A Review on the Immunological Response against Trypanosoma cruzi

Macaluso, Giusi; Grippi, Francesca; Bella, Santina Di; Blanda, Valeria; Gucciardi, Francesca; Torina, Alessandra; Guercio, Annalisa; Cannella, Vincenza

doi:10.3390/pathogens12020282

Cited by 19 publications

(18 citation statements)

References 128 publications

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“…Toll-like receptors play an important role in the elimination of microbes through recognition of pathogen-associated patterns and induction of inflammatory cytokines and type I interferons ( Fitzgerald and Kagan, 2020 ; Motomura et al, 2023 ). T. cruzi molecules such as surface glycoinositolphospholipids (GPIs) and parasite DNA/RNA sequences can be sensed by TLRs ( Macaluso et al, 2023 ). In fact, several investigators have shown the significance and involvement of TLRs in the control of T. cruzi infection ( Caetano et al, 2011 ; Castillo et al, 2017b ; Queiroga et al, 2021 ; Ait Djebbara et al, 2023 ).…”

Section: Resultsmentioning

confidence: 99%

The transcriptome landscape of 3D-cultured placental trophoblasts reveals activation of TLR2 and TLR3/7 in response to low Trypanosoma cruzi parasite exposure

Silberstein,

Chung,

Debrabant

2023

Front. Microbiol.

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Vertical transmission of Trypanosoma cruzi (T. cruzi) become a globalized health problem accounting for 22% of new cases of Chagas disease (CD). Congenital infection is now considered the main route of CD spread in non-endemic countries where no routine disease testing of pregnant women is implemented. The main mechanisms that lead to fetal infection by T. cruzi remain poorly understood. Mother-to-child transmission may occur when bloodstream trypomastigotes interact with the syncytiotrophoblasts (SYNs) that cover the placenta chorionic villi. These highly specialized cells function as a physical barrier and modulate immune responses against pathogen infections. To model the human placenta environment, we have previously used a three-dimensional (3D) cell culture system of SYNs that exhibits differentiation characteristics comparable to placental trophoblasts. Further, we have shown that 3D-grown SYNs are highly resistant to T. cruzi infection. In this work, we used RNA sequencing and whole transcriptome analysis to explore the immunological signatures that drive SYNs’ infection control. We found that the largest category of differentially expressed genes (DEGs) are associated with inflammation and innate immunity functions. Quantitative RT-PCR evaluation of selected DEGs, together with detection of cytokines and chemokines in SYNs culture supernatants, confirmed the transcriptome data. Several genes implicated in the Toll-like receptors signaling pathways were upregulated in 3D-grown SYNs. In fact, TLR2 blockade and TLR3/7 knockdown stimulated T. cruzi growth, suggesting that these molecules play a significant role in the host cell response to infection. Ingenuity Pathway Analysis of DEGs predicted the activation of canonical pathways such as S100 protein family, pathogen induced cytokine storm, wound healing, HIF1α signaling and phagosome formation after T. cruzi exposure. Our findings indicate that SYNs resist infection by eliciting a constitutive pro-inflammatory response and modulating multiple defense mechanisms that interfere with the parasite’s intracellular life cycle, contributing to parasite killing and infection control.

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Section: Resultsmentioning

confidence: 99%

The transcriptome landscape of 3D-cultured placental trophoblasts reveals activation of TLR2 and TLR3/7 in response to low Trypanosoma cruzi parasite exposure

Silberstein,

Chung,

Debrabant

2023

Front. Microbiol.

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“…This review supports existing literature findings, indicating that patients with CD4+ T-cell counts below 200 cells per mm 3 were associated with more severe CNS Chagas disease (Córdova et al ., 2013; Pittella, 2013). As the immune system relies on CD4+ T helper 1 (Th1) cells for protective immunity during the acute and chronic stages of Chagas disease, it is reasonable to expect higher parasitaemia and poor disease control in immunocompromised patients (Brener and Gazzinelli, 1997; Macaluso et al ., 2023). T-cell responses, mediated by both CD4+ and CD8+ T cells, in Chagas disease are rather complex.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of patients in Chagas disease of the central nervous system: a systematic review

Shelton,

Gonzalez

2023

Parasitology

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Chagas disease is a parasitic infection caused by the protozoan Trypanosoma cruzi. One of the complications of the disease is the infection of the central nervous system (CNS), as it can result from either the acute phase or by reactivation during the chronic phase, exhibiting high mortality in immunocompromised patients. This systematic review aimed to determine clinical and paraclinical characteristics of patients with Chagas disease in the CNS. Articles were searched from PubMed, Scopus and LILACS until January 2023. From 2325 articles, 59 case reports and 13 case series of patients with Chagas in the CNS were retrieved from which 138 patients were identified. In this population, 77% of the patients were male, with a median age of 35 years old, from which most of them came from Argentina and Brazil. Most of the individuals were immunocompromised from which 89% were HIV-positive, and 54 patients had an average of 48 cells per mm3 CD4+ T cells. Motor deficits and seizures were the most common manifestation of CNS compromise. Furthermore, 90 patients had a documented CNS lesion by imaging from which 89% were supratentorial and 86% were in the anterior/middle cranial fossa. The overall mortality was of 74%. Among patients who were empirically treated with anti-toxoplasma drugs, 70% died. This review shows how Chagas disease in the CNS is a devastating complication requiring prompt diagnosis and treatment to improve patients’ outcomes.

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“…It is estimated that 7 million individuals are infected worldwide, causing approximately 12 thousand deaths annually ( 1 , 2 ). While most patients affected by T. cruzi are asymptomatic, about 30% of infected individuals develop Chronic Chagas Cardiomyopathy (CCC) ( 3 , 4 ), which is recognized as the most critical clinical manifestation of the disease ( 5 , 6 ). Patients with CCC exhibit electrocardiographic changes that can lead to severe arrhythmias, heart failure, and thromboembolic phenomena.…”

Section: Introductionmentioning

confidence: 99%

Signatures of CD4+ T and B cells are associated with distinct stages of chronic chagasic cardiomyopathy

Vale,

Almeida,

Rimkute

et al. 2024

Front. Immunol.

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IntroductionChagas disease is a neglected parasitic disease caused by Trypanosoma cruzi. While most patients are asymptomatic, around 30% develop Chronic Chagasic Cardiomyopathy (CCC).MethodsHere, we employed high-dimensional flow cytometry to analyze CD4+ T and B cell compartments in patients during the chronic phase of Chagas disease, presenting the asymptomatic and mild or moderate/severe cardiac clinical forms.ResultsEffector CD27-CD4+ T cells were expanded in both CCC groups, and only mild CCC patients showed higher frequencies of effector memory and T follicular helper (Tfh) cells than healthy donors (CTL) and asymptomatic patients. Unsupervised analysis confirmed these findings and further revealed the expansion of a specific subpopulation composed of Tfh, transitional, and central memory CD4+ T cells bearing a phenotype associated with strong activation, differentiation, and exhaustion in patients with mild but not moderate/severe CCC. In contrast, patients with mild and moderate/severe CCC had lower frequencies of CD4+ T cells expressing lower levels of activation markers, suggesting resting status, than CTL. Regarding the B cell compartment, no alterations were found in naïve CD21-, memory cells expressing IgM or IgD, marginal zone, and plasma cells in patients with Chagas disease. However, expansion of class-switched activated and atypical memory B cells was observed in all clinical forms, and more substantially in mild CCC patients.DiscussionTaken together, our results showed that T. cruzi infection triggers changes in CD4+ T and B cell compartments that are more pronounced in the mild CCC clinical form, suggesting an orchestrated cellular communication during Chagas disease.ConclusionOverall, these findings reinforce the heterogeneity and complexity of the immune response in patients with chronic Chagas disease and may provide new insights into disease pathology and potential markers to guide clinical decisions.

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A Review on the Immunological Response against Trypanosoma cruzi

Cited by 19 publications

References 128 publications

The transcriptome landscape of 3D-cultured placental trophoblasts reveals activation of TLR2 and TLR3/7 in response to low Trypanosoma cruzi parasite exposure

The transcriptome landscape of 3D-cultured placental trophoblasts reveals activation of TLR2 and TLR3/7 in response to low Trypanosoma cruzi parasite exposure

Outcomes of patients in Chagas disease of the central nervous system: a systematic review

Signatures of CD4+ T and B cells are associated with distinct stages of chronic chagasic cardiomyopathy

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