Abstract
ABSTRACTToxoplasmosis affects one-third of the human population worldwide. Humans are accidental hosts and are infected after consumption of undercooked meat and water contaminated with Toxoplasma gondii cysts and oocysts, respectively. Neutrophils have been shown to participate in the control of T. gondii infection in mice through a variety of effector mechanisms, such as reactive oxygen species (ROS) and neutrophil extracellular trap (NET) formation. However, few studies have demonstrated the role of neutrophils in individuals naturally infected with T. gondii. In the current study, we evaluated the activation status of neutrophils in individuals with acute or chronic toxoplasmosis and determined the role of T. gondii-induced NET formation in the amplification of the innate and adaptive immune responses. We observed that neutrophils are highly activated during acute infection through increased expression of CD66b. Moreover, neutrophils from healthy donors (HDs) cocultured with tachyzoites produced ROS and formed NETs, with the latter being dependent on glycolysis, succinate dehydrogenase, gasdermin D, and neutrophil elastase. Furthermore, we observed elevated levels of the chemokines (CXC motif) CXCL8 and (CC motif) CCL4 ligands in plasma from patients with acute toxoplasmosis and production by neutrophils from HDs exposed to T. gondii. Finally, we showed that T. gondii-induced NETs activate neutrophils and promote the recruitment of autologous CD4+ T cells and the production of interferon gamma (IFN-γ), tumor necrosis factor (TNF), interleukin 6 (IL-6), IL-17, and IL-10 by peripheral blood mononuclear cells. In conclusion, we demonstrated that T. gondii activates neutrophils and promotes the release of NETs, which amplify human innate and adaptive immune responses.
Highlights
Toxoplasmosis affects one-third of the human population worldwide
We observed a significantly increased frequency of CD661 CD161 cells within peripheral blood mononuclear cells (PBMCs) from acutely infected patients, further showing that neutrophils are activated during acute toxoplasmosis (Fig. 1C)
The expression of Cluster Differentiation 66b marker (CD66b), CD11b, CD88, and CD15, assessed by median fluorescence intensity (MFI), was augmented while the levels of CD62L were reduced in neutrophils that were exposed to T. gondii (Fig. 1E)
Summary
Toxoplasmosis affects one-third of the human population worldwide. Humans are accidental hosts and are infected after consumption of undercooked meat and water contaminated with Toxoplasma gondii cysts and oocysts, respectively. We evaluated the activation status of neutrophils in individuals with acute or chronic toxoplasmosis and determined the role of T. gondiiinduced NET formation in the amplification of the innate and adaptive immune responses. We demonstrated that T. gondii activates neutrophils and promotes the release of NETs, which amplify human innate and adaptive immune responses. We showed that T. gondii-induced NETs activate neutrophils, promote the recruitment of autologous CD41 T cells, and induce the production of cytokines by peripheral blood mononuclear cells, amplifying the innate and adaptive immune responses. Neutrophils are the first cells to migrate to sites of infections, with a variety of mechanisms to sense and eliminate microbes, including phagocytosis, production of reactive oxygen species (ROS), and neutrophil extracellular trap (NET) formation [5, 6]. We demonstrated the role of T. gondii-induced NET formation in the amplification of innate and adaptive immune responses
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