Early serum biomarker networks in infants with distinct retinochoroidal lesion status of congenital toxoplasmosis

Araújo, Thádia Evelyn de; Coelho-dos-Reis, Jordana Grazziela Alves; Béla, Samantha Ribeiro; Carneiro, Ana Carolina Aguiar Vasconcelos; Machado, Anderson Silva; Cardoso, Ludmila Melo; Ribeiro, Ágata Lopes; Dias, Michelle Hallais França; Andrade, Gláucia Manzan Queiroz de; Vasconcelos-Santos, Daniel Vítor; Januário, José Nélio; Teixeira-Carvalho, Andréa; Vítor, Ricardo Wagner Almeida; Ferro, Eloísa Amália Vieira; Martins‐Filho, Olindo Assis

doi:10.1016/j.cyto.2017.02.018

Cited by 11 publications

(15 citation statements)

References 36 publications

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“…In patients with active retinochoroidal lesions due to congenital infection, an expansion of monocytes and NK cells in blood was found (39). The expansion, migration, and activation of these cells might be associated with chemokine/cytokine cross talk (40). Information concerning intraocular cytokine levels in OT has been obtained from aqueous humor (AH) samples, but further studies are needed in order to determine the precise source of these mediators and their contributions to pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis

et al. 2018

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Toxoplasmosis is caused by infection with the protozoan parasite , which has the capacity to infect all warm-blooded animals worldwide. Toxoplasmosis is a major cause of visual defects in the Colombian population; however, the association between genetic polymorphisms in cytokine genes and susceptibility to ocular toxoplasmosis has not been studied in this population. This work evaluates the associations between polymorphisms in genes coding for the cytokines tumor necrosis factor alpha (TNF-α) (rs1799964, rs1800629, rs1799724, rs1800630, and rs361525), interleukin 1β (IL-1β) (rs16944, rs1143634, and rs1143627), IL-1α (rs1800587), gamma interferon (IFN-γ) (rs2430561), and IL-10 (rs1800896 and rs1800871) and the presence of ocular toxoplasmosis (OT) in a sample of a Colombian population (61 patients with OT and 116 healthy controls). Genotyping was performed with the "dideoxynucleotide (ddNTP) primer extension" technique. Functional-effect predictions of single nucleotide polymorphisms (SNPs) were done by using FuncPred. A polymorphism in the IL-10 gene promoter (-1082G/A) was significantly more prevalent in OT patients than in controls ( = 1.93e-08; odds ratio [OR] = 5.27e+03; 95% confidence interval [CI] = 3.18 to 8.739; Bonferroni correction [BONF] = 3.48e-07). In contrast, haplotype "AG" of the IL-10 gene promoter polymorphisms (rs1800896 and rs1800871) was present at a lower frequency in OT patients ( = 7e-04; OR = 0.10; 95% CI = 0.03 to 0.35). The +874A/T polymorphism of IFN-γ was associated with OT ( = 3.37e-05; OR = 4.2; 95% CI = 2.478 to 7.12; BONF = 6.07e-04). Haplotype "GAG" of the IL-1β gene promoter polymorphisms (rs1143634, rs1143627, and rs16944) appeared to be significantly associated with OT ( = 0.0494). The IL-10, IFN-γ, and IL-1β polymorphisms influence the development of OT in the Colombian population.

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Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis

et al. 2018

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“…27 Consistently, we observed almost complete arrest of neutrophils at the human retinal endothelial cell interface in Boyden transwells despite the presence of CXCL8, which is strongly chemotactic for neutrophils, and expressed systemically and in ocular fluids during ocular toxoplasmosis. [28][29][30] We also observed limitation of neutrophil movement toward several chemokines that are present at high levels within the eye during the infection: CXCL1, CXCL2, and CXCL8. 29,31 Our results suggest that in ocular toxoplasmosis, neutrophils enter the eye uninfected, but in response to the retinal infection.…”

Section: Discussionmentioning

confidence: 69%

Neutrophil Activities in Human Ocular Toxoplasmosis: An In Vitro Study With Human Cells

Ashander

Lie

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Retinal damage in ocular toxoplasmosis reflects Toxoplasma gondii-induced cell lysis and reactive inflammation. Human retinal histopathology demonstrates the presence of neutrophils, but activities of this leukocyte subset are unstudied. We conducted in vitro experiments to evaluate roles for neutrophils as retinal taxis for T. gondii and as contributors to the inflammation. METHODS. Human neutrophils were isolated from peripheral blood. Migration to diseaserelevant chemokines was evaluated in transwells, seeded with human retinal endothelial cells for some assays, using neutrophils infected with GT-1 strain T. gondii tachyzoites. Neutrophils were cocultured with T. gondii-infected ARPE-19 and primary human retinal pigment epithelial cells, and production of reactive oxygen species (ROS) was estimated by dihydroethidium reaction. Proteins produced by T. gondii-infected ARPE-19 cells were profiled by immunoarray, and candidate neutrophil-activating proteins were targeted with specific blocking antibody in coculture assays. RESULTS. Infection with T. gondii arrested neutrophil migration across retinal endothelium regardless of the presence of CXCL8. Migration to CXCL1, CXCL2, and CXCL8 also was significantly inhibited in infected neutrophils. Neutrophils generated more ROS when cocultured with infected versus uninfected ARPE-19 cells and three of four primary retinal pigment epithelial cell isolates. Infected ARPE-19 cells augmented the synthesis of 12 neutrophil-activating proteins also expressed by primary retinal pigment epithelial cells. Antibody blockade of granulocyte-macrophage colony-stimulating factor, interleukin-6 (IL-6) and IL-18 significantly reduced ROS production by neutrophils cocultured with T. gondiiinfected ARPE-19 cells. CONCLUSIONS. Our findings support involvement of neutrophils in retinal inflammation, but not parasite transport, in the setting of ocular toxoplasmosis.

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“…Moreover, we have also observed that the combined analysis of CXCL9 and CXCL10 improves the accuracy of these biomarkers to diagnose toxoplasmosis. We have previously shown increased levels of serum CXCL9 and CXCL10 in T. gondii-infected infants early after birth 14 . High levels of chemokines have been also described in the aqueous humor from patients with primary or recurrent ocular toxoplasmosis as compared to disease-free controls 23 .…”

Section: Discussionmentioning

confidence: 90%

“…High levels of chemokines have been also described in the aqueous humor from patients with primary or recurrent ocular toxoplasmosis as compared to disease-free controls 23 . It is well known that the immune response induced by T. gondii infection is mediated by a rich microenvironment of activated cells and soluble inflammatory mediators including chemokines, cytokines and cell factors 14,[24][25][26][27][28][29][30] . It has been already reported that the expression of CXCL9 and CXCL10 in the retina was significantly upregulated in experimental model of ocular toxoplasmosis 28 .…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that besides eliciting a robust antibody response, congenital T. gondii infection results in longlasting cell-mediated immune response, which involve a wide range of cell subsets and soluble molecules 5,[7][8][9][10][11][12][13][14] . Surprisingly, the studies that investigated the potential role of cell immunity in diagnosis of congenital toxoplasmosis or methods with prognostic potential to predict the retinochoroidal lesion status are still scarce.…”

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confidence: 99%

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Putative biomarkers for early diagnosis and prognosis of congenital ocular toxoplasmosis

Araújo

Santos

Gomes

et al. 2020

Sci Rep

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In the present study we have evaluated the performance of several immunological biomarkers for early diagnosis and prognosis of congenital toxoplasmosis. Our results showed that ex vivo serum levels of CXCL9, and the frequencies of circulating CD4+CD25+ T-cells and T. gondii-specific IFN-γ+CD4+ T-cells measured 30–45 days after birth presented high accuracy to distinguish T. gondii-infected infants from healthy age-matched controls (Global Accuracy/AUC = 0.9; 0.9 and 0.8, respectively). Of note was the enhanced performance (Accuracy = 96%) achieved by using a combined stepwise analysis of CD4+CD25+ T-cells and CXCL9. In addition, high global accuracy (AUC = 0.9) with elevated sensitivity (Se = 98%) was also reached by using the total frequency of in vitro IFN-γ-producing T. gondii-specific T-cells (∑ IFN-γ+ CD4+ & CD8+) as a biomarker of congenital toxoplasmosis. Furthermore, the analysis of in vitro T. gondii-specific IL5+CD4+ T-cells and IFN-γ+NK-cells displayed a high accuracy for early prognosis of ocular lesion in infant with congenital toxoplasmosis (Global Accuracy/AUC = 0.8 and 0.9, respectively). Together, these findings support the relevance of employing the elements of the cell-mediated immune response as biomarkers with potential to endorse early diagnosis and prognosis of congenital ocular toxoplasmosis to contribute for a precise clinical management and effective therapeutic intervention.

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Early serum biomarker networks in infants with distinct retinochoroidal lesion status of congenital toxoplasmosis

Cited by 11 publications

References 36 publications

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis

Neutrophil Activities in Human Ocular Toxoplasmosis: An In Vitro Study With Human Cells

Putative biomarkers for early diagnosis and prognosis of congenital ocular toxoplasmosis

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