Myenteric neuroprotective role of aspirin in acute and chronic experimental infections with <i>Trypanosoma cruzi</i>

Oda, Juliano Yasuo; Belém, Mônica de Oliveira; Carlos, Thalita M.; Gouveia, Rita; Luchetti, B. F. C.; Moreira, Neide Martins; Massocatto, Cristina Lorena; Araújo, Silvana Márques de; ́Ana, D. M. G. Sant; Buttow, Nilza Cristina; Pinge‐Filho, Phileno; Araújo, Eduardo J.A.

doi:10.1111/nmo.13102

Cited by 17 publications

(23 citation statements)

References 55 publications

(170 reference statements)

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“…Oliveira et al (2010) observed higher IFN-γ and IL-2 concentrations in serum of rats infected with T. cruzi and treated with meloxicam. Also, increased nitrite production and high numbers of inflammatory infiltrates was observed in the colon of mice infected with T. cruzi and treated with COX-2 inhibitor, regardless of time of infection, or acute or chronic phase (Oda et al, 2017). Additionally, upregulation of IL-1β, nitrite, IL-12, and IL-10 was verified in murine peritoneal macrophages (Malvezi et al, 2014) and human monocytes (Carvalho de Freitas et al, 2017) infected with T. cruzi and treated with aspirin-COX inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Cyclooxygenase (COX)-2 Inhibitors Reduce Toxoplasma gondii Infection and Upregulate the Pro-inflammatory Immune Response in Calomys callosus Rodents and Human Monocyte Cell Line

Aca

Silva

et al. 2019

Front. Microbiol.

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Toxoplasma gondii is able to infect a wide range of vertebrates, including humans. Studies show that cyclooxygenase-2 (COX-2) is a modulator of immune response in multiple types of infection, such as Trypanosoma cruzi . However, the role of COX-2 during T. gondii infection is still unclear. The aim of this study was to investigate the role of COX-2 during infection by moderately or highly virulent strains of T. gondii in Calomys callosus rodents and human THP-1 cells. C. callosus were infected with 50 cysts of T. gondii (ME49), treated with COX-2 inhibitors (meloxicam or celecoxib) and evaluated to check body weight and morbidity. After 40 days, brain and serum were collected for detection of T. gondii by real-time PCR and immunohistochemistry or cytokines by CBA. Furthermore, peritoneal macrophages or THP-1 cells, infected with RH strain or uninfected, were treated with meloxicam or celecoxib to evaluate the parasite proliferation by colorimetric assay and cytokine production by ELISA. Finally, in order to verify the role of prostaglandin E 2 in COX-2 mechanism, THP-1 cells were infected, treated with meloxicam or celecoxib plus PGE 2 , and analyzed to parasite proliferation and cytokine production. The data showed that body weight and morbidity of the animals changed after infection by T. gondii , under both treatments. Immunohistochemistry and real-time PCR showed a reduction of T. gondii in brains of animals treated with both COX-2 inhibitors. Additionally, it was observed that both COX-2 inhibitors controlled the T. gondii proliferation in peritoneal macrophages and THP-1 cells, and the treatment with PGE 2 restored the parasite growth in THP-1 cells blocked to COX-2. In the serum of Calomys , upregulation of pro-inflammatory cytokines was detected, while the supernatants of peritoneal macrophages and THP-1 cells demonstrated significant production of TNF and nitrite, or TNF, nitrite and MIF, respectively, under both COX-2 inhibitors. Finally, PGE 2 treatment in THP-1 cells triggered downmodulation of pro-inflammatory mediators and upregulation of IL-8 and IL-10. Thus, COX-2 is an immune mediator involved in the susceptibility to T. gondii regardless of strain or cell types, since inhibition of this enzyme induced control of infection by upregulating important pro-inflammatory mediators against Toxoplasma .

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Section: Discussionmentioning

confidence: 99%

Cyclooxygenase (COX)-2 Inhibitors Reduce Toxoplasma gondii Infection and Upregulate the Pro-inflammatory Immune Response in Calomys callosus Rodents and Human Monocyte Cell Line

Aca

Silva

et al. 2019

Front. Microbiol.

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“…The upregulated phosphoproteins involved in neurological and inflammatory pathways can damage colonic myenteric neurons during T . cruzi infection [ 20 ]. Bioinformatics analysis of array data also showed an overall increase in the proinflammatory response in HCoEpiC during T .…”

Section: Discussionmentioning

confidence: 99%

Phospho-proteomic analysis of primary human colon epithelial cells during the early Trypanosoma cruzi infection phase

et al. 2018

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The protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease, causes severe morbidity and mortality in afflicted individuals. About 30% of T. cruzi-infected individuals present with cardiac, gastrointestinal tract, and/or neurological disorders. Megacolon, one of the major pathologies of Chagas disease, is accompanied by gastrointestinal motility disorders. The molecular mechanism of T. cruzi-mediated megacolon in Chagas disease is currently unknown. To decipher the molecular mechanism of T. cruzi-induced alteration in the colon during the early infection phase, we exposed primary human colonic epithelial cells (HCoEpiC) to invasive T. cruzi trypomastigotes at multiple time points to determine changes in the phosphoprotein networks in the cells following infection using proteome profiler Human phospho-kinase arrays. We found significant changes in the phosphorylation pattern that can mediate cellular deregulations in colonic epithelial cells after infection. We detected a significant increase in the levels of phosphorylated heat shock protein (p-HSP) 27 and transcription factors that regulate various cellular functions, including c-Jun and CREB. Our study confirmed significant upregulation of phospho (p-) Akt S473, p-JNK, which may directly or indirectly modulate CREB and c-Jun phosphorylation, respectively. We also observed increased levels of phosphorylated CREB and c-Jun in the nucleus. Furthermore, we found that p-c-Jun and p-CREB co-localized in the nucleus at 180 minutes post infection, with a maximum Pearson correlation coefficient of 0.76±0.02. Increased p-c-Jun and p-CREB have been linked to inflammatory and profibrotic responses. T. cruzi infection of HCoEpiC induces an increased expression of thrombospondin-1 (TSP-1), which is fibrogenic at elevated levels. We also found that T. cruzi infection modulates the expression of NF-kB and JAK2-STAT1 signaling molecules which can increase pro-inflammatory flux. Bioinformatics analysis of the phosphoprotein networks derived using the phospho-protein data serves as a blueprint for T. cruzi-mediated cellular transformation of primary human colonic cells during the early phase of T. cruzi infection.

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“…For this, 10 microscopic fields (20× magnification lens) were analyzed in each section (total area 63.8 cm 2 ). Result was obtained by summing the number of inflammatory cell in all histological sections from the same rat which was projected to 1 cm 2,33 …”

Section: Methodsmentioning

confidence: 99%

Toxoplasma gondii infection impairs the colonic motility of rats due to loss of myenteric neurons

Machado

Watanabe

Mendes

et al. 2020

Neurogastroenterology Motil

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Background: Toxoplasma gondii infection causes intestinal inflammation and diarrhea indicating possible intestinal motor dysfunction. Anatomical studies have shown alterations in the colonic myenteric plexus, but it is unknown whether this impacts motility and therefore whether motility is a target for treatment. We determined whether colonic coordinated movements are compromised by toxoplasmic infection and how it is associated with anatomical changes. Methods: Male Wistar rats were evaluated at 6, 12, 24, 48, and 72 hours and 30 days postinfection (dpi) and controls. Infected rats received orally 5 × 10 3 sporulated oocysts of strain ME-49 (genotype II) of T gondii. The colon was collected for anatomical analysis (including the myenteric plexus immunolabeled with HuC/D, nNOS, and ChAT) and motility analysis in vitro (conventional manometry). Fecal output was measured daily. Key Results: At 12 hours postinfection, T gondii caused hypertrophy of the muscularis externa layer of the distal colon. There was loss of total, nitrergic, and cholinergic myenteric neurons in the proximal colon at 30 day postinfection (dpi); however, only loss of cholinergic neurons was found in the distal colon. Contractile complexes in the middle and distal colon were longer in duration in infected animals, which was associated with slower migration of the colonic motor complex. However, gastrointestinal transit time and fecal pellet output remained unchanged during the T gondii infection. Conclusions and Inferences: Toxoplasma gondii caused myenteric neuronal loss in the proximal and distal colon and altered the motility pattern in the middle and distal colon to a more propulsive phenotype.

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Myenteric neuroprotective role of aspirin in acute and chronic experimental infections with Trypanosoma cruzi

Abstract: Early and delayed treatment with low-dose ASA can reduce the morphofunctional damage of colonic myenteric neurons caused by murine T. cruzi infection.

Cited by 17 publications

References 55 publications

Cyclooxygenase (COX)-2 Inhibitors Reduce Toxoplasma gondii Infection and Upregulate the Pro-inflammatory Immune Response in Calomys callosus Rodents and Human Monocyte Cell Line

Cyclooxygenase (COX)-2 Inhibitors Reduce Toxoplasma gondii Infection and Upregulate the Pro-inflammatory Immune Response in Calomys callosus Rodents and Human Monocyte Cell Line

Phospho-proteomic analysis of primary human colon epithelial cells during the early Trypanosoma cruzi infection phase

Toxoplasma gondii infection impairs the colonic motility of rats due to loss of myenteric neurons

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