Diagnosis Test The diagnosis may be done by serological screening of anti- Toxoplasma  antibodies ( IgM and IgG ) while PCR of the  amniotic fluid  or the placenta is the confirmatory test. Acute or chronic infections may be differentiated by IgG avidity tests.   (Khan and Khan, 2018)

13. The transition between tachyzoites and bradyzoites (Acute to Chronic ) is epigenetically regulated and coupled to the cell cycle Epigenetic: refers to heritable changes in an organism that alter gene expression levels without altering the DNA sequence . Types of epigenetic modifications. (A) Histones can undergo phosphorylation ( Ph ), methylation (Me), and acetylation (Ac ). ( B) DNA molecules are methylated by the addition of a methyl group on cytosine bases. ( C) mRNA is translated into a protein product, but this process can be repressed by binding of microRNAs ( miRNA ), a class of noncoding RNA ( ncRNA ). Tachyzoites to Bradyzoites (Gómez- Díaz et al., 2012)

14. In Heterochromatin , histone posttranslational modifications (e.g. histone H3K9 trimethylation ) that prevent the accessibility of RNA polymerase and transcription factors. HDAC3 , which associates with a T. gondii corepressor complex, is one example of an enzyme that is implicated in maintaining a closed chromatin structure by removing acetyl groups from histones. In Euchromatin , enabling access of sequence-specific transcription factors and the RNA polymerase complex. Activity of GCN5b, an acetyl transferase , is associated with active genes. An intermediate chromatin state exists for poised genes , which have bivalent chromatin marks consistent with both heterochromatin and euchromatin . Tachyzoites to Bradyzoites ( (Kim et al., 2020)

15. AP2 factors are considered the major transcription factors in T. gondii . Both repressive and activating AP2 have been characterized and implicated in regulation of the tachyzoite-bradyzoite transition. AP2 factors that activate bradyzoite gene expression are opposed by AP2 that repress bradyzoite gene expression. Alternatively , repressive AP2 may prevent bradyzoite gene expression by competing for target motifs recognized by AP2 that activate bradyzoite gene expression, preventing access of activating AP2 . Tachyzoites to Bradyzoites ( (Kim et al., 2020)

16. Induced Alterations of the Host Host immune response. The infection phenotype, which varies between host and pathogen phenotypes and is environmentally dependent, can induce changes at both the genomic and epigenomic levels. The interrelations between epigenetic variation, phenotypic variation, and host–pathogen interactions. (Gómez- Díaz et al., 2012)

17. T.gondii as an Epigenator Epigenetic effects on the host genome may involve a series of three steps: ( 1) Epigenator triggers the start of the epigenetic pathway. ( 2) I nitiator receives the signal from the epigenator and determines the precise chromatin location and/or DNA environment for the establishment. ( 3) M aintainer functions to sustain the chromatin environment in the initial and succeeding generations, often through regulatory feedback loops. Epigintor Examples: Dense granule protein: GRA16, GRA15 Rhoptry organelle proteins ROP16,ROP18 (Gómez- Díaz et al., 2012)

18. Secreted T. gondii  effectors from dense granules transform host cell signaling pathways Rhoptry effectors that target host pathways ( Hakimi et al., 2017)

19. TgIST translocates to the nucleus after   T. gondii  invasion and inhibits STAT1 by phosphorylation . ROP16 phosphorylate STAT3 and STAT6, mainly leading to a decrease in IL-12 and Th1 response. GRA15 activates this signaling pathway, which may promote cyst formation of the avirulent strain to avoid host immunity (Zhu et al., 2019)

20. Behavior change The brain is principally considered an immune-privileged tissue as it lacks a lymphatic system and tight capillary junctions within the blood-brain barrier prevent diffusion of large molecules, limiting lymphocyte access to the organ. T. gondii  infection of neurons can alter dopamine metabolism .   T. gondii   enters the brain, activation the cell is  associated with the production of a general inflammatory response  in the brain. The neuroinflammation may have a variety of effects on neurobiology, including influences on neurotransmitter metabolism, changes in neurotransmitter receptor levels, and effects on synaptic morphology or connectivity.

21. Relationship between T. gondii and depression/suicidal behavior .   i.e Affect to psychiatric patients (Schizophrenia , bipolar disorder .) (Hsu et al., 2014)

22. Directly and indirectly mediated effects of chronic  T. gondii  infection on host neurophysiology. ( Tedford and McConkey , 2017)

23. Conclusion Toxoplasmosis is the protist infection of Toxoplasma gondii  (T. gondii ). Preventing toxoplasmosis in cats involves measures intended to reduce the incidence of infections and the shedding of oocysts into the environment. Epigenetics is the future bright for the host–pathogen interactions. The host neuronal activity is altered or subverted by chronic  T. gondii  infection,

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25. Thank You Avoid Cats To Avoid Toxoplasma Gondii