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. 2013 Sep 18;8(9):e75246.
doi: 10.1371/journal.pone.0075246. eCollection 2013.

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

Affiliations

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

Wendy Marie Ingram et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

Competing Interests: M.B.E. is co-founder and member of the Board of Directors of PLOS. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. The second author, Leeanne M Goodrich, received funding from a commercial source in the form of a Genentech Scholars Program Undergraduate Research Award. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Assessment of aversion demonstrates loss of fear toward cat urine in Type I- and Type III-infected mice.
[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).
Figure 2
Figure 2. Persistent inflammation during chronic infection with Type III but not Type I parasites.
[A] Quantitative PCR of genomic DNA prepared from 10% of brain homogenate reveals that parasite DNA was readily detectable in Type III-infected animals (i) but undetectable in attenuated Type I-infected animals (ii). [B] Brain leukocytes were percoll purified from the remaining brain and meningeal homogenate, stained for surface markers CD4, CD8, CD19, CD11b, and Ly6G, and assayed using flow cytometry. Total numbers of cells positive for any of these markers are reported for uninfected, Type I-infected, and Type III-infected animals at 4 to 5 mpi. Average percentages of brain leukocyte populations for uninfected, Type I, and Type III animals are displayed in pie charts below each group. [C] Blood serum was collected following the final behavior experiment 4 months post infection (4 mpi). T. gondii specific antibodies were detected using ELISA. Relative absorbance at 405 nm (sample 1∶10 dilution absorbance – HRP no serum control absorbance) is reported for uninfected, Type I, and Type III. Each dot signifies one mouse. Significance was determined by Student’s T-test for [A] and 1 way ANOVA for [B] and [C] where ns indicates p>0.05 and **** indicates p<0.0001 (n = 9 for each group).
Figure 3
Figure 3. Type I and Type III acute infection results in parasite and leukocyte infiltration of the brain region.
[A and D] Parasite presence was assessed using semi-quantitative PCR of genomic DNA prepared from 10% of each mouse brain and meninges at various times post infection. For reference, data from Figure 2A is included which was collected from animals that were used in behavior experiments 4 to 5 months post infection. [A] Type III-infected animals have detectable parasite in brain regions early during acute infection, which is sustained over time. [D] Some attenuated Type I-infected animals have detectable parasite in brain regions early during acute infection, decreasing to undetectable levels (average of uninfected indicated by black dashed line). [B and E] Brain leukocytes were percoll purified from the remaining brain and meningeal homogenate, stained for leukocyte surface markers CD4, CD8, CD19, CD11b, and Ly6G, and assayed using flow cytometry. [B] Type III-infected animals have brain leukocyte numbers above uninfected levels (black dashed line) 13 days following infection which continue to increase over time. [E] Average total cell numbers from Type I-infected animals. Average percentages of brain leukocyte populations for uninfected, Type I-, and Type III-infected animals at selected time points are represented in pie charts below the corresponding data in [B and E]. [C and F] Total brain and meningeal T cells (CD4 plus CD8), indicators of brain region inflammation, are reported for Type III- and attenuated Type I-infected animals. Each dot signifies one mouse. Significance was determined for [C and F] by Student’s T-test where * indicates p<0.02, and ** indicates p<0.002.

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