Transcriptome analysis of the effect of C-C chemokine receptor 5 deficiency on cell response to  Toxoplasma gondii  in brain cells

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Abstract

Background

Infection with Toxoplasma gondii is thought to damage the brain and be a risk factor for neurological and psychotic disorders. The immune response-participating chemokine system has recently been considered vital for brain cell signaling and neural functioning. Here, we investigated the effect of the deficiency of C-C chemokine receptor 5 (CCR5), which is previously reported to be associated with T. gondii infection, on gene expression in the brain during T. gondii infection and the relationship between CCR5 and the inflammatory response against T. gondii infection in the brain.

Results

We performed a genome-wide comprehensive analysis of brain cells from wild-type and CCR5-deficient mice. Mouse primary brain cells infected with T. gondii were subjected to RNA sequencing. The expression levels of some genes, especially in astrocytes and microglia, were altered by CCR5-deficiency during T. gondii infection, and the gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed an enhanced immune response in the brain cells. The expression levels of genes which were highly differentially expressed in vitro were also investigated in the mouse brains during the T. gondii infections. Among the genes tested, only Saa3 (serum amyloid A3) showed partly CCR5-dependent upregulation during the acute infection phase. However, analysis of the subacute phase showed that in addition to Saa3, Hmox1 may also contribute to the protection and/or pathology partly via the CCR5 pathway.

Conclusions

Our results indicate that CCR5 is involved in T. gondii infection in the brain where it contributes to inflammatory responses and parasite elimination. We suggest that the inflammatory response by glial cells through CCR5 might be associated with neurological injury during T. gondii infection to some extent.

Supplementary information

Supplementary information accompanies this paper at 10.1186/s12864-019-6076-4.

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Most cited references 43

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Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis.

Georgios Pappas, Nikos Roussos, Matthew E. Falagas (2009)

Toxoplasma gondii's importance for humans refers mainly to primary infection during pregnancy, resulting in abortion/stillbirth or congenital toxoplasmosis. The authors sought to evaluate the current global status of T. gondii seroprevalence and its correlations with risk factors, environmental and socioeconomic parameters. Literature published during the last decade on toxoplasmosis seroprevalence, in women who were pregnant or of childbearing age, was retrieved. A total of 99 studies were eligible; a further 36 studies offered seroprevalence data from regions/countries for which no data on pregnancy/childbearing age were available. Foci of high prevalence exist in Latin America, parts of Eastern/Central Europe, the Middle East, parts of south-east Asia and Africa. Regional seroprevalence variations relate to individual subpopulations' religious and socioeconomic practices. A trend towards lower seroprevalence is observed in many European countries and the United States of America (USA). There is no obvious climate-related gradient, excluding North and Latin America. Immigration has affected local prevalence in certain countries. We further sought to recognise specific risk factors related to seropositivity; however, such risk factors are not reported systematically. Population awareness may affect recognition of said risks. Global toxoplasmosis seroprevalence is continuingly evolving, subject to regional socioeconomic parameters and population habits. Awareness of these seroprevalence trends, particularly in the case of women of childbearing age, may allow proper public health policies to be enforced, targeting in particular seronegative women of childbearing age in high seroprevalence areas.

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The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase.

Sachie Hiratsuka, Akira Watanabe, Yoshiko Sakurai … (2008)

A large number of macrophages and haematopoietic progenitor cells accumulate in pre-metastatic lungs in which chemoattractants, such as S100A8 and S100A9, are produced by distant primary tumours serving as metastatic soil. The exact mechanism by which these chemoattractants elicit cell accumulation is not known. Here, we show that serum amyloid A (SAA) 3, which is induced in pre-metastatic lungs by S100A8 and S100A9, has a role in the accumulation of myeloid cells and acts as a positive-feedback regulator for chemoattractant secretion. We also show that in lung endothelial cells and macrophages, Toll-like receptor (TLR) 4 acts as a functional receptor for SAA3 in the pre-metastatic phase. In our study, SAA3 stimulated NF-kappaB signalling in a TLR4-dependent manner and facilitated metastasis. This inflammation-like state accelerated the migration of primary tumour cells to lung tissues, but this was suppressed by the inhibition of either TLR4 or SAA3. Thus, blocking SAA3-TLR4 function in the pre-metastatic phase could prove to be an effective strategy for the prevention of pulmonary metastasis.

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GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals.

Avinash Shenoy, David Wellington, Pradeep Kumar … (2012)

Inflammasomes are sensory complexes that alert the immune system to the presence of infection or tissue damage. These complexes assemble NLR (nucleotide binding and oligomerization, leucine-rich repeat) or ALR (absent in melanoma 2-like receptor) proteins to activate caspase-1 cleavage and interleukin (IL)-1β/IL-18 secretion. Here, we identified a non-NLR/ALR human protein that stimulates inflammasome assembly: guanylate binding protein 5 (GBP5). GBP5 promoted selective NLRP3 inflammasome responses to pathogenic bacteria and soluble but not crystalline inflammasome priming agents. Generation of Gbp5(-/-) mice revealed pronounced caspase-1 and IL-1β/IL-18 cleavage defects in vitro and impaired host defense and Nlrp3-dependent inflammatory responses in vivo. Thus, GBP5 serves as a unique rheostat for NLRP3 inflammasome activation and extends our understanding of the inflammasome complex beyond its core machinery.

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Author and article information

Contributors

Yoshifumi Nishikawa: nisikawa@obihiro.ac.jp

Journal

Journal ID (nlm-ta): BMC Genomics

Journal ID (iso-abbrev): BMC Genomics

Title: BMC Genomics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2164

Publication date (Electronic): 11 September 2019

Publication date PMC-release: 11 September 2019

Publication date Collection: 2019

Volume: 20

Electronic Location Identifier: 705

Affiliations

[1 ]ISNI 0000 0001 0688 9267, GRID grid.412310.5, National Research Center for Protozoan Diseases, , Obihiro University of Agriculture and Veterinary Medicine, ; Obihiro, Hokkaido Japan

[2 ]ISNI 0000 0001 1507 4692, GRID grid.263518.b, Division of Animal Science, Department of Agricultural and Life Sciences, Faculty of Agriculture, , Shinshu University, ; Minamiminowa, Nagano, Japan

[3 ]ISNI 0000 0001 2173 7691, GRID grid.39158.36, Research Center for Zoonosis Control, , Hokkaido University, ; Sapporo, Hokkaido Japan

[4 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, Graduate School of Frontier Science, , The University of Tokyo, ; Kashiwa, Chiba, Japan

Article

Publisher ID: 6076

DOI: 10.1186/s12864-019-6076-4

PMC ID: 6737708

PubMed ID: 31506064

SO-VID: 19df0a8c-9e1c-4bdd-b3f0-c9b479fd1a57

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 1 May 2019

Date accepted : 4 September 2019

Funding

Funded by: JSPS

Award ID: 2011/LS003

Award ID: JP15K15118

Award ID: JP17K19538

Award ID: JP17K17570

Award Recipient : Kousuke Umeda Yoshifumi Nishikawa

Funded by: AMED

Award ID: 17fk0108120h0001

Award Recipient : Yoshifumi Nishikawa

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: toxoplasma gondii,c-c chemokine receptor 5,brain,astrocyte,microglia,neuron,transcriptome

Data availability:

ScienceOpen disciplines: Genetics

Keywords: toxoplasma gondii, c-c chemokine receptor 5, brain, astrocyte, microglia, neuron, transcriptome

Transcriptome analysis of the effect of C-C chemokine receptor 5 deficiency on cell response to Toxoplasma gondii in brain cells

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Abstract

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Supplementary information

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Genes & Diseases

Most cited references 43

Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis.

The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase.

GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals.

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