Mice Infected with Low-virulence Strains of Toxoplasma gondii Lose their Innate Aversion to Cat Urine, Even after Extensive Parasite Clearance

Toxoplasma gondii chronic infection in rodent secondary hosts has been reported to lead to a loss of innate, hard-wired fear toward cats, its primary host. However the generality of this response across T. gondii strains and the underlying mechanism for this pathogen mediated behavioral change remain unknown. To begin exploring these questions, we evaluated the effects of infection with two previously uninvestigated isolates from the three major North American clonal lineages of T. gondii, Type III and an attenuated strain of Type I. Using an hour-long open field activity assay optimized for this purpose, we measured mouse aversion toward predator and non-predator urines. We show that loss of innate aversion of cat urine is a general trait caused by infection with any of the three major clonal lineages of parasite. Surprisingly, we found that infection with the attenuated Type I parasite results in sustained loss of aversion at times post infection when neither parasite nor ongoing brain inflammation were detectable. This suggests that T. gondii-mediated interruption of mouse innate aversion toward cat urine may occur during early acute infection in a permanent manner, not requiring persistence of parasitecysts or continuing brain inflammation.Comment: 14 pages, 3 figure

Data from: Mice infected with low-virulence strains of Toxoplasma gondii lose their innate aversion to cat urine, even after extensive parasite clearance

Toxoplasma gondii chronic infection in rodent secondary hosts has been reported to lead to a loss of innate, hard-wired fear toward cats, its primary host. However the generality of this response across T. gondii strains and the underlying mechanism for this pathogen-mediated behavioral change remain unknown. To begin exploring these questions, we evaluated the effects of infection with two previously uninvestigated isolates from the three major North American clonal lineages of T. gondii, Type III and an attenuated strain of Type I. Using an hour-long open field activity assay optimized for this purpose, we measured mouse aversion toward predator and non-predator urines. We show that loss of innate aversion of cat urine is a general trait caused by infection with any of the three major clonal lineages of parasite. Surprisingly, we found that infection with the attenuated Type I parasite results in sustained loss of aversion at times post infection when neither parasite nor ongoing brain inflammation were detectable. This suggests that T. gondii-mediated interruption of mouse innate aversion toward cat urine may occur during early acute infection in a permanent manner, not requiring persistence of parasite cysts or continuing brain inflammation

Motor Monitor Data from Kinder Scientific reduced files - 1 min intervals

Reduced data for 3 weeks, 2 months, and 4 months post infection with Type I or Type III parasites

Assessment of aversion demonstrates loss of fear toward cat urine in Type I- and Type III-infected mice.

<p>[A] Overhead representation of behavioral arena where a small dish containing the ‘target’ solution (yellow disk) is affixed at one end of the behavioral arena. ‘Near Target’ is defined as the area of the arena (white) proximal to the target. ‘Avoidance’ is defined as the most distal region (dark grey) of the enclosure relative to the target. [B] Representative heat maps of mouse place preference during a 60-minute trial of (i) uninfected mice exposed to rabbit urine, and (ii) uninfected, (iii) attenuated Type I-infected, and (iv) low-virulence Type III-infected mice exposed to bobcat urine from trials conducted at 2 months post infection. [C] Aversion ratio, the avoidance time to near target time, of uninfected (red circles), Type I-infected (green triangles), and Type III-infected (blue squares) animals when exposed to bobcat urine (filled shapes) or rabbit urine (open shapes) at 3 weeks, 2 months, and 4 months post infection (n = 10 for each group). Error bars are the Standard Error of the Mean (SEM).</p

OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development

TET enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine and higher oxidized derivatives. TETs stably associate with and are post-translationally modified by the nutrient-sensing enzyme OGT, suggesting a connection between metabolism and the epigenome. Here, we show for the first time that modification by OGT enhances TET1 activity in vitro. We identify a TET1 domain that is necessary and sufficient for binding to OGT and report a point mutation that disrupts the TET1-OGT interaction. We show that this interaction is necessary for TET1 to rescue hematopoetic stem cell production in tet mutant zebrafish embryos, suggesting that OGT promotes TET1’s function during development. Finally, we show that disrupting the TET1-OGT interaction in mouse embryonic stem cells changes the abundance of TET2 and 5-methylcytosine, which is accompanied by alterations in gene expression. These results link metabolism and epigenetic control, which may be relevant to the developmental and disease processes regulated by these two enzymes