CCR5 Controls Immune and Metabolic Functions during Toxoplasma gondii Infection

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.

Protease‐activated receptor 2 contributes to Toxoplasma gondii‐mediated gut inflammation

“…In addition, akin to our situation, there was a similar parasite burden in the small intestine of both animals. Even more surprising, Bonfa et al showed an inverse correlated phenotype where T.gondii ‐infected CCR5 knockout mice displayed increased gut inflammatory lesions but decreased levels of mRNA levels IFNγ and TNFα (and many more cytokines) in the ileum. These studies, including ours, underline the complexity of mechanisms controlling gut inflammation during T. gondii infection and indicate that pathways, unrelated to IFNγ and TNFα, operate during infection and control the intensity of inflammatory gut lesions.…”

CCR5 and CCR5Δ32 in bacterial and parasitic infections: Thinking chemokine receptors outside the HIV box

“…In this context, several studies have shown that CCR5 signalling has different and fundamental roles in T. gondii infection. CCR5 participates in processes that contribute to parasite persistence as well as in the host immune response against the parasite (Bonfá et al, 2014; Denkers, 2003; Diana et al, 2005; Golding et al, 2003; Ibrahim, Bannai, Xuan, & Nishikawa, 2009; Khan et al, 2006; Kikumura, Ishikawa, & Norose, 2012; Luangsay et al, 2003; Nishimura, Umeda, Suwa, Furuoka, & Nishikawa, 2017; Scanga et al, 2002). For example, T. gondii can secrete cyclophilin‐18, a chemokine mimic that binds to CCR5, promoting IL‐12 production, which is one of the molecules used by the parasite to modulate the host immune response (Denkers, 2003).…”

“…For example, T. gondii can secrete cyclophilin‐18, a chemokine mimic that binds to CCR5, promoting IL‐12 production, which is one of the molecules used by the parasite to modulate the host immune response (Denkers, 2003). CCR5 promotes control of T. gondii infection and is important to maintain the metabolic, hepatic and intestinal integrity of the host (Bonfá et al, 2014). Also, CCR5 absence can increase susceptibility to T. gondii (Bonfá et al, 2014; Khan et al, 2006).…”

“…CCR5 promotes control of T. gondii infection and is important to maintain the metabolic, hepatic and intestinal integrity of the host (Bonfá et al, 2014). Also, CCR5 absence can increase susceptibility to T. gondii (Bonfá et al, 2014; Khan et al, 2006). Finally, a recent study suggested that CCR5 participates in the regulation of inflammatory response, tissue injury and elimination of T. gondii infection in the brain (Kobayashi et al, 2019).…”

CCR5 Is Involved in Interruption of Pregnancy in Mice Infected with Toxoplasma gondii during Early Pregnancy

“…Recombinant TgCyp18 has been reported to enhance RANTES expression in macrophages and to control their migration (14,15). CCR5 is essential for controlling infection by T. gondii; CCR5-deficient (CCR5 Ϫ/Ϫ ) mice showed high susceptibility to infection, severe tissue damage, low expression levels of IFN-␥ and IL-12, and high parasite loads compared with wild-type mice (16).…”