Molecular mechanism for the control of virulent Toxoplasma gondii infections in wild-derived mice

Abstract

Some strains of the protozoan parasite Toxoplasma gondii (such as RH) are virulent in laboratory mice because they are not restricted by the Immunity-Related GTPase (IRG) resistance system in these mouse strains. In some wild-derived Eurasian mice (such as CIM) on the other hand, polymorphic IRG proteins inhibit the replication of such virulent T. gondii strains. Here we show that this resistance is due to direct binding of the IRG protein Irgb2-b1CIM to the T. gondii virulence effector ROP5 isoform B. The Irgb2-b1 interface of this interaction is highly polymorphic and under positive selection. South American T. gondii strains are virulent even in wild-derived Eurasian mice. We were able to demonstrate that this difference in virulence is due to polymorphic ROP5 isoforms that are not targeted by Irgb2-b1CIM, indicating co-adaptation of host cell resistance GTPases and T. gondii virulence effectors.

Influence of the Host and Parasite Strain on the Immune Response During Toxoplasma Infection

“…South-American Toxoplasma strains are mostly virulent in mice, which are not indigenous to the continent, and these strains might have adapted to South-American rodents (Lilue et al, 2013 ; Hassan et al, 2019 ; Murillo-León et al, 2019 ). The difference in susceptibility against Toxoplasma in these different mouse (sub)species has been mapped to chromosome 11, which contains the immunity related GTPases (IRGs), a family of proteins that are induced by interferon gamma (IFNγ) and which coat and subsequently vesiculate the parasitophorous vacuole membrane (PVM), leading to the death of the parasite (Lilue et al, 2013 ; Hassan et al, 2019 ; Murillo-León et al, 2019 ). These IRG proteins are highly polymorphic and their function is blocked by the Toxoplasma effectors ROP5 and ROP18 (Fentress et al, 2010 ; Fleckenstein et al, 2012 ; Niedelman et al, 2012 ; Lilue et al, 2013 ).…”

Genome-wide screens identify Toxoplasma gondii determinants of parasite fitness in IFNγ-activated murine macrophages

“…Mice with macrophages that can no longer respond to IFNγ are extremely susceptible to Toxoplasma demonstrating their crucial role in IFNγ-mediated control of Toxoplasma 5 . IFNγ-induced upregulation of immunity-related GTPases (IRGs) and guanylate binding proteins (GBPs) [6][7][8] are key mechanisms for controlling Toxoplasma in mice [9][10][11][12][13] . IRGs and GBPs can bind and vesiculate the PVM, eventually leading to the death of the parasite [14][15][16][17] .…”

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

“…Many ROPs localize to the host‐cytosolic surface of the PV where they can mitigate other effects of the immune response (Figure 1). Examples of this class of effectors are the pseudokinase ROP5 and its serine/threonine kinase partners, ROP17/18 which again depending on the strain of parasite, can cooperate to phosphorylate and thereby inactivate host immunity‐related GTPases (IRGs; (Etheridge et al., 2014; Hunn et al., 2011; Murillo‐Leon et al., 2019)). Although these are crucial ways in which host defenses are rapidly and effectively subverted, this review is focused on the second wave of effectors to be introduced, the GRA proteins which emanate from the parasite's dense granules.…”