Herpes simplex virus type 1 induces simultaneous activation of Toll-like receptors 2 and 4 and expression of the endogenous ligand serum amyloid A in astrocytes

Villalba, Melina; Hott, Melissa; Martin, Carolina; Aguila, Blanca; Valdivia, Sharin; Quezada, Claudia; Zambrano, Ángara; Concha, Miguel; Otth, Carola

doi:10.1007/s00430-012-0247-0

Cited by 49 publications

(38 citation statements)

References 40 publications

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“…Although the functions of Gbp4 and Gbp8 in T. gondii infection are not understood, these molecules might be associated with IFN-␥-dependent host defense. Furthermore, previous research has shown that CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES are chemokines predominantly induced in the brains of BALB/c mice during chronic infection with T. gondii (27).…”

Section: Discussionmentioning

confidence: 93%

Transcriptome Analysis of Mouse Brain Infected with Toxoplasma gondii

et al. 2013

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c Toxoplasma gondii is an obligate intracellular parasite that invades a wide range of vertebrate host cells. Chronic infections with T. gondii become established in the tissues of the central nervous system, where the parasites may directly or indirectly modulate neuronal function. However, the mechanisms underlying parasite-induced neuronal disorder in the brain remain unclear. This study evaluated host gene expression in mouse brain following infection with T. gondii. BALB/c mice were infected with the PLK strain, and after 32 days of infection, histopathological lesions in the frontal lobe were found to be more severe than in other areas of the brain. Total RNA extracted from infected and uninfected mouse brain samples was subjected to transcriptome analysis using RNA sequencing (RNA-seq). In the T. gondii-infected mice, 935 mouse brain genes were upregulated, whereas 12 genes were downregulated. GOstat analysis predicted that the upregulated genes were primarily involved in host immune responses and cell activation. Positive correlations were found between the numbers of parasites in the infected mouse brains and the expression levels of genes involved in host immune responses. In contrast, genes that had a negative correlation with parasite numbers were predicted to be involved in neurological functions, such as small-GTPase-mediated signal transduction and vesicle-mediated transport. Furthermore, differential gene expression was observed between mice exhibiting the clinical signs of toxoplasmosis and those that did not. Our findings may provide insights into the mechanisms underlying neurological changes during T. gondii infection.T oxoplasma gondii, an obligate intracellular parasite, invades a wide variety of cells in its vertebrate hosts. The disease caused by T. gondii is usually asymptomatic but can be severe in immunosuppressed individuals, and cyst reactivation causes toxoplasmic encephalitis in AIDS patients (1). In addition, infection of nonimmune women during pregnancy can lead to congenital infection, with hydrocephaly, microcephaly, or intracerebral calcifications occurring in the fetus (2).Systemic infection by the proliferating stage of the parasite, the tachyzoite, is efficiently controlled by the cellular immune response. However, the pathogen persists in its slowly replicating stage, the bradyzoite, in tissue cysts mainly within the muscle and brain. In chronic infections, parasites within neurons can directly cause neuronal death and atrophy of neuronal processes, while inflammation via production of nitric oxide (NO) and inflammatory cytokines from microglia or immune cells may contribute to the death of neighboring neurons (3). However, the mechanisms underlying parasite-induced neuronal disorder in the brain remain unclear.In mice and rats, the specificity of behavioral modifications induced by T. gondii has been examined across a broad range of behaviors that primarily concern anxiety and learned fear in these animals (4). Recently, it has been suggested that chronic infection with T...

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Section: Discussionmentioning

confidence: 93%

Transcriptome Analysis of Mouse Brain Infected with Toxoplasma gondii

et al. 2013

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“…In macrophages, TLR-2 promotes autophagy (Chuang et al, 2013), and intracranial HSV-1 infection stimulates TLR-2-dependent expression of the inflammatory cytokines IL-1b, IL-6 and TNF-a by microglia, astrocytes, neutrophils and monocytes (Aravalli et al, 2005;Villalba et al, 2012;Wang et al, 2012). However, in both macrophages and human foreskin fibroblasts, HSV-1 actually inhibits the secretion of mature IL-1b, apparently related to the trapping of caspase-1 by actin clusters (Johnson et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…TLR-2 induces inflammatory cytokine production by microglia, astrocytes, neutrophils and monocytes following HSV-1 intracranial infection (Aravalli et al, 2005;Villalba et al, 2012;Wang et al, 2012), but its induction in melanoma cells, in the context of oncolysis, and as related to direct cytokine secretion, is unknown. As autophagy was previously linked to cytokine secretion (Crişan et al, 2011;Harris, 2011), A2058 and A375 cells were mock-infected with PBS or infected with D PK (m.o.i.…”

Section: Inflammatory Cytokines Are Upregulated Through Autophagy-depmentioning

confidence: 99%

ΔPK oncolytic activity includes modulation of the tumour cell milieu

Bollino

Nghiem

et al. 2016

Journal of General Virology

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Oncolytic virotherapy is a unique cancer therapeutic that encompasses tumour cell lysis through both virus replication and programmed cell death (PCD) pathways. Nonetheless, clinical efficacy is relatively modest, likely related to the immunosuppressive tumour milieu. Our studies use the herpes simplex virus type 2 (HSV-2)-based oncolytic virus D PK that has documented anti-tumour activity associated with virus replication, PCD and cancer stem cell lysis. They are designed to examine whether D PK-mediated oncolysis includes the ability to reverse the immunosuppressive tumour microenvironment by altering the balance of cytokines directly secreted by the melanoma cells and to define its mechanism. Here, we show that melanoma cells secreted the immunosuppressive cytokine IL-10, and that secretion was inhibited by D PK through virus replication and c-Jun N-terminal kinase/c-Jun activation. D PK-induced IL-10 inhibition upregulated surface expression of MHC class I chain-related protein A, the ligand for the activating NKG2D receptor expressed on NK-and cytotoxic T-cells. Concomitantly, D PK also upregulated the secretion of inflammatory cytokines TNF-a, granulocyte macrophage colony-stimulating factor and IL-1b through autophagy-mediated activation of Toll-like receptor 2 pathways and pyroptosis, and it inhibited the expression of the negative immune checkpoint regulator cytotoxic T-lymphocyte antigen 4. Pharmacologic inhibition of these processes significantly reduces the oncolytic activity of D PK.

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“…Brain inflammation due to infection is associated with the activation of the local innate immune system. This could be a crucial mechanism leading to the neuronal damage, as it was also described in the case of HSK, where a chronic inflammatory reaction in response to viral reactivation in the eye may lead to vision impairment and even blindness [8–10, 23]. …”

Section: Discussionmentioning

confidence: 99%

Antiviral Action of Synthetic Stigmasterol Derivatives on Herpes Simplex Virus Replication in Nervous CellsIn Vitro

Petrera

Níttolo

Alché

2014

BioMed Research International

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Polyfunctionalized stigmasterol derivatives, (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound 1) and (22S,23S)-3β-bromo-5α,22,23-trihydroxystigmastan-6-one (compound 2), inhibit herpes simplex virus type 1 (HSV-1) replication and spreading in human epithelial cells derived from ocular tissues. Both compounds reduce the incidence and severity of lesions in a murine model of herpetic stromal keratitis when administered in different treatment modalities. Since encephalitis caused by HSV-1 is another immunopathology of viral origin, we evaluate here the antiviral effect of both compounds on HSV-1 infected nervous cell lines as well as their anti-inflammatory action. We found that both stigmasterol derivatives presented low cytotoxicity in the three nervous cell lines assayed. Regarding the antiviral activity, in all cases both compounds prevented HSV-1 multiplication when added after infection, as well as virus propagation. Additionally, both compounds were able to hinder interleukin-6 and Interferon-gamma secretion induced by HSV-1 infection in Neuro-2a cells. We conclude that compounds 1 and 2 have exerted a dual antiviral and anti-inflammatory effect in HSV-1 infected nervous cell lines, which makes them interesting molecules to be further studied.

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Herpes simplex virus type 1 induces simultaneous activation of Toll-like receptors 2 and 4 and expression of the endogenous ligand serum amyloid A in astrocytes

Cited by 49 publications

References 40 publications

Transcriptome Analysis of Mouse Brain Infected with Toxoplasma gondii

Transcriptome Analysis of Mouse Brain Infected with Toxoplasma gondii

ΔPK oncolytic activity includes modulation of the tumour cell milieu

Antiviral Action of Synthetic Stigmasterol Derivatives on Herpes Simplex Virus Replication in Nervous CellsIn Vitro

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