CCR5 controls immune and metabolic functions during Toxoplasma gondii infection
Giuliano Bonfá1, Luciana Benevides1, Maria do Carmo Souza1
1Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
Abstract:
CCR5, an important receptor related to cell recruitment and inflammation, is expressed during experimental Toxoplasma gondii infection. However, its role in the immunopathology of toxoplasmosis is not clearly defined yet. Thus, we inoculated WT and CCR5(-/-) mice with a sub lethal dose of the parasite by oral route. CCR5(-/-) mice were extremely susceptible to infection, presenting higher parasite load and lower tissue expression of IL-12p40, IFN-γ, TNF, IL-6, iNOS, Foxp3, T-bet, GATA-3 and PPARα. Although both groups presented inflammation in the liver with prominent neutrophil infiltration, CCR5(-/-) mice had extensive tissue damage with hepatocyte vacuolization, steatosis, elevated serum triglycerides and transaminases. PPARα agonist Gemfibrozil improved the vacuolization but did not rescue CCR5(-/-) infected mice from high serum triglycerides levels and enhanced mortality. We also found intense inflammation in the ileum of CCR5(-/-) infected mice, with epithelial ulceration, augmented CD4 and decreased frequency of NK cells in the gut lamina propria. Most interestingly, these findings were accompanied by an outstanding accumulation of neutrophils in the ileum, which seemed to be involved in the gut immunopathology, once the depletion of these cells was accompanied by reduced local damage. Altogether, these data demonstrated that CCR5 is essential to the control of T. gondii infection and to maintain the metabolic, hepatic and intestinal integrity. These findings add novel information on the disease pathogenesis and may be relevant for directing future approaches to the treatment of multi-deregulated diseases.
Insights
CCR5 is crucial for controlling Toxoplasma gondii infection. Its absence leads to severe liver and intestinal damage, increased parasite load, and higher mortality, highlighting CCR5
Area of Science:
- Immunology
- Parasitology
- Molecular Biology
Background:
- Chemokine receptor CCR5 (C-C chemokine receptor type 5) is involved in cell recruitment and inflammation.
- The role of CCR5 in the immunopathology of Toxoplasma gondii infection remains unclear.
- Toxoplasmosis is a widespread parasitic infection with significant health implications.
Purpose of the Study:
- To investigate the role of CCR5 in the host's immune response and pathology during experimental Toxoplasma gondii infection.
- To determine the impact of CCR5 deficiency on parasite load, tissue damage, and immune cell infiltration.
- To explore potential therapeutic strategies targeting CCR5.
Main Methods:
- Wild-type (WT) and CCR5(-/-) mice were orally inoculated with a sub-lethal dose of Toxoplasma gondii.
- Parasite load, tissue cytokine and chemokine expression, and immune cell populations were analyzed.
- Liver and intestinal tissues were examined for histopathological changes, and serum biochemistry was assessed.
Main Results:
- CCR5(-/-) mice exhibited extreme susceptibility to infection, with higher parasite burdens and reduced expression of key immune mediators (IL-12p40, IFN-γ, TNF, IL-6).
- Significant liver damage, including hepatocyte vacuolization, steatosis, and elevated serum triglycerides and transaminases, was observed in CCR5(-/-) mice.
- Intense ileal inflammation, epithelial ulceration, and neutrophil accumulation were prominent in CCR5(-/-) mice, contributing to gut immunopathology.
Conclusions:
- CCR5 is essential for controlling Toxoplasma gondii infection and maintaining metabolic, hepatic, and intestinal integrity.
- CCR5 deficiency exacerbates disease severity, leading to multi-organ damage and increased mortality.
- These findings underscore the critical role of CCR5 in host defense against toxoplasmosis and suggest its potential as a therapeutic target.
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