Head-to-head comparisons of Toxoplasma gondii and its near relative Hammondia hammondi reveal dramatic differences in the host response and effectors with species-specific functions

Abstract

Toxoplasma gondii and Hammondia hammondi are closely-related coccidian intracellular parasites that differ in their ability to cause disease in animal and (likely) humans. The role of the host response in these phenotypic differences is not known and to address this we performed a transcriptomic analysis of a monocyte cell line (THP-1) infected with these two parasite species. The pathways altered by infection were shared between species~95% the time, but the magnitude of the host response to H. hammondi was significantly higher compared to T. gondii. Accompanying this divergent host response was an equally divergent impact on the cell cycle of the host cell. In contrast to T. gondii, H. hammondi infection induces cell cycle arrest via pathways linked to DNA-damage responses and cellular senescence and robust secretion of multiple chemokines that are known to be a part of the senescence associated secretory phenotype (SASP). Remarkably, prior T. gondii infection or treatment with T. gondii-conditioned media suppressed responses to H. hammondi infection, and promoted the replication of H. hammondi in recipient cells. Suppression of inflammatory responses to H. hammondi was found to be mediated by the T. gondii effector IST, and this finding was consistent with reduced functionality of the H. hammondi IST ortholog compared to its T. gondii counterpart. Taken together our data suggest that T. gondii manipulation of the host cell is capable of suppressing previously unknown stress and/or DNA-damage induced responses that occur during infection with H. hammondi, and that one important impact of this T. gondii mediated suppression is to promote parasite replication.

Retrospective study of toxoplasmosis prevalence in pregnant women in Benin and its relation with malaria

“…Another explanation could be that the persistent installation of T. gondii in its host involves a dynamic regulation of combined cellular and molecular immunoregulatory networks [52][53][54][55], which can impact the newly infecting Plasmodium parasite using similar pathways. This could result in less production of anti-PfAMA1 IgG to effectively fight plasmodial parasites.…”

MicroRNAs: master regulators in host–parasitic protist interactions

“…However, they may have a role in establishing the infection. Activation of both pathways is aimed at inhibiting apoptosis and progression through the S phase and into G2 / M. This could indicate the importance of the cell cycle stage of the host cell during infection [294]. Notably, the toxoplasma genome codes for endogenous miRNAs, so it is possible that parasites use these to modify the host's cellular functions [279], similarly to that observed for mammalian viruses [276,295].…”

“…Additionally, Myc activates many genes associated with cell growth, including E2F genes, such as E2F1, required for the initial entry to the cell cycle from a quiescent state [293]. E2F1 expression is also increased in cells infected by T. gondii [294]. Paradoxically, the mir-17-92 cluster negatively modulates the E2F1 expression [291].…”

Seizing control: How dense granule effector proteins enable Toxoplasma to take charge

“…These GRAs are ultimately found in various compartments [reviewed in Clough and Frickel (2017) and Mercier and Cesbron‐Delauw (2015)], including: (a) within the PV lumen, some being involved in the generation of an elaborate, nanotubular network; (b) within and on the PVM, including its host‐cytosolic face, and in one case leading to the association of host mitochondria (see below); and 3) within the host cytosol and nucleus after being exported out of the PV. In addition to being secreted by intracellular parasites into the PV lumen, GRAs can be secreted by extracellular parasites, enabling the parasites to impact the extracellular milieu, thereby potentially impacting uninfected cells and general tissue functions (Leroux et al., 2015; Wong et al., 2020). Finally, and although the data for this is incomplete, there is some evidence that the dense granules may not be homogeneous with respect to their protein cargo, possibly allowing the parasite a finer level of control in the packaging and timing of export of GRA effectors (Mercier & Cesbron‐Delauw, 2015).…”

“…Cells infected with Toxoplasma exhibit significant cell cycle alteration, and while the specifics of the alteration vary by cell type, it has generally been reported that Toxoplasma tachyzoites advance the cell into S phase (Molestina et al., 2008) and arrest it in the G2 phase, prior to mitosis (Brunet et al., 2008; Wong et al., 2020). Under certain circumstances this results in a binucleated phenotype as the infected cells fail to undergo proper cytokinesis during mitosis (Velasquez et al., 2019).…”