Gut microbiota mediates anxiety-like behaviors induced by chronic infection of Toxoplasma gondii in mice.

BACKGROUND: Chronic infection with the neurotropic parasite Toxoplasma gondii (T. gondii) can cause anxiety and gut microbiota dysbiosis in hosts. However, the potential role of gut microbiota in anxiety induced by the parasite remains unclear. METHODS: C57BL/6J mice were infected with 10 cysts of T. gondii. Antibiotic depletion of gut microbiota and fecal microbiota transplantation experiments were utilized to investigate the causal relationship between gut microbiota and anxiety. Anxiety-like behaviors were examined by the elevated plus maze test and the open field test; blood, feces, colon and amygdala were collected to evaluate the profiles of serum endotoxin (Lipopolysaccharide, LPS) and serotonin (5-hydroxytryptamine, 5-HT), gut microbiota composition, metabolomics, global transcriptome and neuroinflammation in the amygdala. Furthermore, the effects of Diethyl butylmalonate (DBM, an inhibitor of mitochondrial succinate transporter, which causes the accumulation of endogenous succinate) on the disorders of the gut-brain axis were evaluated. RESULTS: Here, we found that T. gondii chronic infection induced anxiety-like behaviors and disturbed the composition of the gut microbiota in mice. In the amygdala, T. gondii infection triggered the microglial activation and neuroinflammation. In the colon, T. gondii infection caused the intestinal dyshomeostasis including elevated colonic inflammation, enhanced bacterial endotoxin translocation to blood and compromised intestinal barrier. In the serum, T. gondii infection increased the LPS levels and decreased the 5-HT levels. Interestingly, antibiotics ablation of gut microbiota alleviated the anxiety-like behaviors induced by T. gondii infection. More importantly, transplantation of the fecal microbiota from T. gondii-infected mice resulted in anxiety and the transcriptomic alteration in the amygdala of the antibiotic-pretreated mice. Notably, the decreased abundance of succinate-producing bacteria and the decreased production of succinate were observed in the feces of the T. gondii-infected mice. Moreover, DBM administration ameliorated the anxiety and gut barrier impairment induced by T. gondii infection. CONCLUSIONS: The present study uncovers a novel role of gut microbiota in mediating the anxiety-like behaviors induced by chronic T. gondii infection. Moreover, we show that DBM supplementation has a beneficial effect on anxiety. Overall, these findings provide new insights into the treatment of T. gondii-related mental disorders.

Toxoplasma bradyzoites exhibit physiological plasticity of calcium and energy stores controlling motility and egress.

Toxoplasma gondii has evolved different developmental stages for disseminating during acute infection (i.e., tachyzoites) and establishing chronic infection (i.e., bradyzoites). Calcium ion (Ca2+) signaling tightly regulates the lytic cycle of tachyzoites by controlling microneme secretion and motility to drive egress and cell invasion. However, the roles of Ca2+ signaling pathways in bradyzoites remain largely unexplored. Here, we show that Ca2+ responses are highly restricted in bradyzoites and that they fail to egress in response to agonists. Development of dual-reporter parasites revealed dampened Ca2+ responses and minimal microneme secretion by bradyzoites induced in vitro or harvested from infected mice and tested ex vivo. Ratiometric Ca2+ imaging demonstrated lower Ca2+ basal levels, reduced magnitude, and slower Ca2+ kinetics in bradyzoites compared with tachyzoites stimulated with agonists. Diminished responses in bradyzoites were associated with downregulation of Ca2+-ATPases involved in intracellular Ca2+ storage in the endoplasmic reticulum (ER) and acidocalcisomes. Once liberated from cysts by trypsin digestion, bradyzoites incubated in glucose plus Ca2+ rapidly restored their intracellular Ca2+ and ATP stores, leading to enhanced gliding. Collectively, our findings indicate that intracellular bradyzoites exhibit dampened Ca2+ signaling and lower energy levels that restrict egress, and yet upon release they rapidly respond to changes in the environment to regain motility.

Cross-sectional association of Toxoplasma gondii exposure with BMI and diet in US adults.

Toxoplasmosis gondii exposure has been linked to increased impulsivity and risky behaviors, which has implications for eating behavior. Impulsivity and risk tolerance is known to be related with worse diets and a higher chance of obesity. There is little known, however, about the independent link between Toxoplasma gondii (T. gondii) exposure and diet-related outcomes. Using linear and quantile regression, we estimated the relationship between T. gondii exposure and BMI, total energy intake (kcal), and diet quality as measured by the Health Eating Index-2015 (HEI) among 9,853 adults from the 2009-2014 National Health and Nutrition Examination Survey. Previous studies have shown different behavioral responses to T. gondii infection among males and females, and socioeconomic factors are also likely to be important as both T. gondii and poor diet are more prevalent among U.S. populations in poverty. We therefore measured the associations between T. gondii and diet-related outcomes separately for men and women and for respondents in poverty. Among females <200% of the federal poverty level Toxoplasmosis gondii exposure was associated with a higher BMI by 2.0 units (95% CI [0.22, 3.83]) at median BMI and a lower HEI by 5.05 units (95% CI [-7.87, -2.24]) at the 25th percentile of HEI. Stronger associations were found at higher levels of BMI and worse diet quality among females. No associations were found among males. Through a detailed investigation of mechanisms, we were able to rule out T. gondii exposure from cat ownership, differing amounts of meat, and drinking water source as potential confounding factors; environmental exposure to T. gondii as well as changes in human behavior due to parasitic infection remain primary mechanisms.

Neglected Parasitic Infections: What Family Physicians Need to Know-A CDC Update.

Chagas disease, cysticercosis, and toxoplasmosis affect millions of people in the United States and are considered neglected parasitic diseases. Few resources are devoted to their surveillance, prevention, and treatment. Chagas disease, transmitted by kissing bugs, primarily affects people who have lived in Mexico, Central America, and South America, and it can cause heart disease and death if not treated. Chagas disease is diagnosed by detecting the parasite in blood or by serology, depending on the phase of disease. Antiparasitic treatment is indicated for most patients with acute disease. Treatment for chronic disease is recommended for people younger than 18 years and generally recommended for adults younger than 50 years. Treatment decisions should be individualized for all other patients. Cysticercosis can manifest in muscles, the eyes, and most critically in the brain (neurocysticercosis). Neurocysticercosis accounts for 2.1% of all emergency department visits for seizures in the United States. Diagnosing neurocysticercosis involves serology and neuroimaging. Treatment includes symptom control and antiparasitic therapy. Toxoplasmosis is estimated to affect 11% of people older than six years in the United States. It can be acquired by ingesting food or water that has been contaminated by cat feces; it can also be acquired by eating undercooked, contaminated meat. Toxoplasma infection is usually asymptomatic; however, people who are immunosuppressed can develop more severe neurologic symptoms. Congenital infection can result in miscarriage or adverse fetal effects. Diagnosis is made with serologic testing, polymerase chain reaction testing, or parasite detection in tissue or fluid specimens. Treatment is recommended for people who are immunosuppressed, pregnant patients with recently acquired infection, and people who are immunocompetent with visceral disease or severe symptoms.

Chronic Toxoplasma gondii infection and sleep-wake alterations in mice.

AIM: Toxoplasma gondii (Tg) is an intracellular parasite infecting more than a third of the human population. Yet, the impact of Tg infection on sleep, a highly sensitive index of brain functions, remains unknown. We designed an experimental mouse model of chronic Tg infection to assess the effects on sleep-wake states. METHODS: Mice were infected using cysts of the type II Prugniaud strain. We performed chronic sleep-wake recordings and monitoring as well as EEG power spectral density analysis in order to assess the quantitative and qualitative changes of sleep-wake states. Pharmacological approach was combined to evaluate the direct impact of the infection and inflammation caused by Tg. RESULTS: Infected mouse exhibited chronic sleep-wake alterations over months, characterized by a marked increase (>20%) in time spent awake and in cortical EEG θ power density of all sleep-wake states. Meanwhile, slow-wave sleep decreased significantly. These effects were alleviated by an anti-inflammatory treatment using corticosteroid dexamethasone. CONCLUSION: We demonstrated for the first time the direct consequences of Tg infection on sleep-wake states. The persistently increased wakefulness and reduced sleep fit with the parasite's strategy to enhance dissemination through host predation and are of significance in understanding the neurodegenerative and neuropsychiatric disorders reported in infected patients.

Toxoplasma gondii secreted effectors co-opt host repressor complexes to inhibit necroptosis.

Toxoplasma gondii translocates effector proteins into its host cell to subvert various host pathways. T. gondii effector TgIST blocks the transcription of interferon-stimulated genes to reduce immune defense. Interferons upregulate numerous genes, including protein kinase R (PKR), which induce necrosome formation to activate mixed-lineage-kinase-domain-like (MLKL) pseudokinase and induce necroptosis. Whether these interferon functions are targeted by Toxoplasma is unknown. Here, we examine secreted effectors that localize to the host cell nucleus and find that the chronic bradyzoite stage secretes effector TgNSM that targets the NCoR/SMRT complex, a repressor for various transcription factors, to inhibit interferon-regulated genes involved in cell death. TgNSM acts with TgIST to block IFN-driven expression of PKR and MLKL, thus preventing host cell necroptotic death and protecting the parasite's intracellular niche. The mechanism of action of TgNSM uncovers a role of NCoR/SMRT in necroptosis, assuring survival of intracellular cysts and chronic infection.

Frequency and visual outcomes of ocular toxoplasmosis in an adult Brazilian population.

Although ocular toxoplasmosis is a leading cause of posterior uveitis worldwide, there is scarce information about the real-life frequency of ocular lesions, visual outcomes, and risk factors for poor prognosis. We conducted a community-based cross-sectional study with 721 adults living in Cássia dos Coqueiros, Southeast Brazil, consisted of visual acuity measurement, dilated ocular examination, a risk-factor questionnaire, and peripheral blood collection for anti-T. gondii serology. Presumed toxoplasmic lesions were recorded on video and analyzed by experienced and masked ophthalmologists. Ocular toxoplasmosis was determined if at least one suspected lesion was appointed by two graders in the presence of positive anti-T. gondii serology. Forty-eight eyes (n = 42 participants; 6.7% among those with positive anti-T. gondii serology) with ocular toxoplasmosis were found. Most lesions were single (n = 28; 58.3%), peripheral (n = 34; 77.1%) and unilateral (85.7% of participants); no active lesions were found. Older age was associated with lesions larger than one-disc diameter (p = 0.047), and lower social stratum (OR: 2.89; CI 1.2-6.97; p = 0.018) was associated with the presence of toxoplasmic lesions. Although there were no differences in visual acuity between participants and eyes with or without ocular lesions (p > 0.05), unilateral blindness associated with ocular toxoplasmosis was identified in a reduced number of individuals.

Association between latent toxoplasmosis and fertility parameters of men.

BACKGROUND: About a third of people in the world are infected with Toxoplasma gondii. This parasite has been found in the reproductive organs and semen of males of many animal species as well as humans. The effects of toxoplasmosis on sperm count, motility and morphology were confirmed in rats. A higher prevalence of toxoplasmosis has been observed in infertile men. On the other hand, no significant effect of infection on semen parameters in men was found in one already published study. OBJECTIVES: To compare the prevalence of toxoplasmosis in men with and without semen pathology and to examine in detail the possible impact of infection on semen volume, sperm count, motility and morphology. MATERIALS AND METHODS: The pre-registered cross-sectional study included 669 men who visited the Centre for Assisted Reproduction in Prague from June 2016 until June 2018. RESULTS: The incidence of fertility problems was significantly higher in the 163 Toxoplasma-infected men (48.47%) than in the 506 Toxoplasma-free men (42.29%), τ = 0.049, P = 0.029. After correction for multiple tests, we found significantly lower sperm concentration, concentration of progressively motile sperm, and concentration of non-progressively motile sperm in Toxoplasma-positive men than in Toxoplasma-negative men using partial Kendall correlation with age controlled. In addition, toxoplasmosis correlated with sperm quality in smokers but not in non-smokers. DISCUSSION AND CONCLUSION: Our results suggest that latent toxoplasmosis affects certain semen parameters (sperm count and motility), but does not seem to affect sperm morphology and semen volume. Impairment of semen parameters may be either a side effect of the presence of Toxoplasma gondii in male reproductive organs or a product of manipulation activity of the parasite aimed to increase the efficiency of the sexual route of its transmission. Tobacco smoking also appears to exacerbate the negative impact of toxoplasmosis on semen parameters.

Toxoplasma gondii infection impairs the colonic motility of rats due to loss of myenteric neurons.

BACKGROUND: Toxoplasma gondii infection causes intestinal inflammation and diarrhea indicating possible intestinal motor dysfunction. Anatomical studies have shown alterations in the colonic myenteric plexus, but it is unknown whether this impacts motility and therefore whether motility is a target for treatment. We determined whether colonic coordinated movements are compromised by toxoplasmic infection and how it is associated with anatomical changes. METHODS: Male Wistar rats were evaluated at 6, 12, 24, 48, and 72 hours and 30 days postinfection (dpi) and controls. Infected rats received orally 5 × 103 sporulated oocysts of strain ME-49 (genotype II) of T gondii. The colon was collected for anatomical analysis (including the myenteric plexus immunolabeled with HuC/D, nNOS, and ChAT) and motility analysis in vitro (conventional manometry). Fecal output was measured daily. KEY RESULTS: At 12 hours postinfection, T gondii caused hypertrophy of the muscularis externa layer of the distal colon. There was loss of total, nitrergic, and cholinergic myenteric neurons in the proximal colon at 30 day postinfection (dpi); however, only loss of cholinergic neurons was found in the distal colon. Contractile complexes in the middle and distal colon were longer in duration in infected animals, which was associated with slower migration of the colonic motor complex. However, gastrointestinal transit time and fecal pellet output remained unchanged during the T gondii infection. CONCLUSIONS AND INFERENCES: Toxoplasma gondii caused myenteric neuronal loss in the proximal and distal colon and altered the motility pattern in the middle and distal colon to a more propulsive phenotype.

Pathophysiology of ocular toxoplasmosis: Facts and open questions.

Infections with the protozoan parasite Toxoplasma gondii are frequent, but one of its main consequences, ocular toxoplasmosis (OT), remains poorly understood. While its clinical description has recently attracted more attention and publications, the underlying pathophysiological mechanisms are only sparsely elucidated, which is partly due to the inherent difficulties to establish relevant animal models. Furthermore, the particularities of the ocular environment explain why the abundant knowledge on systemic toxoplasmosis cannot be just transferred to the ocular situation. However, studies undertaken in mouse models have revealed a central role of interferon gamma (IFNγ) and, more surprisingly, interleukin 17 (IL17), in ocular pathology and parasite control. These studies also show the importance of the genetic background of the infective Toxoplasma strain. Indeed, infections due to exotic strains show a completely different pathophysiology, which translates in a different clinical outcome. These elements should lead to more individualized therapy. Furthermore, the recent advance in understanding the immune response during OT paved the way to new research leads, involving immune pathways poorly studied in this particular setting, such as type I and type III interferons. In any case, deeper knowledge of the mechanisms of this pathology is needed to establish new, more targeted treatment schemes.

Noradrenergic Signaling and Neuroinflammation Crosstalk Regulate Toxoplasma gondii-Induced Behavioral Changes.

Infections of the nervous system elicit neuroimmune responses and alter neurotransmission, affecting host neurological functions. Chronic infection with the apicomplexan parasite Toxoplasma correlates with certain neurological disorders in humans and alters behavior in rodents. Here, we propose that the crosstalk between neurotransmission and neuroinflammation may underlie some of these cognitive changes. We discuss how T. gondii infection suppresses noradrenergic signaling and how the restoration of this pathway improves behavioral aberrations, suggesting that altered neurotransmission and neuroimmune responses may act in concert to perturb behavior. This interaction might apply to other infectious agents, such as viruses, that elicit cognitive changes. We hypothesize that neurotransmitter signaling in immune cells can contribute to behavioral changes associated with brain infection, offering opportunities for potential therapeutic targeting.

Toxoplasma gondii seropositivity and serointensity and cognitive function in adults.

Infecting approximately one-third of the world's human population, Toxoplasma gondii has been associated with cognitive function. Here, we sought to further characterize the association between Toxoplasma gondii and cognitive function in a community sample of adults aged approximately 40 to70 years. Using adjusted linear regression models, we found associations of Toxoplasma gondii seropositivity with worse reasoning (b = -.192, p < .05) and matrix pattern completion (b = -.681, p < .01), of higher anti-Toxoplasma gondii p22 antibody levels with worse reasoning (b = -.078, p < .01) and slower Trails (numeric) performance (b = 5.962, p < .05), of higher anti-Toxoplasma gondii sag1 levels with worse reasoning (b = -.081, p < .05) and worse matrix pattern completion (b = -.217, p < .05), and of higher mean of the anti-Toxoplasma gondii p22 and sag1 levels with worse reasoning (b = -.112, p < .05), slower Trails (numeric) performance (b = 9.195, p < .05), and worse matrix pattern completion (b = -.245, p < .05). Neither age nor educational attainment moderated associations between the measures of Toxoplasma gondii seropositivity or serointensity. Sex, however, moderated the association between the sag1 titer and digit-symbol substitution and the association between the mean of the p22 and sag1 levels and digit-symbol substitution, and income moderated the association between Toxoplasma gondii seropositivity and numeric memory and the association between the p22 level and symbol-digit substitution. Based on the available neuropsychological tasks in this study, Toxoplasma gondii seropositivity and serointensity were associated with some aspects of poorer executive function in adults.

DNA double-strand breaks in the Toxoplasma gondii-infected cells by the action of reactive oxygen species.

BACKGROUND: Toxoplasma gondii is an obligate parasite of all warm-blooded animals around the globe. Once infecting a cell, it manipulates the host's DNA damage response that is yet to be elucidated. The objectives of the present study were three-fold: (i) to assess DNA damages in T. gondii-infected cells in vitro; (ii) to ascertain causes of DNA damage in T. gondii-infected cells; and (iii) to investigate activation of DNA damage responses during T. gondii infection. METHODS: HeLa, Vero and HEK293 cells were infected with T. gondii at a multiplicity of infection (MOI) of 10:1. Infected cells were analyzed for a biomarker of DNA double-strand breaks (DSBs) γH2AX at 10 h, 20 h or 30 h post-infection using both western blot and immunofluorescence assay. Reactive oxygen species (ROS) levels were measured using 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA), and ROS-induced DNA damage was inhibited by a ROS inhibitor N-acetylcysteine (NAC). Lastly, DNA damage responses were evaluated by detecting the active form of ataxia telangiectasia mutated/checkpoint kinase 2 (ATM/CHK2) by western blot. RESULTS: γH2AX levels in the infected HeLa cells were significantly increased over time during T. gondii infection compared to uninfected cells. NAC treatment greatly reduced ROS and concomitantly diminished γH2AX in host cells. The phosphorylated ATM/CHK2 were elevated in T. gondii-infected cells. CONCLUSIONS: Toxoplasma gondii infection triggered DNA DSBs with ROS as a major player in host cells in vitro. It also activated DNA damage response pathway ATM/CHK2. Toxoplasma gondii manages to keep a balance between survival and apoptosis of its host cells for the benefit of its own survival.

Neuroprotective Effect of Chronic Intracranial Toxoplasma gondii Infection in a Mouse Cerebral Ischemia Model.

Toxoplasma gondii is an obligate intracellular protozoan parasite that can invade various organs in the host body, including the central nervous system. Chronic intracranial T. gondii is known to be associated with neuroprotection against neurodegenerative diseases through interaction with host brain cells in various ways. The present study investigated the neuroprotective effects of chronic T. gondii infection in mice with cerebral ischemia experimentally produced by middle cerebral artery occlusion (MCAO) surgery. The neurobehavioral effects of cerebral ischemia were assessed by measurement of Garcia score and Rotarod behavior tests. The volume of brain ischemia was measured by triphenyltetrazolium chloride staining. The expression levels of related genes and proteins were determined. After cerebral ischemia, corrected infarction volume was significantly reduced in T. gondii infected mice, and their neurobehavioral function was significantly better than that of the uninfection control group. Chronic T. gondii infection induced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) in the brain before MCAO. T. gondii infection also increased the expression of vascular endothelial growth factor after the cerebral ischemia. It is suggested that chronic intracerebral infection of T. gondii may be a potential preconditioning strategy to reduce neural deficits associated with cerebral ischemia and induce brain ischemic tolerance through the regulation of HIF-1α expression.

Effects of Toxoplasma gondii infection on the function and integrity of human cerebrovascular endothelial cells and the influence of verapamil treatment in vitro.

Toxoplasma gondii can cause parasitic encephalitis, a life-threatening infection that predominately occurs in immunocompromised individuals. T. gondii has the ability to invade the brain, but the mechanisms by which this parasite crosses the blood-brain-barrier (BBB) remain incompletely understood. The present study reports the changes associated with infection and replication of T. gondii within human brain microvascular endothelial cells (BMECs) in vitro. Our results indicated that exposure to T. gondii had an adverse impact on the function and integrity of the BMECs - through induction of cell cycle arrest, disruption of the BMEC barrier integrity, reduction of cellular viability and vitality, depolarization of the mitochondrial membrane potential, increase of the DNA fragmentation, and alteration of the expression of immune response and tight junction genes. The calcium channel/P-glycoprotein transporter inhibitor verapamil was effective in inhibiting T. gondii crossing the BMECs in a dose-dependent manner. The present study showed that T. gondii can compromise several functions of BMECs and demonstrated the ability of verapamil to inhibit T. gondii crossing of the BMECs in vitro.

The Cataleptic, Asymmetric, Analgesic, and Brain Biochemical Effects of Parkinson's Disease Can Be Affected by Toxoplasma gondii Infection.

PURPOSE: Parkinson's disease (PD) is a neurodegenerative disorder with progressive motor defects. Therefore, the aim of the present investigation was to examine whether catalepsy, asymmetry, and nociceptive behaviors; the Nissl-body and neuron distribution; brain-derived neurotrophic factor (BDNF); malondialdehyde (MDA); total antioxidant capacity (TAC) levels; and the percentage of dopamine depletion of striatal neurons in the rat model of Parkinson's disease (PD) can be affected by Toxoplasma gondii (TG) infection. METHODS: Fifty rats were divided into five groups: control (intact rats), sham (rats which received an intrastriatal injection of artificial cerebrospinal fluid (ACSF)), PD control (induction of PD without TG infection), TG control (rats infected by TG without PD induction), and PD infected (third week after PD induction, infection by TG was done). PD was induced by the unilateral intrastriatal microinjection of 6-hydroxydopamine (6-OHDA) and ELISA quantified dopamine, BDNF, MDA, and TAC in the striatum tissue. Cataleptic, asymmetrical, nociceptive, and histological alterations were determined by bar test, elevated body swing test, formalin test, and Nissl-body and neuron counting in the striatal neurons. RESULTS: The results demonstrated that PD could significantly increase the number of biased swings, descent latency time, and nociceptive behavior and decrease the distribution of Nissl-stained neurons compared to the control and sham groups. TG infection significantly improved biased swing, descent latency time, nociceptive behavior, and the Nissl-body distribution in striatal neurons in comparison to the PD control group. The striatal level of BDNF in the PD-infected and TG control groups significantly increased relative to the PD control group. The striatal MDA was significantly higher in the PD control than other groups, while striatal TAC was significantly lower in the PD control than other groups. CONCLUSIONS: The current study indicates that TG infection could improve the cataleptic, asymmetric, nociceptive and behaviors; the level of striatal dopamine release; BDNF levels; TAC; and MDA in PD rats.

The association of Toxoplasma gondii IgG and cognitive function scores: NHANES 2013-2014.

Toxoplasma gondii (T. gondii) causes chronic, latent infections of global concern. Its subclinical influence on behavior and cognition are poorly understood. The objective of this research is to determine the relationship of T. gondii IgG with cognition using National Health and Nutrition Examination Survey data, 2013-2014 in older adults ≥60 years. A composite cognitive function score was created by adding the scores of the memory test, language/verbal fluency, and working memory test. T. gondii IgG was dichotomized at <33 IU/mL (negative) and ≥33 IU/mL (positive). There were 19.2% of the participants who were T. gondii IgG+. The memory function and language/verbal fluency subtests failed to reach significance; however, the difference in the working memory test was significant. In the multivariable ordinal logistic regression analysis, controlling for potential confounders, the odds of cognitive function scores decreasing in quartiles among people with positive vs. negative T. gondii IgG are 1.55 (95% CI: 1.08, 2.21; p = .0170). Establishing an evidence base for the association of T. gondii IgG and cognition is complex, but essential.

Pathogenic Infection in Male Mice Changes Sperm Small RNA Profiles and Transgenerationally Alters Offspring Behavior.

Germline epigenetic factors influence transgenerational inheritance of behavioral traits upon changes in experience and environment. Immune activation due to infection can also modulate brain function, but whether this experience can be passed down to offspring remains unknown. Here, we show that infection of the male lineage with the common human parasite Toxoplasma results in transgenerational behavioral changes in offspring in a sex-dependent manner. Small RNA sequencing of sperm reveals significant transcriptional differences of infected animals compared to controls. Zygote microinjection of total small RNA from sperm of infected mice partially recapitulates the behavioral phenotype of naturally born offspring, suggesting an epigenetic mechanism of behavioral inheritance in the first generation. Our results demonstrate that sperm epigenetic factors can contribute to intergenerational inheritance of behavioral changes after pathogenic infection, which could have major public health implications.