Immune evasion and dissemination of Toxoplasma gondii
Toxoplasma gondii is an obligate intracellular protozoan parasite which propagates in a complex life cycle where infection of Felidae family-members (Cats) results in sexual recombination whereas all other warm-blooded animals are intermediate hosts. Approximately one third of the human population is estimated to be chronically infected by this parasite. Infection is acquired orally by ingestion of undercooked meat harboring tissue cysts or through accidental intake of oocysts in contaminated foodstuffs. Acute disease is generally mild, but may lead to severe neurological and ocular manifestations in the developing fetus. Chronic infection brings subtle pathology, such as memory impairment and latent anxiety, but may upon reactivation in immunocompromised patients cause potentially lethal toxoplasmic encephalitis.
The population structure of Toxoplasma is dominated by three clonal lineages (type I, II, III) and type II predominates in human infections. Immunity to Toxoplasma is biased towards a Th1 type response which mediates long term protection against reactivated disease. Dendritic cells (DCs) and Natural killer (NK) cells are important players in the acute phase of infection and IL-12 and IFN-gamma produced by these cells respectively are essential mediators of resistance to the parasite.
The overall objective of this work has been to investigate dynamics of parasite dissemination and its impact on the pathogenesis of infection. We have pursued the hypothesis that Toxoplasma enables successful dissemination and immune evasion by using leukocytes as Trojan horses during infection. Focus has primarily been on parasite-DC interactions in relation to infection with different parasite strains and on NK cell interactions with infected DCs. In summary we have shown the following:
1. Active invasion of DCs and macrophages by Toxoplasma tachyzoites in vitro induces a state of hypermotility in these cells, enabling transmigration across endothelial monolayers in the absence of auxiliary chemotactic stimuli. Host cell hypermotility is induced by all tree archetypical lineages of Toxoplasma but the intensity of the phenotype is clearly higher for type II parasites. Hypermotility further requires an intracellular parasite and can be blocked by PTX treatment which uncouples the signaling pathway of trimeric Gi-proteins.
2. Adoptive transfer of Toxoplasma infected DCs accelerated dissemination of parasites to the spleen, MLN, brain and testis, and resulted in exacerbation of infection compared to inoculation of free parasites. PTX-treatment of infected DCs prior to inoculation reversed the observed enhanced dissemination. All tree archetypical lineages exhibited increased dissemination after adoptive transfer of DC-borne parasite but this mode of dissemination clearly favored type II and type III parasites more than type I in syngenic mice.
3. NK cells are the preferentially infected lymphocyte population shortly after parasite inoculation of mice. Infected DCs, but not infected NK cells, exhibit increased sensitivity to NK cell-mediated killing in vitro. NK cell killing of infected DCs results in the egress of viable parasites and the successive invasion of adjacent NK cells. This mechanism of NK cell infection is perforin-dependent in vitro.
The data presented in this thesis shows that parasite strain-dependent manipulation of host cell motility, favors DC-borne parasite dissemination via a Trojan horse type of mechanism, and that NK cell-mediated cellular cytotoxicity may contribute to the parasite s sequestration and mediate immune evasion shortly after infection.
List of scientific papers
I. Lambert H, Hitziger N, Dellacasa I, Svensson M, Barragan A (2006). Induction of dendritic cell migration upon Toxoplasma gondii infection potentiates parasite dissemination. Cell Microbiol. 8(10): 1611-23
https://pubmed.ncbi.nlm.nih.gov/16984416
II. Persson CM, Lambert H, Vutova PP, Dellacasa-Lindberg I, Nederby J, Yagita H, Ljunggren HG, Grandien A, Barragan A, Chambers BJ (2009). Transmission of Toxoplasma gondii from infected dendritic cells to natural killer cells. Infect Immun. 77(3): 970-6. Epub 2009 Jan 12
https://pubmed.ncbi.nlm.nih.gov/19139191
III. Lambert H, Vutova PP, Adams WC, Loré K, Barragan A (2009). The Toxoplasma gondii-shuttling function of dendritic cells is linked to the parasite genotype. Infect Immun. 77(4): 1679-88. Epub 2009 Feb 9
https://pubmed.ncbi.nlm.nih.gov/19204091
IV. Lambert H, Dellacasa-Lindberg I, Barragan A (2009). Impact of infected leukocytes on Toxoplasma dissemination. [Manuscript]
History
Defence date
2009-09-14Department
- Department of Medicine, Huddinge
Publication year
2009Thesis type
- Doctoral thesis
ISBN
978-91-7409-570-8Number of supporting papers
4Language
- eng