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Transcriptional Analyses Identify Genes That Modulate Bovine Macrophage Response to Toxoplasma Infection and Immune Stimulation.

ABSTRACT: The obligate intracellular parasite, Toxoplasma gondii, is highly prevalent among livestock species. Although cattle are generally resistant to Toxoplasma strains circulating in Europe and North America, the underlying mechanisms are largely unknown. Here, we report that bovine bone marrow-derived macrophage (BMDM) pre-stimulated with interferon gamma (IFN?) restricts intracellular Toxoplasma growth independently of nitric oxide. While Toxoplasma promoted the expression of genes associated with alternative macrophage activation and lipid metabolism, IFN? abrogated parasite-induced transcriptional responses and promoted the expression of genes linked to the classical macrophage activation phenotype. Additionally, several chemokines, including CCL22, that are linked to parasite-induced activation of the Wnt/?-catenin signaling were highly expressed in Toxoplasma-exposed naïve BMDMs. A chemical Wnt/?-catenin signaling pathway antagonist (IWR-1-endo) significantly reduced intracellular parasite burden in naïve BMDMs, suggesting that Toxoplasma activates this pathway to evade bovine macrophage anti-parasitic responses. Congruently, intracellular burden of a mutant Toxoplasma strain (RH?ASP5) that does not secrete dense granule proteins into the host cell, which is an essential requirement for parasite-induced activation of the Wnt/?-catenin pathway, was significantly reduced in naïve BMDMs. However, both the Wnt/?-catenin antagonist and RHASP?5 did not abolish parasite burden differences in naïve and IFN?-stimulated BMDMs. Finally, we observed that parasites infecting IFN?-stimulated BMDMs largely express genes associated with the slow dividing bradyzoite stage. Overall, this study provides novel insights into bovine macrophage transcriptional response to Toxoplasma. It establishes a foundation for a mechanistic analysis IFN?-induced bovine anti-Toxoplasma responses and the counteracting Toxoplasma survival strategies.

SUBMITTER: Gossner A

PROVIDER: S-EPMC7508302 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Transcriptional Analyses Identify Genes That Modulate Bovine Macrophage Response to Toxoplasma Infection and Immune Stimulation.

Gossner Anton A Hassan Musa A MA

Frontiers in cellular and infection microbiology 20200820

The obligate intracellular parasite, Toxoplasma gondii, is highly prevalent among livestock species. Although cattle are generally resistant to Toxoplasma strains circulating in Europe and North America, the underlying mechanisms are largely unknown. Here, we report that bovine bone marrow-derived macrophage (BMDM) pre-stimulated with interferon gamma (IFNγ) restricts intracellular Toxoplasma growth independently of nitric oxide. While Toxoplasma promoted the expressi ...[more]

PMID: 33014886

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Project description:Purpose:This study was aimed to profile the transcriptome changes during Toxoplasma infection with porcine alveolar macrophages. for this purpose, Porcine alveolar macrophages (PAMs,3D4/21) were infected by Toxoplasma Me49 strain in vitro. The transcriptome changes were captured by dual RNA-seq analyses. Methods: Transcriptomic profiles of infection samples (Me49 infected PAMs) and controls (Me49 and PAMs, respectively) were generated by deep sequencing, in triplicate, using Illumina HiseqPE150. The sequence reads that passed quality filters were analyzed at the transcript level with TopHat (v2.0.12) followed by HTSeq (v0.6.1). The Cufflinks (v2.1.1) was used to construct and identify novel transcripts. qRT–PCR validation was performed using SYBR Green assays. Results: Using an optimized data analysis workflow, More than 30 million paired-end reads were generated for the Me49 controls and 93% of the clean reads were mapped to the Me49 reference genome. Nearly 2~3 times more reads were produced in the PAMs alone or infected PAMs samples. Among these, 60% to 80% of clean reads were mapped to the Sus Scrofa genome. In the infection groups, approximately 16% of total clean reads were aligned to the Me49 reference genome. RNA-seq data indicated the remarkable transcripts changes of both sides during infection process. More than 800 and 1800 genes (fold change ≥2 and adjusted p value <0.05) were significantly regulated in PAMS and Me49, respectively. Altered expression of 15 genes was confirmed with qRT–PCR, demonstrating the high degree of sensitivity of the RNA-seq method. The differentially expressed genes in Toxoplasma were mainly related to metabolic process and macromolecule synthesis as reflected by enhanced activity of FASII pathway. Further analyses of differentially expressed genes in PAMs uncovered unique responses of porcine macrophages to Toxoplasma infection. These analyses provide novel insights into Toxoplasma interaction with it’s hosts. Conclusions: Our study represents the first detailed dual analyses of porcine alveolar macrophages and Me49 with biologic replicates, generated by RNA-seq technology. The optimized data analysis workflows reported here provide the overall transcripts changes both PAMs and Me49. The results showed the unexpected responses of PAMs to Toxoplasma infection. These widen our understanding of interactions between Toxoplasma and it’s hosts.

Project description:BackgroundToxoplasma gondii (T. gondii) is a worldwide distributed protozoan parasite which has infected a wide range of warm-blooded animals and humans. The most common form of T. gondii infection is asymptomatic (latent); nevertheless, latent toxoplasmosis can induce various alterations of sex hormones, especially testosterone, in infected humans and animals. On the other hand, testosterone is involved in behavioral traits and reproductive functions in both sexes. Hence, the purpose of this systematic review is to summarize the available evidence regarding the association between T. gondii infection and testosterone alteration.MethodsIn the setting of a systematic review, an electronic search (any date to 10 January 2023) without language restrictions was performed using Science Direct, Web of Science, PubMed, Scopus, and Google Scholar. The PRISMA guidelines were followed. Following the initial search, a total of 12,306 titles and abstracts were screened initially; 12,281 were excluded due to the lack of eligibility criteria or duplication. Finally, 24 articles met the included criteria. A mean±standard deviation (SD) was calculated to assess the difference of testosterone between T. gondii positive and T. gondii negative humans. The possibility of publication bias was assessed using Egger's regression. P-value < 0.05 was considered statistically significant.ResultsThis systematic review identified 24 articles (18 studies in humans and six studies in animals). Most human studies (13 out of 19) reported an increased level of testosterone following latent toxoplasmosis in males, while three studies reported decreased levels and two studies reported an insignificant change. Eleven articles (seven datasets in males and seven datasets in females) were eligible to be included in the data synthesis. Based on the random-effects model, the pooled mean± SD of testosterone in T. gondii positive than T. gondii negative was increased by 0.73 and 0.55 units in males and females, respectively. The Egger's regression did not detect a statistically significant publication bias in males and females (p = value = 0.95 and 0.71), respectively. Three studies in male animals (rats, mice, and spotted hyenas) and two studies in female animals (mice and spotted hyenas) reported a decline in testosterone in infected compared with non-infected animals. While, one study in female rats reported no significant changes of testosterone in infected than non-infected animals. Moreover, two studies in male rats reported an increased level of testosterone in infected than non-infected animals.ConclusionsThis study provides new insights about the association between T. gondii infection and testosterone alteration and identifies relevant data gaps that can inform and encourage further studies. The consequence of increased testosterone levels following T. gondii infection could partly be associated with increased sexual behavior and sexual transmission of the parasite. On the other hand, declining testosterone levels following T. gondii infection may be associated with male reproductive impairments, which were observed in T. gondii-infected humans and animals. Furthermore, these findings suggest the great need for more epidemiological and experimental investigations in depth to understand the relationship between T. gondii infection and testosterone alteration alongside with future consequences of testosterone alteration.

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Transcriptional Analyses Identify Genes That Modulate Bovine Macrophage Response to Toxoplasma Infection and Immune Stimulation.

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Transcriptional Analyses Identify Genes That Modulate Bovine Macrophage Response to <i>Toxoplasma</i> Infection and Immune Stimulation.

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