Dataset Information

Toxoplasma gondii-Induced Long-Term Changes in the Upper Intestinal Microflora during the Chronic Stage of Infection.

ABSTRACT: Toxoplasma gondii is an obligate intracellular parasite with worldwide distribution. Felines are the definitive hosts supporting the complete life cycle of T. gondii. However, other warm-blooded animals such as rodents and humans can also be infected. Infection of such secondary hosts results in long-term infection characterized by the presence of tissue cysts in the brain and other organs. While it is known that T. gondii infection in rodents is associated with behavioral changes, the mechanisms behind these changes remain unclear. Alterations of the host intestinal microflora are recognized as a prominent role player in shaping host behavior and cognition. It has been shown that acute T. gondii infection of mice results in microflora changes as a result of gastrointestinal inflammation in inbred mouse models. The long-term effects of chronic T. gondii infection on microbial communities, however, are unknown. In this study, after we verified using our model in terms of measuring microflora changes during an acute episode of toxoplasmosis, we assessed the microbiome changes that occur during a long-term infection; then we further investigated these changes in a follow-up study of chronic infection. These analyses were performed by constructing and sequencing 16S rRNA amplicon DNA libraries from small intestine fecal specimens. We found that acute infection with the GT1 strain of T. gondii caused an enrichment of Bacteroidetes compared with controls in CD1 mice. Strikingly, this enrichment upheld throughout long-term chronic infection. The potential biological consequences of this alteration in rodents and humans should be subjected to further exploration.

SUBMITTER: Prandovszky E

PROVIDER: S-EPMC6236704 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Toxoplasma gondii-Induced Long-Term Changes in the Upper Intestinal Microflora during the Chronic Stage of Infection.

Prandovszky Emese E Li Ye Y Sabunciyan Sarven S Steinfeldt Curtis B CB Avalos Lauro Nathaniel LN Gressitt Kristin L KL White James R JR Severance Emily G EG Pletnikov Mikhail V MV Xiao Jianchun J Yolken Robert H RH

Scientifica 20181101

Toxoplasma gondii is an obligate intracellular parasite with worldwide distribution. Felines are the definitive hosts supporting the complete life cycle of T. gondii. However, other warm-blooded animals such as rodents and humans can also be infected. Infection of such secondary hosts results in long-term infection characterized by the presence of tissue cysts in the brain and other organs. While it is known that T. gondii infection in rodents is associated with behavioral c ...[more]

PMID: 30515345

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Project description:Toxoplasma gondii is a prevalent parasite of mammals and birds including up to 30% of humans world-wide. Primary infection of immunocompetent hosts leads to a robust cell-mediated immune response, which controls but does not clear the infection, thus enabling long-term parasite persistence in brain and muscle tissues. Chronic toxoplasmosis in mice is associated with resistance to heterologous pathogens and this has been related to increased numbers of inflammatory monocytes. Here we have analyzed whether chronic T. gondii infection impacts the subset distribution and the phenotype of peripheral human monocytes in vivo and their responses to parasite infection in vitro. CD14+ monocytes from T. gondii-seropositive blood donors expressed significantly less FcγRIII (CD16) than those from seronegative controls, but they did not show a shift in the distribution of classical, intermediate and non-classical monocyte subpopulations. Percentages of CD62L+ and CD64+ monocytes were however decreased and increased, respectively, in chronically infected individuals as compared to naïve controls. Infection of monocyte-enriched PBMCs from both seropositive and seronegative individuals with T. gondii led to an increase of CD14+CD16- classical monocytes and a decrease of CD14+CD16+ double positive monocytes. Remarkably, after in vitro parasite infection, expression of the chemokine receptor CCR2 was severely impaired in monocytes from both, individuals with chronic toxoplasmosis and seronegative controls. In contrast, only monocytes from chronically infected humans but not those from controls dose-dependently up-regulated HLA-DR, DP, DQ expression following in vitro infection. Furthermore, monocyte-enriched PBMCs from seropositive individuals up-regulated IL-12 mRNA more vigorously after in vitro infection than cells from naïve controls. Collectively, our results establish that infection of humans with T. gondii exerts long-term effects on the phenotype and responsiveness of blood monocytes. This may have important implications for innate immune responses to T. gondii and unrelated pathogens.

Project description:BackgroundIt has become increasingly evident that the immune and nervous systems are closely intertwined, relying on one another during regular homeostatic conditions. Prolonged states of imbalance between neural and immune homeostasis, such as chronic neuroinflammation, are associated with a higher risk for neural damage. Toxoplasma gondii is a highly successful neurotropic parasite causing persistent subclinical neuroinflammation, which is associated with psychiatric and neurodegenerative disorders. Little is known, however, by what means neuroinflammation and the associated neural impairment can be modulated by peripheral inflammatory processes.MethodsExpression of immune and synapse-associated genes was assessed via quantitative real-time PCR to investigate how T. gondii infection-induced chronic neuroinflammation and associated neuronal alterations can be reshaped by a subsequent acute intestinal nematode co-infection. Immune cell subsets were characterized via flow cytometry in the brain of infected mice. Sulfadiazine and interferon-?-neutralizing antibody were applied to subdue neuroinflammation.ResultsNeuroinflammation induced by T. gondii infection of mice was associated with increased microglia activation, recruitment of immune cells into the brain exhibiting Th1 effector functions, and enhanced production of Th1 and pro-inflammatory molecules (IFN-?, iNOS, IL-12, TNF, IL-6, and IL-1?) following co-infection with Heligmosomoides polygyrus. The accelerated cerebral Th1 immune response resulted in enhanced T. gondii removal but exacerbated the inflammation-related decrease of synapse-associated gene expression. Synaptic proteins EAAT2 and GABAA?1, which are involved in the excitation/inhibition balance in the CNS, were affected in particular. These synaptic alterations were partially recovered by reducing neuroinflammation indirectly via antiparasitic treatment and especially by application of IFN-?-neutralizing antibody. Impaired iNOS expression following IFN-? neutralization directly affected EAAT2 and GABAA?1 signaling, thus contributing to the microglial regulation of neurons. Besides, reduced CD36, TREM2, and C1qa gene expression points toward inflammation induced synaptic pruning as a fundamental mechanism.ConclusionOur results suggest that neuroimmune responses following chronic T. gondii infection can be modulated by acute enteric nematode co-infection. While consecutive co-infection promotes parasite elimination in the CNS, it also adversely affects gene expression of synaptic proteins, via an IFN-?-dependent manner.

Dataset Information

Toxoplasma gondii-Induced Long-Term Changes in the Upper Intestinal Microflora during the Chronic Stage of Infection.

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<i>Toxoplasma gondii-</i>Induced Long-Term Changes in the Upper Intestinal Microflora during the Chronic Stage of Infection.

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